Dynorphin: Difference between revisions

prodynorphin
Identifiers
Symbol	PDYN
Entrez	5173
HUGO	8820
OMIM	131340
RefSeq	NM_024411
UniProt	P01213
Other data
Locus	Chr. 20 pter-p12.2

VisualWikitext

Latest revision as of 07:10, 10 January 2019

Dynorphins (Dyn) are a class of opioid peptides that arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 (PC2), multiple active peptides are released: dynorphin A, dynorphin B, and α/β-neo-endorphin.^[1] Depolarization of a neuron containing prodynorphin stimulates PC2 processing, which occurs within synaptic vesicles in the presynaptic terminal.^[2] Occasionally, prodynorphin is not fully processed, leading to the release of “big dynorphin.” This 32-amino acid molecule consists of both dynorphin A and dynorphin B.^[3]

Dynorphin A, dynorphin B, and big dynorphin all contain a high proportion of basic amino acid residues, in particular lysine and arginine (29.4%, 23.1%, and 31.2% basic residues, respectively), as well as many hydrophobic residues (41.2%, 30.8%, and 34.4% hydrophobic residues, respectively).^[4] Although dynorphins are found widely distributed in the CNS, they have the highest concentrations in the hypothalamus, medulla, pons, midbrain, and spinal cord.^[5] Dynorphins are stored in large (80-120 nm diameter) dense-core vesicles that are considerably larger than vesicles storing neurotransmitters. These large dense-core vesicles differ from small synaptic vesicles in that a more intense and prolonged stimulus is needed to cause the large vesicles to release their contents into the synaptic cleft. Dense-core vesicle storage is characteristic of opioid peptides storage.^[6]

The first clues to the functionality of dynorphins came from Goldstein et al.^[7] in their work with opioid peptides. The group discovered an endogenous opioid peptide in the porcine pituitary that proved difficult to isolate. By sequencing the first 13 amino acids of the peptide, they created a synthetic version of the peptide with a similar potency to the natural peptide. Goldstein et al.^[7] applied the synthetic peptide to the guinea ileum longitudinal muscle and found it to be an extraordinarily potent opioid peptide. The peptide was called dynorphin (from the Greek dynamis=power) to describe its potency.^[7]

Dynorphins exert their effects primarily through the κ-opioid receptor (KOR), a G-protein-coupled receptor. Two subtypes of KORs have been identified: K1 and K2.^[3] Although KOR is the primary receptor for all dynorphins, the peptides do have some affinity for the μ-opioid receptor (MOR), δ-opioid receptor (DOR), and the N-methyl-D-aspartic acid (NMDA)-type glutamate receptor.^[6]^[8] Different dynorphins show different receptor selectivities and potencies at receptors. Big dynorphin and dynorphin A have the same selectivity for human KOR, but dynorphin A is more selective for KOR over MOR and DOR than is big dynorphin. Big dynorphin is more potent at KORs than is dynorphin A. Both big dynorphin and dynorphin A are more potent and more selective than dynorphin B.^[9]

Production

Dynorphin is produced in many different parts of the brain, including the hypothalamus, the striatum, the hippocampus and the spinal cord. Gene expression patterns from the Allen Brain Atlases in mouse, macaque and humans can be seen here.

Dynorphin has many different physiological actions, depending upon its site of production.^[10]

For example, dynorphin that is made in magnocellular vasopressin neurons of the supraoptic nucleus is important in the patterning of electrical activity. Dynorphin produced in magnocellular oxytocin neurons is a negative feedback inhibitor of oxytocin secretion.^[10]
Dynorphin produced in the arcuate nucleus and in orexin neurons of the lateral hypothalamus affects the control of appetite.^[10]

Analgesia

Dynorphin has been shown to be a modulator of pain response. Han and Xie found that injecting dynorphin into the subarachnoid space of the rat spinal cord produced dose-dependent analgesia that was measured by tail-flick latency.^[11] Analgesia was partially eliminated by opioid antagonist naloxone.^[11]

Han and Xie found dynorphin to be 6-10 times more potent than morphine on a per mole basis.^[11] In addition, morphine tolerance did not reduce dynorphin-induced analgesia.^[11] Ren et al. demonstrated some of the complexities related to dynorphin induced analgesia.^[12] The authors found that combining subanalgesic levels of morphine and dynorphin A_1-13, a version of dynorphin A containing only the first 13 amino acids of the peptide, in the rat spinal cord had additive effects. However, when dynorphin A_1-13 was injected into the intracerebroventriulcar (ICV) region of the brain, it had an antagonist effect on morphine-induced analgesia.

A study by Lai et al. found that dynorphin might actually stimulate pain.^[8] The group found that it acts on the bradykinin receptor as well as KOR. The N-terminal tyrosine of dynorphin A is necessary to activate opioid receptors such as KOR, but is unnecessary in binding to bradykinin receptors.^[8] Lai et al. studied the effects of dynorphin A_2-13 that did not contain the N-terminal tyrosine. Based on the results of dynorphin A_2-13, the authors proposed a mechanism in which dynorphin A activates bradykinin receptors and thus stimulates pain response.^[8]

According to this mechanism, dynorphin activates bradykinin receptors, which triggers the release of calcium ions into the cell through voltage-sensitive channels in the cell membrane.^[8] Blocking bradykinin receptors in the lumbar region of the spinal cord reversed persistent pain.^[8] A multiple pathway system might help explain the conflicting effects of dynorphin in the CNS.

Svensson et al. provided another possible mechanism by which dynorphin might cause pain in the spinal cord.^[13] The authors found that administration of truncated dynorphin A_2-17, which does not bind to opioid receptors, causes an increase in phosphorylated p38 mitogen-activated protein kinase (MAPK) in microglia in the dorsal horn of the spinal cord. Activated p38 has been previously linked to the NMDA-evoked prostaglandin release, which causes pain.^[14] Thus, dynorphin could also induce pain in the spinal cord through a non-opioid p38 pathway.

Other studies have identified a role for dynorphin and kappa opioid receptor stimulation in neuropathic pain.^[15] This same group also showed that the dynorphin-KOR system mediates astrocyte proliferation through the activation of p38 MAPK that was required for the effects of neuropathic pain on analgesic responses.^[16] Taken together, these reports suggest that dynorphin can elicit multiple effects on both Kappa opioid, and non-opioid pathways to modulate analgesic responses.

Addiction

Cocaine addiction results from complex molecular changes in the brain following multiple exposures to cocaine.^[17] Dynorphins have been shown to be an important part of this process. Although a single exposure to cocaine does not affect brain dynorphin levels, repeated exposures to the drug increases dynorphin concentrations in the striatum and substantia nigra in rats.^[18]

One proposed molecular mechanism for increased dynorphin levels involves transcriptional regulation by CREB (3’, 5’-monophosphate response element binding protein). According to the model proposed by Carlezon et al., use of cocaine increases the expression of cAMP and cAMP-dependent protein kinase (PKA).^[19] PKA leads to the activation of CREB, which increases the expression of dynorphin in the nucleus accumbens and dorsal striatum, brain areas important in addiction.^[19] Dynorphin decreases dopamine release by binding to KORs on dopamine nerve terminals.^[20]

Cocaine

Carlezon et al.^[19] performed several experiments to validate this model. They found that, when mice were injected with cocaine, they preferred to be in the place where they were injected (showed stronger place preference) significantly more than control mice (injected with saline) did. However, in mice overexpressing CREB under a constitutive promoter, place aversion was observed.^[19] This indicates that increasing CREB reverses the positive effects of cocaine. Northern blot analysis several days after CREB overexpression showed a marked increase in dynorphin mRNA in the nucleus accumbens.^[19]

Blocking KORs with an antagonist (norBNI) blocked the aversive effects caused by CREB overexpression.^[19] Thus, cocaine use ultimately appears to lead to an increase in the transcription of prodynorphin mRNA. Dynorphin inhibits dopamine release, which could account the reinforcing properties of cocaine.^[21]

There is also evidence suggesting that increased amounts of dynorphin can protect humans from cocaine addiction. According to research at Rockefeller University, the gene for dynorphin is present in two versions: a “high output” and a “low output” functional variation.^[22] The high output functional variation of the gene contains polymorphisms in the promoter regions that are speculated to cause it to produce more copies of dynorphin mRNA, which would give people carrying this variation a “built-in defense system” against drug addiction.^[22]

Stress and depression

Land et al. first described a mechanism of dysphoria in which corticotropin-releasing factor (CRF) provokes dynorphin release.^[23] While control mice displayed aversive behaviors in response to forced swim tests and foot shocks, mice lacking dynorphin did not show any such signs of aversion. They noted that injecting CRF led to aversive behaviors in mice with functional genes for dynorphin even in the absence of stress, but not in those with dynorphin gene deletions. Place aversion was eliminated when the receptor CRF2 was blocked with an antagonist.^[23]

Together these results led Land et al. to conclude that dysphoric elements of stress occur when CRF2 stimulates dynorphin release and activates KOR.^[23] The group further postulated that this pathway might be involved in drug seeking behavior. In support of this, it was shown previously that stress can reinstate cocaine-seeking behavior in mice through a CRF mechanism.^[24]

Dynorphin has also been shown to influence drug seeking behavior and is required for stress-induced, but not prime-induced, reinstatement of cocaine seeking.^[25]^[26] A downstream element of this pathway was later identified by Bruchas et al.^[27] The authors found that KOR activates p38, a member of the mitogen-activated protein kinase (MAPK) family, through phosphorylation. Activation of p38 is necessary to produce KOR-dependent behaviors.^[27]

Because of its role in mediating dysphoria, dynorphin has also been investigated in relation to depression. Newton et al.^[28] studied the effects of CREB and dynorphin on learned helplessness (an animal model for depression) in mice. Overexpression of dominant negative CREB (mCREB) in transgenic mice had an antidepressant effect (in terms of behavior), whereas overexpressing wild-type CREB caused an increase in depression-like symptoms.^[28] As described previously, CREB increases transcription of prodynorphin, which gives rise to different dynorphin subtypes.^[19] Newton et al.^[28] supported this mechanism, as the mCREB was colocalized with decreased expression of prodynorphin. Also, direct antagonism of dynorphin caused antidepressant-like effects similar to those seen with mCREB expression.^[28] Thus, the CREB-dynorphin pathway regulates mood as well as cocaine rewards.

Shirayama et al.^[29] used several animal depression models in rats to describe the effects of dynorphins A and B in depression. The authors found that learned helplessness increases the levels of dynorphins A and B in the hippocampus and nucleus accumbens and that injecting KOR antagonist norBNI induces recovery from learned helplessness. Immobilization stress causes increases in the levels of both dynorphins A and B in the hippocampus and nucleus accumbens.^[29] Forced swim stress increases the levels of dynorphin A in the hippocampus. Shirayama et al.^[29] concluded that both dynorphins A and B were important in stress response. The authors proposed several mechanisms to account for the effects of the KOR antagonist norBNI on learned helplessness. First, increased dynorphin levels block the release of glutamate, a neurotransmitter involved in plasticity in the hippocampus, which would inhibit new learning.^[29]

Blocking dynorphin effects would allow glutamate to be released and restore functional plasticity in the hippocampus, reversing the phenomenon of learned helplessness. In addition, blocking dynorphin would enhance dopamine signaling and thus reduce depressive symptoms associated with stress.^[29] The authors suggest that KOR antagonists might have potential in treating depression in humans.

Appetite and circadian rhythms

Dynorphins are important in maintaining homeostasis through appetite control and circadian rhythms. Przewlocki et al.^[30] found that, during the day, dynorphins are naturally elevated in the neurointermediate lobe of the pituitary (NI pituitary) and depressed in the hypothalamus. This pattern is reversed at night.^[30] In addition, mice deprived of food and water, or of water alone, had increased levels of dynorphin in the hypothalamus during the day.^[30] Deprivation of water alone also decreased the dynorphin levels in the NI pituitary.^[30] These findings led Przewlocki et al.^[30] to conclude that dynorphins are essential in maintaining homeostasis.

Dynorphin has been implicated as an appetite stimulant. A number of studies^[31] in rats have shown that increasing the dynorphin levels stimulates eating. Opioid antagonists, such as naloxone, can reverse the effects of elevated dynorphin.^[32] This inhibition is especially strong in obese animals or animals that have access to particularly appealing food.^[33] Inui et al.^[34] found that administering dynorphin to dogs increased both their food and water intake. Dynorphin plays a role in the eating behavior of hibernating animals. Nizeilski et al.^[35] examined dynorphin levels in the ground squirrel, which undergoes periods of excessive eating and periods of starvation before winter. They found that dynorphin levels increased during the starvation periods. Berman et al.^[36] studied the levels of dynorphin during periods of food restriction. The group found that while food did not alter the expression of dynorphin B, it increases dynorphin A levels in several rat brain regions (hypothalamus, nucleus accumbens, and bed nucleus of the stria terminalis).

Recent research on dynorphin knockout mice did not find differences between knockout and control animals in food intake, but found that fat storage was reduced in male knockout mice.^[37] Fatty acids were oxidized more quickly in knockout animals.^[37]

Studies have also shown that ingesting a high-fat diet increases the gene expression of dynorphin in the hypothalamus.^[38] Thus, dynorphin may cause overeating when a high-fat diet is available.^[38]^[39] Morley & Levine were the first to describe the role of opioid peptides in stress-related eating. In their study, mice had their tails pinched (causes stress), which induced eating. Stress-related eating was reduced by injecting naloxone, an opioid peptide antagonist.^[39]

Mandenoff et al.^[33] proposed that, although endogenous opioids are not necessary to maintain body weight and energy expenditure under predictable circumstances, they become activated under stressful conditions. They found that endogenous opioids, such as dynorphin, stimulate appetite and decrease energy expenditure. Taken together, the studies above suggest an important evolutionary mechanism in which more food is eaten, more nutrients are stored, and less energy is expended by an organism during times of stress.

Temperature regulation

In addition to their role in weight control, dynorphins have been found to regulate body temperature. Opioid peptides were first investigated in hyperthermia, where it was found that MOR agonists stimulate this response when injected into the periaqueductal gray (PAG) region of the brain.^[3] Xin et al.^[40] showed that delivery of dynorphin A_1-17 (a KOR agonist) through microdialysis into the PAG region induced hypothermia in rats. The authors found that the severity of hypothermia was proportional to the dose of dynorphin A_1-17 administered. Hypothermia could be prevented by administering KOR antagonist norBNI to the rat.^[40] Xin et al.^[40] hypothesized that while MOR agonists mediate hyperthermia, KOR agonists, such as dynorphin, mediate hypothermia.

Sharma and Alm^[41] found that subjecting rats to heat (38˚C) caused dynorphins to be upregulated in the cerebral cortex, hippocampus, cerebellum, and the brain stem. Further, authors found that administration of nitric oxide synthase (NOS) inhibitors reduced dynorphin A1-17 levels in the brain and attenuated symptoms related to heat stress. Sharma and Alm^[41] concluded that hyperthermia increases dynorphin levels, which may cause damage and promote heat stress reaction. They further hypothesized that nitric oxide was part of this mechanism. Ansonoff et al.^[42] found that hypothermic effects are mediated through K1 (κ-opioid receptor 1), but not K2. The authors applied a KOR agonist to K1 knockout mice, which eliminated hypothermic response. Thus, K2 does not appear to have a role in the hypothermic mechanism

Clinical significance

Dynorphin derivatives are generally considered to be of little clinical use because of their very short duration of action.^[43]

References

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External links

Dynorphins at the US National Library of Medicine Medical Subject Headings (MeSH)

[pmid9422738-1] Day R, Lazure C, Basak A, Boudreault A, Limperis P, Dong W, Lindberg I (January 1998). "Prodynorphin processing by proprotein convertase 2. Cleavage at single basic residues and enhanced processing in the presence of carboxypeptidase activity". J. Biol. Chem. 273 (2): 829–36. doi:10.1074/jbc.273.2.829. PMID 9422738.

[pmid16966485-2] Yakovleva T, Bazov I, Cebers G, Marinova Z, Hara Y, Ahmed A, Vlaskovska M, Johansson B, Hochgeschwender U, Singh IN, Bruce-Keller AJ, Hurd YL, Kaneko T, Terenius L, Ekström TJ, Hauser KF, Pickel VM, Bakalkin G (October 2006). "Prodynorphin storage and processing in axon terminals and dendrites". FASEB J. 20 (12): 2124–6. doi:10.1096/fj.06-6174fje. PMID 16966485.

[Nyberg-3] 3.0 ^3.1 ^3.2 Nyberg F, Hallberg M (2007). "Neuropeptides in hyperthermia". Prog. Brain Res. Progress in Brain Research. 162: 277–93. doi:10.1016/S0079-6123(06)62014-1. ISBN 978-0-444-51926-9. PMID 17645924.

[pmid15894804-4] Marinova Z, Vukojevic V, Surcheva S, Yakovleva T, Cebers G, Pasikova N, Usynin I, Hugonin L, Fang W, Hallberg M, Hirschberg D, Bergman T, Langel U, Hauser KF, Pramanik A, Aldrich JV, Gräslund A, Terenius L, Bakalkin G (July 2005). "Translocation of dynorphin neuropeptides across the plasma membrane. A putative mechanism of signal transmission". J. Biol. Chem. 280 (28): 26360–70. doi:10.1074/jbc.M412494200. PMID 15894804.

[Goldstein2-5] Goldstein A, Ghazarossian VE (October 1980). "Immunoreactive dynorphin in pituitary and brain". Proc. Natl. Acad. Sci. U.S.A. 77 (10): 6207–10. doi:10.1073/pnas.77.10.6207. PMC 350244. PMID 6108564.

[Drake-6] 6.0 ^6.1 Drake CT, Chavkin C, Milner TA (2007). "Opioid systems in the dentate gyrus". Prog. Brain Res. Progress in Brain Research. 163: 245–63. doi:10.1016/S0079-6123(07)63015-5. ISBN 978-0-444-53015-8. PMID 17765723.

[Goldstein1-7] 7.0 ^7.1 ^7.2 Goldstein A, Tachibana S, Lowney LI, Hunkapiller M, Hood L (December 1979). "Dynorphin-(1-13), an extraordinarily potent opioid peptide". Proc. Natl. Acad. Sci. U.S.A. 76 (12): 6666–70. doi:10.1073/pnas.76.12.6666. PMC 411929. PMID 230519.

[Lai-8] 8.0 ^8.1 ^8.2 ^8.3 ^8.4 ^8.5 Lai J, Luo MC, Chen Q, Ma S, Gardell LR, Ossipov MH, Porreca F (December 2006). "Dynorphin A activates bradykinin receptors to maintain neuropathic pain". Nat. Neurosci. 9 (12): 1534–40. doi:10.1038/nn1804. PMID 17115041.

[pmid16515546-9] Merg F, Filliol D, Usynin I, Bazov I, Bark N, Hurd YL, Yakovleva T, Kieffer BL, Bakalkin G (April 2006). "Big dynorphin as a putative endogenous ligand for the kappa-opioid receptor". J. Neurochem. 97 (1): 292–301. doi:10.1111/j.1471-4159.2006.03732.x. PMID 16515546.

[Citation_needed-10] 10.0 ^10.1 ^10.2 Citation needed

[Han-11] 11.0 ^11.1 ^11.2 ^11.3 Han JS, Xie CW (February 1984). "Dynorphin: potent analgesic effect in spinal cord of the rat". Sci. Sin., Ser. B, Chem. Biol. Agric. Med. Earth Sci. 27 (2): 169–77. PMID 6147015.

[Ren-12] Ren MF, Lu CH, Han JS (1985). "Dynorphin-A-(1-13) antagonizes morphine analgesia in the brain and potentiates morphine analgesia in the spinal cord". Peptides. 6 (6): 1015–20. doi:10.1016/0196-9781(85)90423-1. PMID 2871545.

[Svensson2005-13] Svensson CI, Hua XY, Powell HC, Lai J, Porreca F, Yaksh TL (October 2005). "Prostaglandin E2 release evoked by intrathecal dynorphin is dependent on spinal p38 mitogen activated protein kinase". Neuropeptides. 39 (5): 485–94. doi:10.1016/j.npep.2005.08.002. PMID 16176831.

[Svensson2003-14] Svensson CI, Hua XY, Protter AA, Powell HC, Yaksh TL (June 2003). "Spinal p38 MAP kinase is necessary for NMDA-induced spinal PGE(2) release and thermal hyperalgesia". NeuroReport. 14 (8): 1153–7. doi:10.1097/00001756-200306110-00010. PMID 12821799.

[Xu-15] Xu M, Petraschka M, McLaughlin JP, Westenbroek RE, Caron MG, Lefkowitz RJ, Czyzyk TA, Pintar JE, Terman GW, Chavkin C (May 2004). "Neuropathic Pain Activates the Endogenous κ Opioid System in Mouse Spinal Cord and Induces Opioid Receptor Tolerance". J. Neurosci. 24 (19): 4576–84. doi:10.1523/JNEUROSCI.5552-03.2004. PMC 2376823. PMID 15140929.

[Xu_2007-16] Xu M, Bruchas MR, Ippolito DL, Gendron L, Chavkin C (March 2007). "Sciatic Nerve Ligation-Induced Proliferation of Spinal Cord Astrocytes Is Mediated by κ Opioid Activation of p38 Mitogen-Activated Protein Kinase". J. Neurosci. 27 (10): 2570–81. doi:10.1523/JNEUROSCI.3728-06.2007. PMC 2104780. PMID 17344394.

[Nestler-17] Nestler EJ, Aghajanian GK (October 1997). "Molecular and cellular basis of addiction". Science. 278 (5335): 58–63. doi:10.1126/science.278.5335.58. PMID 9311927.

[Sivam-18] Sivam SP (September 1989). "Cocaine selectively increases striatonigral dynorphin levels by a dopaminergic mechanism". J. Pharmacol. Exp. Ther. 250 (3): 818–24. PMID 2476548.

[Carlezon-19] 19.0 ^19.1 ^19.2 ^19.3 ^19.4 ^19.5 ^19.6 Carlezon WA, Thome J, Olson VG, Lane-Ladd SB, Brodkin ES, Hiroi N, Duman RS, Neve RL, Nestler EJ (December 1998). "Regulation of cocaine reward by CREB". Science. 282 (5397): 2272–5. doi:10.1126/science.282.5397.2272. PMID 9856954.

[Krebs-20] Krebs MO, Gauchy C, Desban M, Glowinski J, Kemel ML (April 1994). "Role of dynorphin and GABA in the inhibitory regulation of NMDA-induced dopamine release in striosome- and matrix-enriched areas of the rat striatum". J. Neurosci. 14 (4): 2435–43. PMID 7908960.

[You-21] You ZB, Herrera-Marschitz M, Terenius L (September 1999). "Modulation of neurotransmitter release in the basal ganglia of the rat brain by dynorphin peptides". J. Pharmacol. Exp. Ther. 290 (3): 1307–15. PMID 10454508.

[Clavin-22] 22.0 ^22.1 Clavin W (2002-04-14). "Dynorphin : Nature's own antidote to cocaine ( and pleasure? )". Retrieved 2009-07-10.

[Land-23] 23.0 ^23.1 ^23.2 Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C (January 2008). "The Dysphoric Component of Stress Is Encoded by Activation of the Dynorphin κ-Opioid System". J. Neurosci. 28 (2): 407–14. doi:10.1523/JNEUROSCI.4458-07.2008. PMC 2612708. PMID 18184783.

[pmid15930388-24] Wang B, Shaham Y, Zitzman D, Azari S, Wise RA, You ZB (June 2005). "Cocaine experience establishes control of midbrain glutamate and dopamine by corticotropin-releasing factor: a role in stress-induced relapse to drug seeking". J. Neurosci. 25 (22): 5389–96. doi:10.1523/JNEUROSCI.0955-05.2005. PMID 15930388.

[Beardsley-25] Beardsley PM, Howard JL, Shelton KL, Carroll FI (November 2005). "Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by footshock stressors vs cocaine primes and its antidepressant-like effects in rats". Psychopharmacology. 183 (1): 118–26. doi:10.1007/s00213-005-0167-4. PMID 16184376.

[Redila-26] Redila VA, Chavkin C (September 2008). "Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system". Psychopharmacology. 200 (1): 59–70. doi:10.1007/s00213-008-1122-y. PMC 2680147. PMID 18575850.

[Bruchas-27] 27.0 ^27.1 Bruchas MR, Land BB, Aita M, Xu M, Barot SK, Li S, Chavkin C (October 2007). "Stress-Induced p38 Mitogen-Activated Protein Kinase Activation Mediates κ-Opioid-Dependent Dysphoria". J. Neurosci. 27 (43): 11614–23. doi:10.1523/JNEUROSCI.3769-07.2007. PMC 2481272. PMID 17959804.

[Newton-28] 28.0 ^28.1 ^28.2 ^28.3 Newton SS, Thome J, Wallace TL, Shirayama Y, Schlesinger L, Sakai N, Chen J, Neve R, Nestler EJ, Duman RS (December 2002). "Inhibition of cAMP response element-binding protein or dynorphin in the nucleus accumbens produces an antidepressant-like effect". J. Neurosci. 22 (24): 10883–90. PMID 12486182.

[Shirayama-29] 29.0 ^29.1 ^29.2 ^29.3 ^29.4 Shirayama Y, Ishida H, Iwata M, Hazama GI, Kawahara R, Duman RS (September 2004). "Stress increases dynorphin immunoreactivity in limbic brain regions and dynorphin antagonism produces antidepressant-like effects". J. Neurochem. 90 (5): 1258–68. doi:10.1111/j.1471-4159.2004.02589.x. PMID 15312181.

[Prz-30] 30.0 ^30.1 ^30.2 ^30.3 ^30.4 Przewłocki R, Lasón W, Konecka AM, Gramsch C, Herz A, Reid LD (January 1983). "The opioid peptide dynorphin, circadian rhythms, and starvation". Science. 219 (4580): 71–3. doi:10.1126/science.6129699. PMID 6129699.

[Lambert-31] Lambert PD, Wilding JP, al-Dokhayel AA, Bohuon C, Comoy E, Gilbey SG, Bloom SR (July 1993). "A role for neuropeptide-Y, dynorphin, and noradrenaline in the central control of food intake after food deprivation". Endocrinology. 133 (1): 29–32. doi:10.1210/en.133.1.29. PMID 8100519.

[Morley-32] Morley LE (1995). "The Role of Peptides in Appetite Regulation across Species". American Zoologist. 35 (6): 437–445. doi:10.1093/icb/35.6.437.

[Man-33] 33.0 ^33.1 Mandenoff A, Fumeron F, Apfelbaum M, Margules DL (March 1982). "Endogenous opiates and energy balance". Science. 215 (4539): 1536–8. doi:10.1126/science.7063865. PMID 7063865.

[pmid1716066-34] Inui A, Okita M, Nakajima M, Inoue T, Sakatani N, Oya M, Morioka H, Okimura Y, Chihara K, Baba S (September 1991). "Neuropeptide regulation of feeding in dogs". Am. J. Physiol. 261 (3 Pt 2): R588–94. PMID 1716066.

[pmid2874573-35] Nizielski SE, Levine AS, Morley JE, Hall KA, Gosnell BA (1986). "Seasonal variation in opioid modulation of feeding in the 13-lined ground squirrel". Physiol. Behav. 37 (1): 5–9. doi:10.1016/0031-9384(86)90375-6. PMID 2874573.

[pmid7895045-36] Berman Y, Devi L, Carr KD (November 1994). "Effects of chronic food restriction on prodynorphin-derived peptides in rat brain regions". Brain Res. 664 (1–2): 49–53. doi:10.1016/0006-8993(94)91952-6. PMID 7895045.

[Sainsbury-37] 37.0 ^37.1 Sainsbury A, Lin S, McNamara K, Slack K, Enriquez R, Lee NJ, Boey D, Smythe GA, Schwarzer C, Baldock P, Karl T, Lin EJ, Couzens M, Herzog H (July 2007). "Dynorphin knockout reduces fat mass and increases weight loss during fasting in mice". Mol. Endocrinol. 21 (7): 1722–35. doi:10.1210/me.2006-0367. PMID 17456788.

[Leib-38] 38.0 ^38.1 Leibowitz SF (August 2007). "Overconsumption of dietary fat and alcohol: Mechanisms involving lipids and hypothalamic peptides". Physiol. Behav. 91 (5): 513–21. doi:10.1016/j.physbeh.2007.03.018. PMC 2077813. PMID 17481672.

[MorleyL-39] 39.0 ^39.1 Morley JE, Levine AS (September 1980). "Stress-induced eating is mediated through endogenous opiates". Science. 209 (4462): 1259–61. doi:10.1126/science.6250222. PMID 6250222.

[Xin-40] 40.0 ^40.1 ^40.2 Xin L, Geller EB, Adler MW (April 1997). "Body temperature and analgesic effects of selective mu and kappa opioid receptor agonists microdialyzed into rat brain". J. Pharmacol. Exp. Ther. 281 (1): 499–507. PMID 9103537.

[Sharma-41] 41.0 ^41.1 Sharma HS, Alm P (2002). "Nitric oxide synthase inhibitors influence dynorphin A (1–17) immunoreactivity in the rat brain following hyperthermia". Amino Acids. 23 (1–3): 247–59. doi:10.1007/s00726-001-0136-0. PMID 12373545.

[Ansonoff-42] Ansonoff MA, Zhang J, Czyzyk T, Rothman RB, Stewart J, Xu H, Zjwiony J, Siebert DJ, Yang F, Roth BL, Pintar JE (August 2006). "Antinociceptive and hypothermic effects of Salvinorin A are abolished in a novel strain of kappa-opioid receptor-1 knockout mice". J. Pharmacol. Exp. Ther. 318 (2): 641–8. doi:10.1124/jpet.106.101998. PMID 16672569.

[43] Brugos B, Arya V, Hochhaus G (2004). "Stabilized dynorphin derivatives for modulating antinociceptive activity in morphine tolerant rats: effect of different routes of administration". AAPS J. 6 (4): e36. doi:10.1208/aapsj060436. PMC 2751232. PMID 15760101.

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@@ Line 1: / Line 1: @@
-{{protein
+{{infobox protein
 |Name=prodynorphin
 |caption=
@@ Line 20: / Line 20: @@
 {{Portal|Neuroscience}}
-'''Dynorphins''' are a class of [[opioid peptides]] that arise from the precursor [[protein]] prodynorphin.  When prodynorphin is cleaved during processing by proprotein convertase 2 (PC2), multiple active peptides are released: [[dynorphin A]], [[dynorphin B]], and α/β-neo-endorphin.<ref name="pmid9422738">{{cite journal | author = Day R, Lazure C, Basak A, Boudreault A, Limperis P, Dong W, Lindberg I | title = Prodynorphin processing by proprotein convertase 2. Cleavage at single basic residues and enhanced processing in the presence of carboxypeptidase activity | journal = J. Biol. Chem. | volume = 273 | issue = 2 | pages = 829–36 | year = 1998 | month = January | pmid = 9422738 | doi = 10.1074/jbc.273.2.829| url = | issn = }}</ref> Depolarization of a [[neuron]] containing prodynorphin stimulates PC2 processing, which occurs within synaptic vesicles in the presynaptic terminal.<ref name="pmid16966485">{{cite journal | author = Yakovleva T, Bazov I, Cebers G, Marinova Z, Hara Y, Ahmed A, Vlaskovska M, Johansson B, Hochgeschwender U, Singh IN, Bruce-Keller AJ, Hurd YL, Kaneko T, Terenius L, Ekström TJ, Hauser KF, Pickel VM, Bakalkin G | title = Prodynorphin storage and processing in axon terminals and dendrites | journal = FASEB J. | volume = 20 | issue = 12 | pages = 2124–6 | year = 2006 | month = October | pmid = 16966485 | doi = 10.1096/fj.06-6174fje | url = | issn = }}</ref> Occasionally, prodynorphin is not fully processed, leading to the release of “big dynorphin.”  This 32-amino acid molecule consists of both dynorphin A and dynorphin B.<ref name="Nyberg">{{cite journal | author = Nyberg F, Hallberg M | title = Neuropeptides in hyperthermia | journal = Prog. Brain Res. | volume = 162 | issue = | pages = 277–93 | year = 2007 | pmid = 17645924 | doi = 10.1016/S0079-6123(06)62014-1 | url = | issn = }}</ref>
+'''Dynorphins''' ('''Dyn''') are a class of [[opioid peptides]] that arise from the precursor [[protein]] [[prodynorphin]].  When prodynorphin is cleaved during processing by [[proprotein convertase 2]] (PC2), multiple active peptides are released: [[dynorphin A]], [[dynorphin B]], and [[α-neo-endorphin|α]]/[[β-neo-endorphin]].<ref name="pmid9422738">{{cite journal |vauthors=Day R, Lazure C, Basak A, Boudreault A, Limperis P, Dong W, Lindberg I | title = Prodynorphin processing by proprotein convertase 2. Cleavage at single basic residues and enhanced processing in the presence of carboxypeptidase activity | journal = J. Biol. Chem. | volume = 273 | issue = 2 | pages = 829–36 |date=January 1998 | pmid = 9422738 | doi = 10.1074/jbc.273.2.829| url =  }}</ref> Depolarization of a [[neuron]] containing prodynorphin stimulates PC2 processing, which occurs within synaptic [[Vesicle (biology)|vesicles]] in the presynaptic terminal.<ref name="pmid16966485">{{cite journal |vauthors=Yakovleva T, Bazov I, Cebers G, Marinova Z, Hara Y, Ahmed A, Vlaskovska M, Johansson B, Hochgeschwender U, Singh IN, Bruce-Keller AJ, Hurd YL, Kaneko T, Terenius L, Ekström TJ, Hauser KF, Pickel VM, Bakalkin G | title = Prodynorphin storage and processing in axon terminals and dendrites | journal = FASEB J. | volume = 20 | issue = 12 | pages = 2124–6 |date=October 2006 | pmid = 16966485 | doi = 10.1096/fj.06-6174fje | url =  }}</ref> Occasionally, prodynorphin is not fully processed, leading to the release of “big dynorphin.”  This 32-amino acid molecule consists of both dynorphin A and dynorphin B.<ref name="Nyberg">{{cite journal |vauthors=Nyberg F, Hallberg M | title = Neuropeptides in hyperthermia | journal = Prog. Brain Res. | volume = 162 | issue = | pages = 277–93 | year = 2007 | pmid = 17645924 | doi = 10.1016/S0079-6123(06)62014-1 | url =  | series = Progress in Brain Research | isbn = 978-0-444-51926-9 }}</ref>
-Dynorphin A, dynorphin B, and big dynorphin all contain a high proportion of basic amino acid residues, in particular lysine and arginine (29.4%, 23.1%, and 31.2% basic residues, respectively), as well as many hydrophobic residues (41.2%, 30.8%, and 34.4% hydrophobic residues, respectively).<ref name="pmid15894804">{{cite journal | author = Marinova Z, Vukojevic V, Surcheva S, Yakovleva T, Cebers G, Pasikova N, Usynin I, Hugonin L, Fang W, Hallberg M, Hirschberg D, Bergman T, Langel U, Hauser KF, Pramanik A, Aldrich JV, Gräslund A, Terenius L, Bakalkin G | title = Translocation of dynorphin neuropeptides across the plasma membrane. A putative mechanism of signal transmission | journal = J. Biol. Chem. | volume = 280 | issue = 28 | pages = 26360–70 | year = 2005 | month = July | pmid = 15894804 | doi = 10.1074/jbc.M412494200 | url = | issn = }}</ref> Although dynorphins are found widely distributed in the CNS, they have the highest concentrations in the [[hypothalamus]], [[medulla oblongata|medulla]], [[pons]], [[midbrain]], and [[spinal cord]].<ref name="Goldstein2">{{cite journal | author = Goldstein A, Ghazarossian VE | title = Immunoreactive dynorphin in pituitary and brain | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 77 | issue = 10 | pages = 6207–10 | year = 1980 | month = October | pmid = 6108564 | pmc = 350244 | doi = 10.1073/pnas.77.10.6207| url = | issn = }}</ref> Dynorphins are stored in large (80-120&nbsp;nm diameter) dense-core [[vesicle (biology)|vesicles]] that are considerably larger than vesicles storing [[neurotransmitters]].  These large dense-core vesicles differ from small synaptic vesicles in that a more intense and prolonged stimulus is needed to cause the large vesicles to release their contents into the [[synaptic cleft]].  Dense-core vesicle storage is characteristic of opioid peptides storage.<ref name="Drake">{{cite journal | author = Drake CT, Chavkin C, Milner TA | title = Opioid systems in the dentate gyrus | journal = Prog. Brain Res. | volume = 163 | issue = | pages = 245–63 | year = 2007 | pmid = 17765723 | doi = 10.1016/S0079-6123(07)63015-5 | url = | issn = }}</ref>
-The first clues to the functionality of dynorphins came from Goldstein et al.<ref name="Goldstein1">{{cite journal | author = Goldstein A, Tachibana S, Lowney LI, Hunkapiller M, Hood L | title = Dynorphin-(1-13), an extraordinarily potent opioid peptide | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 76 | issue = 12 | pages = 6666–70 | year = 1979 | month = December | pmid = 230519 | pmc = 411929 | doi = 10.1073/pnas.76.12.6666| url = | issn = }}</ref> in their work with opioid peptides.  The group discovered an endogenous opioid peptide in the porcine pituitary that proved difficult to isolate.  By sequencing the first 13 amino acids of the peptide, they created a synthetic version of the peptide with a similar potency to the natural peptide.  Goldstein et al.<ref name="Goldstein1"/> applied the synthetic peptide to the guinea ileum longitudinal muscle and found it to be an extraordinarily potent opioid peptide.  The peptide was called dynorphin (from the Greek dynamis=power) to describe its potency.<ref name="Goldstein1"/>
+Dynorphin A, dynorphin B, and [[big dynorphin]] all contain a high proportion of basic amino acid residues, in particular lysine and arginine (29.4%, 23.1%, and 31.2% basic residues, respectively), as well as many hydrophobic residues (41.2%, 30.8%, and 34.4% hydrophobic residues, respectively).<ref name="pmid15894804">{{cite journal |vauthors=Marinova Z, Vukojevic V, Surcheva S, Yakovleva T, Cebers G, Pasikova N, Usynin I, Hugonin L, Fang W, Hallberg M, Hirschberg D, Bergman T, Langel U, Hauser KF, Pramanik A, Aldrich JV, Gräslund A, Terenius L, Bakalkin G | title = Translocation of dynorphin neuropeptides across the plasma membrane. A putative mechanism of signal transmission | journal = J. Biol. Chem. | volume = 280 | issue = 28 | pages = 26360–70 |date=July 2005 | pmid = 15894804 | doi = 10.1074/jbc.M412494200 | url =  }}</ref> Although dynorphins are found widely distributed in the CNS, they have the highest concentrations in the [[hypothalamus]], [[medulla oblongata|medulla]], [[pons]], [[midbrain]], and [[spinal cord]].<ref name="Goldstein2">{{cite journal |vauthors=Goldstein A, Ghazarossian VE | title = Immunoreactive dynorphin in pituitary and brain | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 77 | issue = 10 | pages = 6207–10 |date=October 1980 | pmid = 6108564 | pmc = 350244 | doi = 10.1073/pnas.77.10.6207| url =  }}</ref> Dynorphins are stored in large (80-120&nbsp;nm diameter) dense-core vesicles that are considerably larger than vesicles storing [[neurotransmitters]].  These large [[dense-core vesicles]] differ from small synaptic vesicles in that a more intense and prolonged stimulus is needed to cause the large vesicles to release their contents into the [[synaptic cleft]].  Dense-core vesicle storage is characteristic of opioid peptides storage.<ref name="Drake">{{cite journal |vauthors=Drake CT, Chavkin C, Milner TA | title = Opioid systems in the dentate gyrus | journal = Prog. Brain Res. | volume = 163 | issue = | pages = 245–63 | year = 2007 | pmid = 17765723 | doi = 10.1016/S0079-6123(07)63015-5 | url =  | series = Progress in Brain Research | isbn = 978-0-444-53015-8 }}</ref>
+The first clues to the functionality of dynorphins came from Goldstein et al.<ref name="Goldstein1">{{cite journal |vauthors=Goldstein A, Tachibana S, Lowney LI, Hunkapiller M, Hood L | title = Dynorphin-(1-13), an extraordinarily potent opioid peptide | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 76 | issue = 12 | pages = 6666–70 |date=December 1979 | pmid = 230519 | pmc = 411929 | doi = 10.1073/pnas.76.12.6666| url =  }}</ref> in their work with opioid peptides.  The group discovered an endogenous opioid peptide in the porcine pituitary that proved difficult to isolate.  By sequencing the first 13 amino acids of the peptide, they created a synthetic version of the peptide with a similar potency to the natural peptide.  Goldstein et al.<ref name="Goldstein1"/> applied the synthetic peptide to the guinea ileum longitudinal muscle and found it to be an extraordinarily potent opioid peptide.  The peptide was called dynorphin (from the Greek dynamis=power) to describe its potency.<ref name="Goldstein1"/>
+Dynorphins exert their effects primarily through the [[κ-opioid receptor]] (KOR), a [[G-protein-coupled receptor]].  Two subtypes of KORs have been identified: K1 and K2.<ref name="Nyberg"/>  Although KOR is the primary receptor for all dynorphins, the peptides do have some affinity for the [[μ-opioid receptor]] (MOR), [[δ-opioid receptor]] (DOR), and the N-methyl-D-aspartic acid ([[NMDA]])-type glutamate receptor.<ref name="Drake"/><ref name="Lai">{{cite journal |vauthors=Lai J, Luo MC, Chen Q, Ma S, Gardell LR, Ossipov MH, Porreca F | title = Dynorphin A activates bradykinin receptors to maintain neuropathic pain | journal = Nat. Neurosci. | volume = 9 | issue = 12 | pages = 1534–40 |date=December 2006 | pmid = 17115041 | doi = 10.1038/nn1804 | url =  }}</ref> Different dynorphins show different receptor selectivities and potencies at receptors.  Big dynorphin and dynorphin A have the same selectivity for human KOR, but dynorphin A is more selective for KOR over MOR and DOR than is big dynorphin.  Big dynorphin is more potent at KORs than is dynorphin A.  Both big dynorphin and dynorphin A are more potent and more selective than dynorphin B.<ref name="pmid16515546">{{cite journal |vauthors=Merg F, Filliol D, Usynin I, Bazov I, Bark N, Hurd YL, Yakovleva T, Kieffer BL, Bakalkin G | title = Big dynorphin as a putative endogenous ligand for the kappa-opioid receptor | journal = J. Neurochem. | volume = 97 | issue = 1 | pages = 292–301 |date=April 2006 | pmid = 16515546 | doi = 10.1111/j.1471-4159.2006.03732.x | url =  }}</ref>
-Dynorphins exert their effects primarily through the [[κ-opioid receptor]] (KOR), a G-protein-coupled receptor.  Two subtypes of KORs have been identified: K1 and K2.<ref name="Nyberg"/>  Although KOR is the primary receptor for all dynorphins, the peptides do have some affinity for the μ-opioid receptor (MOR), δ-opioid receptor (DOR), N-methyl-D-aspartic acid ([[NMDA]])-type glutamate receptor <ref name="Drake"/><ref name="Lai">{{cite journal | author = Lai J, Luo MC, Chen Q, Ma S, Gardell LR, Ossipov MH, Porreca F | title = Dynorphin A activates bradykinin receptors to maintain neuropathic pain | journal = Nat. Neurosci. | volume = 9 | issue = 12 | pages = 1534–40 | year = 2006 | month = December | pmid = 17115041 | doi = 10.1038/nn1804 | url = | issn = }}</ref> Different dynorphins show different receptor selectivities and potencies at receptors.  Big dynorphin and dynorphin A have the same selectivity for human KOR, but dynorphin A is more selective for KOR over MOR and DOR than is big dynorphin.  Big dynorphin is more potent at KORs than is dynorphin A.  Both big dynorphin and dynorphin A are more potent and more selective than dynorphin B.<ref name="pmid16515546">{{cite journal | author = Merg F, Filliol D, Usynin I, Bazov I, Bark N, Hurd YL, Yakovleva T, Kieffer BL, Bakalkin G | title = Big dynorphin as a putative endogenous ligand for the kappa-opioid receptor | journal = J. Neurochem. | volume = 97 | issue = 1 | pages = 292–301 | year = 2006 | month = April | pmid = 16515546 | doi = 10.1111/j.1471-4159.2006.03732.x | url = | issn = }}</ref>
 ==Production==
-Dynorphin is produced in many different parts of the brain, including the [[hypothalamus]], the [[hippocampus]] and the [[spinal cord]], and has many different physiological actions, depending upon its site of production.
+Dynorphin is produced in many different parts of the brain, including the [[hypothalamus]], the [[striatum]], the [[hippocampus]] and the [[spinal cord]]. Gene expression patterns from the [[Allen Brain Atlas]]es in mouse, macaque and humans can be seen [http://www.brain-map.org/search/index.html?query=pdyn here].
-* For example, dynorphin that is made in magnocellular [[vasopressin]] neurons of the [[supraoptic nucleus]] is important in the patterning of electrical activity. Dynorphin produced in magnocellular [[oxytocin]] neurons is a [[negative feedback]] inhibitor of [[oxytocin]] secretion.
-* Dynorphin produced in the [[arcuate nucleus]] and in [[orexin]] neurons of the [[lateral hypothalamus]] affects the control of [[appetite]].
+Dynorphin has many different physiological actions, depending upon its site of production.<ref name="Citation needed">Citation needed</ref>
+* For example, dynorphin that is made in magnocellular [[vasopressin]] neurons of the [[supraoptic nucleus]] is important in the patterning of electrical activity. Dynorphin produced in magnocellular [[oxytocin]] neurons is a [[negative feedback]] inhibitor of [[oxytocin]] secretion.<ref name="Citation needed"/>
+* Dynorphin produced in the [[arcuate nucleus]] and in [[orexin]] neurons of the [[lateral hypothalamus]] affects the control of [[appetite]].<ref name="Citation needed"/>
 ==Analgesia==
-Dynorphin has been shown to be a modulator of pain response.  Han and Xie found that injecting dynorphin into the subarachnoid space of the rat spinal cord produced dose-dependent analgesia that was measured by tail-flick latency.<ref name="Han">{{cite journal | author = Han JS, Xie CW | title = Dynorphin: potent analgesic effect in spinal cord of the rat | journal = Sci. Sin., Ser. B, Chem. Biol. Agric. Med. Earth Sci. | volume = 27 | issue = 2 | pages = 169–77 | year = 1984 | month = February | pmid = 6147015 | doi = | url = | issn = }}</ref> Analgesia was partially eliminated by opioid antagonist naloxone.<ref name="Han"/>
+Dynorphin has been shown to be a modulator of pain response.  Han and Xie found that injecting dynorphin into the subarachnoid space of the rat spinal cord produced dose-dependent analgesia that was measured by tail-flick latency.<ref name="Han">{{cite journal |vauthors=Han JS, Xie CW | title = Dynorphin: potent analgesic effect in spinal cord of the rat | journal = Sci. Sin., Ser. B, Chem. Biol. Agric. Med. Earth Sci. | volume = 27 | issue = 2 | pages = 169–77 |date=February 1984 | pmid = 6147015 | doi = | url =  }}</ref> Analgesia was partially eliminated by opioid antagonist naloxone.<ref name="Han"/>
-Han and Xie found dynorphin to be 6-10 times more potent than [[morphine]] on a per mole basis.<ref name="Han"/> In addition, morphine tolerance did not reduce dynorphin-induced analgesia.<ref name="Han"/>  Ren et al. demonstrated some of the complexities related to dynorphin induced analgesia.<ref name="Ren">{{cite journal | author = Ren MF, Lu CH, Han JS | title = Dynorphin-A-(1-13) antagonizes morphine analgesia in the brain and potentiates morphine analgesia in the spinal cord | journal = Peptides | volume = 6 | issue = 6 | pages = 1015–20 | year = 1985 | pmid = 2871545 | doi = 10.1016/0196-9781(85)90423-1| url = | issn = }}</ref> The authors found that combining subanalgesic levels of morphine and dynorphin A<sub>1-13</sub>, a version of dynorphin A containing only the first 13 amino acids of the peptide, in the rat spinal chord had additive effects.  However, when dynorphin A<sub>1-13</sub> was injected into the intracerebroventriulcar (ICV) region of the brain, it had an antagonist effect on morphine-induced analgesia.
+Han and Xie found dynorphin to be 6-10 times more potent than [[morphine]] on a per mole basis.<ref name="Han"/> In addition, morphine tolerance did not reduce dynorphin-induced analgesia.<ref name="Han"/>  Ren et al. demonstrated some of the complexities related to dynorphin induced analgesia.<ref name="Ren">{{cite journal |vauthors=Ren MF, Lu CH, Han JS | title = Dynorphin-A-(1-13) antagonizes morphine analgesia in the brain and potentiates morphine analgesia in the spinal cord | journal = Peptides | volume = 6 | issue = 6 | pages = 1015–20 | year = 1985 | pmid = 2871545 | doi = 10.1016/0196-9781(85)90423-1| url =  }}</ref> The authors found that combining subanalgesic levels of morphine and dynorphin A<sub>1-13</sub>, a version of dynorphin A containing only the first 13 amino acids of the peptide, in the rat spinal cord had additive effects.  However, when dynorphin A<sub>1-13</sub> was injected into the intracerebroventriulcar (ICV) region of the brain, it had an antagonist effect on morphine-induced analgesia.
-A study by Lai et al. found that dynorphin might actually stimulate pain.<ref name="Lai"/> The group found that dynorphin acts on the bradykinin receptor as well as KOR. The N-terminal tyrosine of dynorphin A is necessary to activate opioid receptors such as KOR, but is unnecessary in binding to bradykinin receptors.<ref name="Lai"/> Lai et al. studied the effects of dynorphin A<sub>2-13</sub> that did not contain the N-terminal tyrosine. Based on the results of dynorphin A<sub>2-13</sub>, the authors proposed a mechanism in which dynorphin A activates bradykinin receptors and thus stimulates pain response.<ref name="Lai"/> According to this mechanism, dynorphin activates bradykinin receptors, which triggers the release of calcium ions into the cell through voltage-sensitive channels in the cell membrane.<ref name="Lai"/> Blocking bradykinin receptors in the lumbar region of the spinal cord reversed persistent pain.<ref name="Lai"/> A multiple pathway system might help explain the conflicting effects of dynorphin in the CNS.
+A study by Lai et al. found that dynorphin might actually stimulate pain.<ref name="Lai"/> The group found that it acts on the bradykinin receptor as well as KOR. The N-terminal tyrosine of dynorphin A is necessary to activate opioid receptors such as KOR, but is unnecessary in binding to bradykinin receptors.<ref name="Lai"/> Lai et al. studied the effects of dynorphin A<sub>2-13</sub> that did not contain the N-terminal tyrosine. Based on the results of dynorphin A<sub>2-13</sub>, the authors proposed a mechanism in which dynorphin A activates bradykinin receptors and thus stimulates pain response.<ref name="Lai"/>
-Svensson et al. provided another possible mechanism by which dynorphin might cause pain in the spinal cord.<ref name="Svensson2005">{{cite journal | author = Svensson CI, Hua XY, Powell HC, Lai J, Porreca F, Yaksh TL | title = Prostaglandin E2 release evoked by intrathecal dynorphin is dependent on spinal p38 mitogen activated protein kinase | journal = Neuropeptides | volume = 39 | issue = 5 | pages = 485–94 | year = 2005 | month = October | pmid = 16176831 | doi = 10.1016/j.npep.2005.08.002 | url = | issn = }}</ref> The authors found that administration of truncated dynorphin A<sub>2-17</sub>, which does not bind to opioid receptors, causes an increase in phosphorylated p38 mitogen-activated protein kinase (MAPK) in [[microglia]] in the [[dorsal horn]] of the spinal chord. Activated p38 has been previously linked to the NMDA-evoked [[prostaglandin]] release, which causes pain.<ref name="Svensson2003">{{cite journal | author = Svensson CI, Hua XY, Protter AA, Powell HC, Yaksh TL | title = Spinal p38 MAP kinase is necessary for NMDA-induced spinal PGE(2) release and thermal hyperalgesia | journal = Neuroreport | volume = 14 | issue = 8 | pages = 1153–7 | year = 2003 | month = June | pmid = 12821799 | doi = 10.1097/01.wnr.0000075448.17390.99 | url = | issn = | doi_brokendate = 2009-07-10 }}</ref> Thus, dynorphin could also induce pain in the spinal cord through a non-opioid p38 pathway.
+According to this mechanism, dynorphin activates bradykinin receptors, which triggers the release of calcium ions into the cell through voltage-sensitive channels in the cell membrane.<ref name="Lai"/> Blocking bradykinin receptors in the lumbar region of the spinal cord reversed persistent pain.<ref name="Lai"/> A multiple pathway system might help explain the conflicting effects of dynorphin in the CNS.
-Other studies have identified a role for dynorphin and kappa opioid receptor stimulation in neuropathic pain.<ref name="Xu">{{cite journal | author = Xu M, Petraschka M, McLaughlin JP, Westenbroek RE, Caron MG, Lefkowitz RJ, Czyzyk TA, Pintar JE, Terman GW, Chavkin C | title = Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance | journal = J. Neurosci. | volume = 24 | issue = 19 | pages = 4576–84 | year = 2004 | month = May | pmid = 15140929 | pmc = 2376823 | doi = 10.1523/JNEUROSCI.5552-03.2004 | url = | issn = }}</ref> This same group also showed that the dynorphin-KOR system mediates [[astrocyte]] proliferation through the activation of p38 MAPK that was required for the effects of neuropathic pain on analgesic responses.<ref name="Xu 2007">{{cite journal | author = Xu M, Bruchas MR, Ippolito DL, Gendron L, Chavkin C | title = Sciatic nerve ligation-induced proliferation of spinal cord astrocytes is mediated by kappa opioid activation of p38 mitogen-activated protein kinase | journal = J. Neurosci. | volume = 27 | issue = 10 | pages = 2570–81 | year = 2007 | month = March | pmid = 17344394 | pmc = 2104780 | doi = 10.1523/JNEUROSCI.3728-06.2007 | url = | issn = }}</ref> Taken together, these reports suggest that dynorphin can elicit multiple effects on both Kappa opioid, and non-opioid pathways to modulate analgesic responses.
+Svensson et al. provided another possible mechanism by which dynorphin might cause pain in the spinal cord.<ref name="Svensson2005">{{cite journal |vauthors=Svensson CI, Hua XY, Powell HC, Lai J, Porreca F, Yaksh TL | title = Prostaglandin E2 release evoked by intrathecal dynorphin is dependent on spinal p38 mitogen activated protein kinase | journal = Neuropeptides | volume = 39 | issue = 5 | pages = 485–94 |date=October 2005 | pmid = 16176831 | doi = 10.1016/j.npep.2005.08.002 | url =  }}</ref> The authors found that administration of truncated dynorphin A<sub>2-17</sub>, which does not bind to opioid receptors, causes an increase in phosphorylated p38 mitogen-activated protein kinase (MAPK) in [[microglia]] in the [[posterior horn of spinal cord|dorsal horn]] of the spinal cord. Activated p38 has been previously linked to the NMDA-evoked [[prostaglandin]] release, which causes pain.<ref name="Svensson2003">{{cite journal |vauthors=Svensson CI, Hua XY, Protter AA, Powell HC, Yaksh TL | title = Spinal p38 MAP kinase is necessary for NMDA-induced spinal PGE(2) release and thermal hyperalgesia | journal = NeuroReport | volume = 14 | issue = 8 | pages = 1153–7 |date=June 2003 | pmid = 12821799 |url=http://journals.lww.com/neuroreport/Abstract/2003/06110/Spinal_p38_MAP_kinase_is_necessary_for.10.aspx | doi = 10.1097/00001756-200306110-00010 }}</ref> Thus, dynorphin could also induce pain in the spinal cord through a non-opioid p38 pathway.
+Other studies have identified a role for dynorphin and kappa opioid receptor stimulation in neuropathic pain.<ref name="Xu">{{cite journal |vauthors=Xu M, Petraschka M, McLaughlin JP, Westenbroek RE, Caron MG, Lefkowitz RJ, Czyzyk TA, Pintar JE, Terman GW, Chavkin C | title = Neuropathic Pain Activates the Endogenous κ Opioid System in Mouse Spinal Cord and Induces Opioid Receptor Tolerance | journal = J. Neurosci. | volume = 24 | issue = 19 | pages = 4576–84 |date=May 2004 | pmid = 15140929 | pmc = 2376823 | doi = 10.1523/JNEUROSCI.5552-03.2004 | url =  }}</ref> This same group also showed that the dynorphin-KOR system mediates [[astrocyte]] proliferation through the activation of p38 MAPK that was required for the effects of neuropathic pain on analgesic responses.<ref name="Xu 2007">{{cite journal |vauthors=Xu M, Bruchas MR, Ippolito DL, Gendron L, Chavkin C | title = Sciatic Nerve Ligation-Induced Proliferation of Spinal Cord Astrocytes Is Mediated by κ Opioid Activation of p38 Mitogen-Activated Protein Kinase | journal = J. Neurosci. | volume = 27 | issue = 10 | pages = 2570–81 |date=March 2007 | pmid = 17344394 | pmc = 2104780 | doi = 10.1523/JNEUROSCI.3728-06.2007 | url =  }}</ref> Taken together, these reports suggest that dynorphin can elicit multiple effects on both Kappa opioid, and non-opioid pathways to modulate analgesic responses.
 ==Addiction==
-Cocaine addiction results from complex molecular changes in the brain following multiple exposures to cocaine.<ref name="Nestler">{{cite journal | author = Nestler EJ, Aghajanian GK | title = Molecular and cellular basis of addiction | journal = Science | volume = 278 | issue = 5335 | pages = 58–63 | year = 1997 | month = October | pmid = 9311927 | doi = 10.1126/science.278.5335.58| url = | issn = }}</ref> Dynorphins have been shown to be an important part of this process. Although a single exposure to cocaine does not affect brain dynorphin levels, repeated exposures to the drug increases dynorphin concentrations in the [[striatum]] and [[substantia nigra]] in rats.<ref name="Sivam">{{cite journal | author = Sivam SP | title = Cocaine selectively increases striatonigral dynorphin levels by a dopaminergic mechanism | journal = J. Pharmacol. Exp. Ther. | volume = 250 | issue = 3 | pages = 818–24 | year = 1989 | month = September | pmid = 2476548 | doi = | url = | issn = }}</ref> One proposed molecular mechanism for increased dynorphin levels involves transcriptional regulation by [[CREB]] (3’, 5’-monophosphate response element binding protein). According to the model proposed by Carlezon et al., use of cocaine increases the expression of [[Cyclic adenosine monophosphate|cAMP]] and cAMP-dependent protein kinase ([[PKA]]).<ref name="Carlezon">{{cite journal | author = Carlezon WA, Thome J, Olson VG, Lane-Ladd SB, Brodkin ES, Hiroi N, Duman RS, Neve RL, Nestler EJ | title = Regulation of cocaine reward by CREB | journal = Science | volume = 282 | issue = 5397 | pages = 2272–5 | year = 1998 | month = December | pmid = 9856954 | doi = 10.1126/science.282.5397.2272| url = | issn = }}</ref> PKA leads to the activation of CREB, which increases the expression of dynorphin in the nucleus accumbens and dorsal striatum, brain areas important in addiction.<ref name="Carlezon"/> Dynorphin decreases [[dopamine]] release by binding to KORs on dopamine nerve terminals,<ref name="Krebs">{{cite journal | author = Krebs MO, Gauchy C, Desban M, Glowinski J, Kemel ML | title = Role of dynorphin and GABA in the inhibitory regulation of NMDA-induced dopamine release in striosome- and matrix-enriched areas of the rat striatum | journal = J. Neurosci. | volume = 14 | issue = 4 | pages = 2435–43 | year = 1994 | month = April | pmid = 7908960 | doi = | url = | issn = }}</ref> which leads to drug tolerance and withdrawal symptoms (Berke and Hymen, 2000).
+Cocaine addiction results from complex molecular changes in the brain following multiple exposures to cocaine.<ref name="Nestler">{{cite journal |vauthors=Nestler EJ, Aghajanian GK | title = Molecular and cellular basis of addiction | journal = Science | volume = 278 | issue = 5335 | pages = 58–63 |date=October 1997 | pmid = 9311927 | doi = 10.1126/science.278.5335.58| url =  }}</ref> Dynorphins have been shown to be an important part of this process. Although a single exposure to cocaine does not affect brain dynorphin levels, repeated exposures to the drug increases dynorphin concentrations in the [[striatum]] and [[substantia nigra]] in rats.<ref name="Sivam">{{cite journal | author = Sivam SP | title = Cocaine selectively increases striatonigral dynorphin levels by a dopaminergic mechanism | journal = J. Pharmacol. Exp. Ther. | volume = 250 | issue = 3 | pages = 818–24 |date=September 1989 | pmid = 2476548 | doi = | url =  }}</ref>
+One proposed molecular mechanism for increased dynorphin levels involves transcriptional regulation by [[CREB]] (3’, 5’-monophosphate response element binding protein). According to the model proposed by Carlezon et al., use of cocaine increases the expression of [[Cyclic adenosine monophosphate|cAMP]] and cAMP-dependent protein kinase ([[Protein kinase A|PKA]]).<ref name="Carlezon">{{cite journal |vauthors=Carlezon WA, Thome J, Olson VG, Lane-Ladd SB, Brodkin ES, Hiroi N, Duman RS, Neve RL, Nestler EJ | title = Regulation of cocaine reward by CREB | journal = Science | volume = 282 | issue = 5397 | pages = 2272–5 |date=December 1998 | pmid = 9856954 | doi = 10.1126/science.282.5397.2272| url =  }}</ref> PKA leads to the activation of CREB, which increases the expression of dynorphin in the nucleus accumbens and dorsal striatum, brain areas important in addiction.<ref name="Carlezon"/> Dynorphin decreases [[dopamine]] release by binding to KORs on dopamine nerve terminals.<ref name="Krebs">{{cite journal |vauthors=Krebs MO, Gauchy C, Desban M, Glowinski J, Kemel ML | title = Role of dynorphin and GABA in the inhibitory regulation of NMDA-induced dopamine release in striosome- and matrix-enriched areas of the rat striatum | journal = J. Neurosci. | volume = 14 | issue = 4 | pages = 2435–43 |date=April 1994 | pmid = 7908960 | doi = | url =  }}</ref>
+=== Cocaine ===
+Carlezon et al.<ref name="Carlezon"/> performed several experiments to validate this model. They found that, when mice were injected with cocaine, they preferred to be in the place where they were injected (showed stronger place preference) significantly more than control mice (injected with saline) did.  However, in mice overexpressing CREB under a constitutive promoter, place aversion was observed.<ref name="Carlezon"/> This indicates that increasing CREB reverses the positive effects of cocaine.  [[Northern blot]] analysis several days after CREB overexpression showed a marked increase in dynorphin mRNA in the nucleus accumbens.<ref name="Carlezon"/>
+Blocking KORs with an antagonist (norBNI) blocked the aversive effects caused by CREB overexpression.<ref name="Carlezon"/> Thus, cocaine use ultimately appears to lead to an increase in the transcription of prodynorphin mRNA. Dynorphin inhibits dopamine release, which could account the reinforcing properties of cocaine.<ref name="You">{{cite journal |vauthors=You ZB, Herrera-Marschitz M, Terenius L | title = Modulation of neurotransmitter release in the basal ganglia of the rat brain by dynorphin peptides | journal = J. Pharmacol. Exp. Ther. | volume = 290 | issue = 3 | pages = 1307–15 |date=September 1999 | pmid = 10454508 | doi = | url =  }}</ref>
-Carlezon et al.<ref name="Carlezon"/> performed several experiments to validate this model. They found that, when mice were injected with cocaine, they preferred to be in the place where they were injected (showed stronger place preference) significantly more than control mice (injected with saline) did.  However, in mice overexpressing CREB under a constitutive promoter, place aversion was observed.<ref name="Carlezon"/> This indicates that increasing CREB reverses the positive effects of cocaine.  [[Northern blot]] analysis several days after CREB overexpression showed a marked increase in dynorphin mRNA in the nucleus accumbens.<ref name="Carlezon"/> Blocking KORs with an antagonist (norBNI) blocked the aversive effects caused by CREB overexpression.<ref name="Carlezon"/> Thus, cocaine use ultimately appears to lead to an increase in the transcription of prodynorphin mRNA. Dynorphin inhibits dopamine release,<ref name="You">{{cite journal | author = You ZB, Herrera-Marschitz M, Terenius L | title = Modulation of neurotransmitter release in the basal ganglia of the rat brain by dynorphin peptides | journal = J. Pharmacol. Exp. Ther. | volume = 290 | issue = 3 | pages = 1307–15 | year = 1999 | month = September | pmid = 10454508 | doi = | url = | issn = }}</ref> that would counter the pleasurable effects of cocaine caused by the release of dopamine.<ref name="Clavin">{{cite web | url = http://dynorphin.com/ | title = Dynorphin : Nature's own antidote to cocaine ( and pleasure? ) | author = Clavin W | authorlink = | coauthors = | date = 2002-04-14 | format = | work = | publisher = | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2009-07-10}}</ref> There is also evidence suggesting that increased amounts of dynorphin can protect humans from cocaine addiction. According to research at Rockefeller University, the gene for dynorphin is present in two versions: a “high output” and a “low output” functional variation.<ref name=Clavin/> The high output functional variation of the gene contains polymorphisms in the promoter regions that are speculated to cause it to produce more copies of dynorphin mRNA, which would give people carrying this variation a “built-in defense system” against drug addiction.<ref name=Clavin/>
+There is also evidence suggesting that increased amounts of dynorphin can protect humans from cocaine addiction. According to research at Rockefeller University, the gene for dynorphin is present in two versions: a “high output” and a “low output” functional variation.<ref name="Clavin">{{cite web | url = http://dynorphin.com/ | title = Dynorphin : Nature's own antidote to cocaine ( and pleasure? ) | author = Clavin W | date = 2002-04-14 | work = | publisher = | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2009-07-10}}</ref> The high output functional variation of the gene contains polymorphisms in the promoter regions that are speculated to cause it to produce more copies of dynorphin mRNA, which would give people carrying this variation a “built-in defense system” against drug addiction.<ref name=Clavin/>
 ==Stress and depression==
-Land et al. first described a mechanism of dysphoria in which [[corticotropin-releasing factor]] (CRF) provokes dynorphin release.<ref name="Land">{{cite journal | author = Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C | title = The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system | journal = J. Neurosci. | volume = 28 | issue = 2 | pages = 407–14 | year = 2008 | month = January | pmid = 18184783 | pmc = 2612708 | doi = 10.1523/JNEUROSCI.4458-07.2008 | url = | issn = }}</ref> While control mice displayed aversive behaviors in response to forced swim tests and foot shocks, mice lacking dynorphin did not show any such signs of aversion. They noted that injecting CRF led to aversive behaviors in mice with functional genes for dynorphin even in the absence of stress, but not in those with dynorphin gene deletions. Place aversion was eliminated when the receptor CRF2 was blocked with an antagonist.<ref name=Land/> Together these results led Land et al. to conclude that dysphoric elements of stress occur when CRF2 stimulates dynorphin release and activates KOR.<ref name=Land/> The group further postulated that this pathway might be involved in drug seeking behavior. In support of this, it was shown previously that stress can reinstate cocaine-seeking behavior in mice through a CRF mechanism.<ref name="pmid15930388">{{cite journal | author = Wang B, Shaham Y, Zitzman D, Azari S, Wise RA, You ZB | title = Cocaine experience establishes control of midbrain glutamate and dopamine by corticotropin-releasing factor: a role in stress-induced relapse to drug seeking | journal = J. Neurosci. | volume = 25 | issue = 22 | pages = 5389–96 | year = 2005 | month = June | pmid = 15930388 | doi = 10.1523/JNEUROSCI.0955-05.2005 | url = | issn = }}</ref> Dynorphin has also been shown to influence drug seeking behavior and  is required for stress-induced, but not prime-induced, reinstatement of cocaine seeking.<ref name="Beardsley">{{cite journal | author = Beardsley PM, Howard JL, Shelton KL, Carroll FI | title = Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by footshock stressors vs cocaine primes and its antidepressant-like effects in rats | journal = Psychopharmacology (Berl.) | volume = 183 | issue = 1 | pages = 118–26 | year = 2005 | month = November | pmid = 16184376 | doi = 10.1007/s00213-005-0167-4 | url = | issn = }}</ref><ref name="Redila">{{cite journal | author = Redila VA, Chavkin C | title = Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system | journal = Psychopharmacology (Berl.) | volume = 200 | issue = 1 | pages = 59–70 | year = 2008 | month = September | pmid = 18575850 | pmc = 2680147 | doi = 10.1007/s00213-008-1122-y | url = | issn = }}</ref> A downstream element of this pathway was later identified by Bruchas et al.<ref name="Bruchas">{{cite journal | author = Bruchas MR, Land BB, Aita M, Xu M, Barot SK, Li S, Chavkin C | title = Stress-induced p38 mitogen-activated protein kinase activation mediates kappa-opioid-dependent dysphoria | journal = J. Neurosci. | volume = 27 | issue = 43 | pages = 11614–23 | year = 2007 | month = October | pmid = 17959804 | pmc = 2481272 | doi = 10.1523/JNEUROSCI.3769-07.2007 | url = | issn = }}</ref> The authors found that KOR activates p38, a member of the mitogen-activated protein kinase (MAPK) family, through phosphorylation.  Activation of p38 is necessary to produce KOR-dependent behaviors.<ref name=Bruchas/>
+Land et al. first described a mechanism of dysphoria in which [[corticotropin-releasing factor]] (CRF) provokes dynorphin release.<ref name="Land">{{cite journal |vauthors=Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C | title = The Dysphoric Component of Stress Is Encoded by Activation of the Dynorphin κ-Opioid System | journal = J. Neurosci. | volume = 28 | issue = 2 | pages = 407–14 |date=January 2008 | pmid = 18184783 | pmc = 2612708 | doi = 10.1523/JNEUROSCI.4458-07.2008 | url =  }}</ref> While control mice displayed aversive behaviors in response to forced swim tests and foot shocks, mice lacking dynorphin did not show any such signs of aversion. They noted that injecting CRF led to aversive behaviors in mice with functional genes for dynorphin even in the absence of stress, but not in those with dynorphin gene deletions. Place aversion was eliminated when the receptor CRF2 was blocked with an antagonist.<ref name=Land/>
+Together these results led Land et al. to conclude that dysphoric elements of stress occur when CRF2 stimulates dynorphin release and activates KOR.<ref name=Land/> The group further postulated that this pathway might be involved in drug seeking behavior. In support of this, it was shown previously that stress can reinstate cocaine-seeking behavior in mice through a CRF mechanism.<ref name="pmid15930388">{{cite journal |vauthors=Wang B, Shaham Y, Zitzman D, Azari S, Wise RA, You ZB | title = Cocaine experience establishes control of midbrain glutamate and dopamine by corticotropin-releasing factor: a role in stress-induced relapse to drug seeking | journal = J. Neurosci. | volume = 25 | issue = 22 | pages = 5389–96 |date=June 2005 | pmid = 15930388 | doi = 10.1523/JNEUROSCI.0955-05.2005 | url =  }}</ref>
+Dynorphin has also been shown to influence drug seeking behavior and  is required for stress-induced, but not prime-induced, reinstatement of cocaine seeking.<ref name="Beardsley">{{cite journal |vauthors=Beardsley PM, Howard JL, Shelton KL, Carroll FI | title = Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by footshock stressors vs cocaine primes and its antidepressant-like effects in rats | journal = Psychopharmacology | volume = 183 | issue = 1 | pages = 118–26 |date=November 2005 | pmid = 16184376 | doi = 10.1007/s00213-005-0167-4 | url =  }}</ref><ref name="Redila">{{cite journal |vauthors=Redila VA, Chavkin C | title = Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system | journal = Psychopharmacology | volume = 200 | issue = 1 | pages = 59–70 |date=September 2008 | pmid = 18575850 | pmc = 2680147 | doi = 10.1007/s00213-008-1122-y | url =  }}</ref> A downstream element of this pathway was later identified by Bruchas et al.<ref name="Bruchas">{{cite journal |vauthors=Bruchas MR, Land BB, Aita M, Xu M, Barot SK, Li S, Chavkin C | title = Stress-Induced p38 Mitogen-Activated Protein Kinase Activation Mediates κ-Opioid-Dependent Dysphoria | journal = J. Neurosci. | volume = 27 | issue = 43 | pages = 11614–23 |date=October 2007 | pmid = 17959804 | pmc = 2481272 | doi = 10.1523/JNEUROSCI.3769-07.2007 | url =  }}</ref> The authors found that KOR activates p38, a member of the mitogen-activated protein kinase (MAPK) family, through phosphorylation.  Activation of p38 is necessary to produce KOR-dependent behaviors.<ref name=Bruchas/>
-Because of its role in mediating dysphoria, dynorphin has also been investigated in relation to [[Depression (mood)|depression]]. Newton et al.<ref name="Newton">{{cite journal | author = Newton SS, Thome J, Wallace TL, Shirayama Y, Schlesinger L, Sakai N, Chen J, Neve R, Nestler EJ, Duman RS | title = Inhibition of cAMP response element-binding protein or dynorphin in the nucleus accumbens produces an antidepressant-like effect | journal = J. Neurosci. | volume = 22 | issue = 24 | pages = 10883–90 | year = 2002 | month = December | pmid = 12486182 | doi = | url = | issn = }}</ref> studied the effects of CREB and dynorphin on [[learned helplessness]] (an animal model for depression) in mice. Overexpression of dominant negative CREB (mCREB) in transgenic mice had an antidepressant effect (in terms of behavior), whereas overexpressing wild-type CREB caused an increase in depression-like symptoms.<ref name=Newton/> As described previously, CREB increases transcription of prodynorphin, which gives rise to different dynorphin subtypes.<ref name=Carlezon/> Newton et al.<ref name=Newton/> supported this mechanism, as the mCREB was colocalized with decreased expression of prodynorphin.  Also, direct antagonism of dynorphin caused antidepressant-like effects similar to those seen with mCREB expression.<ref name=Newton/> Thus, the CREB-dynorphin pathway regulates mood as well as cocaine rewards.
+Because of its role in mediating [[dysphoria]], dynorphin has also been investigated in relation to [[Depression (mood)|depression]]. Newton et al.<ref name="Newton">{{cite journal |vauthors=Newton SS, Thome J, Wallace TL, Shirayama Y, Schlesinger L, Sakai N, Chen J, Neve R, Nestler EJ, Duman RS | title = Inhibition of cAMP response element-binding protein or dynorphin in the nucleus accumbens produces an antidepressant-like effect | journal = J. Neurosci. | volume = 22 | issue = 24 | pages = 10883–90 |date=December 2002 | pmid = 12486182 | doi = | url =  }}</ref> studied the effects of CREB and dynorphin on [[learned helplessness]] (an animal model for depression) in mice. Overexpression of dominant negative CREB (mCREB) in transgenic mice had an antidepressant effect (in terms of behavior), whereas overexpressing wild-type CREB caused an increase in depression-like symptoms.<ref name=Newton/> As described previously, CREB increases transcription of prodynorphin, which gives rise to different dynorphin subtypes.<ref name=Carlezon/> Newton et al.<ref name=Newton/> supported this mechanism, as the mCREB was colocalized with decreased expression of prodynorphin.  Also, direct antagonism of dynorphin caused antidepressant-like effects similar to those seen with mCREB expression.<ref name=Newton/> Thus, the CREB-dynorphin pathway regulates mood as well as cocaine rewards.
-Shirayama et al.<ref name="Shirayama">{{cite journal | author = Shirayama Y, Ishida H, Iwata M, Hazama GI, Kawahara R, Duman RS | title = Stress increases dynorphin immunoreactivity in limbic brain regions and dynorphin antagonism produces antidepressant-like effects | journal = J. Neurochem. | volume = 90 | issue = 5 | pages = 1258–68 | year = 2004 | month = September | pmid = 15312181 | doi = 10.1111/j.1471-4159.2004.02589.x | url = | issn = }}</ref> used several animal depression models in rats to describe the effects of dynorphins A and B in depression. The authors found that learned helplessness increases the levels of dynorphins A and B in the hippocampus and nucleus accumbens and that injecting KOR antagonist norBNI induces recovery from learned helplessness. Immobilization stress causes increases levels of both dynorphins A and B in the hippocampus and nucleus accumbens.<ref name=Shirayama/> Forced swim stress increases the levels of dynorphin A in the hippocampus. Shirayama et al.<ref name=Shirayama/> concluded that both dynorphins A and B were important in stress response. The authors proposed several mechanisms to account for the effects of the KOR antagonist norBNI on learned helplessness. First, increased dynorphin levels block the release of [[glutamate]], a neurotransmitter involved in [[Neuroplasticity|plasticity]] in the hippocampus, which would inhibit new learning.<ref name=Shirayama/> Blocking dynorphin effects would allow glutamate to be released and restore functional plasticity in the hippocampus, reversing the phenomenon of learned helplessness. In addition, blocking dynorphin would enhance dopamine signaling and thus reduce depressive symptoms associated with stress.<ref name=Shirayama/> The authors suggest that KOR antagonists might have potential in treating depression in humans.
+Shirayama et al.<ref name="Shirayama">{{cite journal |vauthors=Shirayama Y, Ishida H, Iwata M, Hazama GI, Kawahara R, Duman RS | title = Stress increases dynorphin immunoreactivity in limbic brain regions and dynorphin antagonism produces antidepressant-like effects | journal = J. Neurochem. | volume = 90 | issue = 5 | pages = 1258–68 |date=September 2004 | pmid = 15312181 | doi = 10.1111/j.1471-4159.2004.02589.x | url =  }}</ref> used several animal depression models in rats to describe the effects of dynorphins A and B in depression. The authors found that learned helplessness increases the levels of dynorphins A and B in the hippocampus and nucleus accumbens and that injecting KOR antagonist norBNI induces recovery from learned helplessness. Immobilization stress causes increases in the levels of both dynorphins A and B in the hippocampus and nucleus accumbens.<ref name=Shirayama/> Forced swim stress increases the levels of dynorphin A in the hippocampus. Shirayama et al.<ref name=Shirayama/> concluded that both dynorphins A and B were important in stress response. The authors proposed several mechanisms to account for the effects of the KOR antagonist norBNI on learned helplessness. First, increased dynorphin levels block the release of [[glutamate]], a neurotransmitter involved in [[Neuroplasticity|plasticity]] in the hippocampus, which would inhibit new learning.<ref name=Shirayama/>
+Blocking dynorphin effects would allow glutamate to be released and restore functional plasticity in the hippocampus, reversing the phenomenon of learned helplessness. In addition, blocking dynorphin would enhance dopamine signaling and thus reduce depressive symptoms associated with stress.<ref name=Shirayama/> The authors suggest that KOR antagonists might have potential in treating depression in humans.
 ==Appetite and circadian rhythms==
-Dynorphins are important in maintaining [[homeostasis]] through appetite control and [[circadian rhythms]]. Przewlocki et al.<ref name="Prz">{{cite journal | author = Przewłocki R, Lasón W, Konecka AM, Gramsch C, Herz A, Reid LD | title = The opioid peptide dynorphin, circadian rhythms, and starvation | journal = Science | volume = 219 | issue = 4580 | pages = 71–3 | year = 1983 | month = January | pmid = 6129699 | doi = 10.1126/science.6129699| url = | issn = }}</ref> found that, during the day, dynorphins are naturally elevated in the neurointermediate lobe of the pituitary (NI pituitary) and depressed in the hypothalamus. This pattern is reversed at night.<ref name=Prz/> In addition, mice deprived of food and water, or of water alone, had increased levels of dynorphin in the hypothalamus during the day.<ref name=Prz/> Deprivation of water alone also decreased the dynorphin levels in the NI pituitary.<ref name=Prz/> These findings led Przewlocki et al.<ref name=Prz/> to conclude that dynorphins are essential in maintaining homeostasis.
+Dynorphins are important in maintaining [[homeostasis]] through appetite control and [[circadian rhythms]]. Przewlocki et al.<ref name="Prz">{{cite journal |vauthors=Przewłocki R, Lasón W, Konecka AM, Gramsch C, Herz A, Reid LD | title = The opioid peptide dynorphin, circadian rhythms, and starvation | journal = Science | volume = 219 | issue = 4580 | pages = 71–3 |date=January 1983 | pmid = 6129699 | doi = 10.1126/science.6129699| url =  }}</ref> found that, during the day, dynorphins are naturally elevated in the neurointermediate lobe of the pituitary (NI pituitary) and depressed in the hypothalamus. This pattern is reversed at night.<ref name=Prz/> In addition, mice deprived of food and water, or of water alone, had increased levels of dynorphin in the hypothalamus during the day.<ref name=Prz/> Deprivation of water alone also decreased the dynorphin levels in the NI pituitary.<ref name=Prz/> These findings led Przewlocki et al.<ref name=Prz/> to conclude that dynorphins are essential in maintaining homeostasis.
-Dynorphin has been implicated as an appetite stimulant. A number of studies<ref name="Lambert">{{cite journal | author = Lambert PD, Wilding JP, al-Dokhayel AA, Bohuon C, Comoy E, Gilbey SG, Bloom SR | title = A role for neuropeptide-Y, dynorphin, and noradrenaline in the central control of food intake after food deprivation | journal = Endocrinology | volume = 133 | issue = 1 | pages = 29–32 | year = 1993 | month = July | pmid = 8100519 | doi = 10.1210/en.133.1.29| url = | issn = }}</ref> in rats have shown that increasing the dynorphin levels stimulates eating. Opioid antagonists, such as [[naloxone]], can reverse the effects of elevated dynorphin.<ref name="Morley">{{cite journal | author = Morley LE | title = The Role of Peptides in Appetite Regulation across Species | journal =  American Zoologist | volume = 35 | issue = 6 | pages = 437–445 | year = 1995 | month = | doi = 10.1093/icb/35.6.437  | url = | issn = }}</ref> This inhibition is especially strong in obese animals or animals that have access to particularly appealing food.<ref name="Man">{{cite journal | author = Mandenoff A, Fumeron F, Apfelbaum M, Margules DL | title = Endogenous opiates and energy balance | journal = Science | volume = 215 | issue = 4539 | pages = 1536–8 | year = 1982 | month = March | pmid = 7063865 | doi = 10.1126/science.7063865| url = | issn = }}</ref> Inui et al.<ref name="pmid1716066">{{cite journal | author = Inui A, Okita M, Nakajima M, Inoue T, Sakatani N, Oya M, Morioka H, Okimura Y, Chihara K, Baba S | title = Neuropeptide regulation of feeding in dogs | journal = Am. J. Physiol. | volume = 261 | issue = 3 Pt 2 | pages = R588–94 | year = 1991 | month = September | pmid = 1716066 | doi = | url = | issn = }}</ref> found that administering dynorphin to dogs increased both their food and water intake.  Dynorphin plays a role in the eating behavior of hibernating animals.  Nizeilski et al.<ref name="pmid2874573">{{cite journal | author = Nizielski SE, Levine AS, Morley JE, Hall KA, Gosnell BA | title = Seasonal variation in opioid modulation of feeding in the 13-lined ground squirrel | journal = Physiol. Behav. | volume = 37 | issue = 1 | pages = 5–9 | year = 1986 | pmid = 2874573 | doi = 10.1016/0031-9384(86)90375-6| url = | issn = }}</ref> examined dynorphin levels in the ground squirrel, which undergoes periods of excessive eating and periods of starvation before winter.  They found that dynorphin levels increased during the starvation periods.  Berman et al.<ref name="pmid7895045">{{cite journal | author = Berman Y, Devi L, Carr KD | title = Effects of chronic food restriction on prodynorphin-derived peptides in rat brain regions | journal = Brain Res. | volume = 664 | issue = 1-2 | pages = 49–53 | year = 1994 | month = November | pmid = 7895045 | doi = 10.1016/0006-8993(94)91952-6| url = | issn = }}</ref> studied the levels of dynorphin during periods of food restriction.  The group found that while food did not alter the expression of dynorphin B, it increases dynorphin A levels in several rat brain regions ([[hypothalamus]], [[nucleus accumbens]], and bed nucleus of the stria terminalis).
+Dynorphin has been implicated as an appetite stimulant. A number of studies<ref name="Lambert">{{cite journal |vauthors=Lambert PD, Wilding JP, al-Dokhayel AA, Bohuon C, Comoy E, Gilbey SG, Bloom SR | title = A role for neuropeptide-Y, dynorphin, and noradrenaline in the central control of food intake after food deprivation | journal = Endocrinology | volume = 133 | issue = 1 | pages = 29–32 |date=July 1993 | pmid = 8100519 | doi = 10.1210/en.133.1.29| url =  }}</ref> in rats have shown that increasing the dynorphin levels stimulates eating. Opioid antagonists, such as [[naloxone]], can reverse the effects of elevated dynorphin.<ref name="Morley">{{cite journal | author = Morley LE | title = The Role of Peptides in Appetite Regulation across Species | journal =  American Zoologist | volume = 35 | issue = 6 | pages = 437–445 | year = 1995 | month = | doi = 10.1093/icb/35.6.437  | url =  }}</ref> This inhibition is especially strong in obese animals or animals that have access to particularly appealing food.<ref name="Man">{{cite journal |vauthors=Mandenoff A, Fumeron F, Apfelbaum M, Margules DL | title = Endogenous opiates and energy balance | journal = Science | volume = 215 | issue = 4539 | pages = 1536–8 |date=March 1982 | pmid = 7063865 | doi = 10.1126/science.7063865| url =  }}</ref> Inui et al.<ref name="pmid1716066">{{cite journal |vauthors=Inui A, Okita M, Nakajima M, Inoue T, Sakatani N, Oya M, Morioka H, Okimura Y, Chihara K, Baba S | title = Neuropeptide regulation of feeding in dogs | journal = Am. J. Physiol. | volume = 261 | issue = 3 Pt 2 | pages = R588–94 |date=September 1991 | pmid = 1716066 | doi = | url =  }}</ref> found that administering dynorphin to dogs increased both their food and water intake.  Dynorphin plays a role in the eating behavior of hibernating animals.  Nizeilski et al.<ref name="pmid2874573">{{cite journal |vauthors=Nizielski SE, Levine AS, Morley JE, Hall KA, Gosnell BA | title = Seasonal variation in opioid modulation of feeding in the 13-lined ground squirrel | journal = Physiol. Behav. | volume = 37 | issue = 1 | pages = 5–9 | year = 1986 | pmid = 2874573 | doi = 10.1016/0031-9384(86)90375-6| url =  }}</ref> examined dynorphin levels in the ground squirrel, which undergoes periods of excessive eating and periods of starvation before winter.  They found that dynorphin levels increased during the starvation periods.  Berman et al.<ref name="pmid7895045">{{cite journal |vauthors=Berman Y, Devi L, Carr KD | title = Effects of chronic food restriction on prodynorphin-derived peptides in rat brain regions | journal = Brain Res. | volume = 664 | issue = 1–2 | pages = 49–53 |date=November 1994 | pmid = 7895045 | doi = 10.1016/0006-8993(94)91952-6| url =  }}</ref> studied the levels of dynorphin during periods of food restriction.  The group found that while food did not alter the expression of dynorphin B, it increases dynorphin A levels in several rat brain regions ([[hypothalamus]], [[nucleus accumbens]], and bed nucleus of the stria terminalis).
-Recent research on dynorphin [[knockout mice]] did not find differences between knockout and control animals in food intake, but found that fat storage was reduced in male knockout mice.<ref name="Sainsbury">{{cite journal | author = Sainsbury A, Lin S, McNamara K, Slack K, Enriquez R, Lee NJ, Boey D, Smythe GA, Schwarzer C, Baldock P, Karl T, Lin EJ, Couzens M, Herzog H | title = Dynorphin knockout reduces fat mass and increases weight loss during fasting in mice | journal = Mol. Endocrinol. | volume = 21 | issue = 7 | pages = 1722–35 | year = 2007 | month = July | pmid = 17456788 | doi = 10.1210/me.2006-0367 | url = | issn = }}</ref> Fatty acids were oxidized more quickly in knockout animals.<ref name=Sainsbury/>
+Recent research on dynorphin [[knockout mice]] did not find differences between knockout and control animals in food intake, but found that fat storage was reduced in male knockout mice.<ref name="Sainsbury">{{cite journal |vauthors=Sainsbury A, Lin S, McNamara K, Slack K, Enriquez R, Lee NJ, Boey D, Smythe GA, Schwarzer C, Baldock P, Karl T, Lin EJ, Couzens M, Herzog H | title = Dynorphin knockout reduces fat mass and increases weight loss during fasting in mice | journal = Mol. Endocrinol. | volume = 21 | issue = 7 | pages = 1722–35 |date=July 2007 | pmid = 17456788 | doi = 10.1210/me.2006-0367 | url =  }}</ref> Fatty acids were oxidized more quickly in knockout animals.<ref name=Sainsbury/>
-Studies have also shown that ingesting a high-fat diet increases the gene expression of dynorphin in the hypothalamus.<ref name="Leib">{{cite journal | author = Leibowitz SF | title = Overconsumption of dietary fat and alcohol: mechanisms involving lipids and hypothalamic peptides | journal = Physiol. Behav. | volume = 91 | issue = 5 | pages = 513–21 | year = 2007 | month = August | pmid = 17481672 | pmc = 2077813 | doi = 10.1016/j.physbeh.2007.03.018 | url = | issn = }}</ref> Thus, dynorphin may cause overeating when a high-fat diet is available.<ref name=Leib/><ref name="MorleyL">{{cite journal | author = Morley JE, Levine AS | title = Stress-induced eating is mediated through endogenous opiates | journal = Science | volume = 209 | issue = 4462 | pages = 1259–61 | year = 1980 | month = September | pmid = 6250222 | doi = 10.1126/science.6250222| url = | issn = }}</ref>  were the first to describe the role of opioid peptides in stress-related eating. In their study, mice had their tails pinched (causes stress), which induced eating. Stress-related eating was reduced by injecting naloxone, an opioid peptide antagonist.<ref name=MorleyL/> Mandenoff et al.<ref name=Man/> proposed that, although endogenous opioids are not necessary to maintain body weight and energy expenditure under predictable circumstances, they become activated under stressful conditions. They found that endogenous opioids, such as dynorphin, stimulate appetite and decrease energy expenditure. Taken together, the studies above suggest an important evolutionary mechanism in which more food is eaten, more nutrients are stored, and less energy is expended by an organism during times of stress.
+Studies have also shown that ingesting a high-fat diet increases the gene expression of dynorphin in the hypothalamus.<ref name="Leib">{{cite journal | author = Leibowitz SF | title = Overconsumption of dietary fat and alcohol: Mechanisms involving lipids and hypothalamic peptides | journal = Physiol. Behav. | volume = 91 | issue = 5 | pages = 513–21 |date=August 2007 | pmid = 17481672 | pmc = 2077813 | doi = 10.1016/j.physbeh.2007.03.018 | url =  }}</ref> Thus, dynorphin may cause overeating when a high-fat diet is available.<ref name=Leib/><ref name="MorleyL">{{cite journal |vauthors=Morley JE, Levine AS | title = Stress-induced eating is mediated through endogenous opiates | journal = Science | volume = 209 | issue = 4462 | pages = 1259–61 |date=September 1980 | pmid = 6250222 | doi = 10.1126/science.6250222| url =  }}</ref> Morley & Levine were the first to describe the role of opioid peptides in stress-related eating. In their study, mice had their tails pinched (causes stress), which induced eating. Stress-related eating was reduced by injecting naloxone, an opioid peptide antagonist.<ref name=MorleyL/>
+Mandenoff et al.<ref name=Man/> proposed that, although endogenous opioids are not necessary to maintain body weight and energy expenditure under predictable circumstances, they become activated under stressful conditions. They found that endogenous opioids, such as dynorphin, stimulate appetite and decrease energy expenditure. Taken together, the studies above suggest an important evolutionary mechanism in which more food is eaten, more nutrients are stored, and less energy is expended by an organism during times of stress.
 ==Temperature regulation==
-In addition to their role in weight control, dynorphins have been found to regulate body temperature.  Opioid peptides were first investigated in [[hyperthermia]], where it was found that MOR agonists stimulate this response when injected into the periaqueductal gray (PAG) region of the brain.<ref name=Nyberg/> Xin et al.<ref name="Xin">{{cite journal | author = Xin L, Geller EB, Adler MW | title = Body temperature and analgesic effects of selective mu and kappa opioid receptor agonists microdialyzed into rat brain | journal = J. Pharmacol. Exp. Ther. | volume = 281 | issue = 1 | pages = 499–507 | year = 1997 | month = April | pmid = 9103537 | doi = | url = | issn = }}</ref> showed that delivery of dynorphin A<sub>1-17</sub> (a KOR agonist) through [[microdialysis]] into the PAG region induced hypothermia in rats.  The authors found that the severity of [[hypothermia]] was proportional to the dose of dynorphin A<sub>1-17</sub> administered.  Hypothermia could be prevented by administering KOR antagonist norBNI to the rat.<ref name=Xin/> Xin et al.<ref name=Xin/> hypothesized that while MOR agonists mediate hyperthermia, KOR agonists, such as dynorphin, mediate hypothermia.  Sharma and Alm<ref name="Sharma">{{cite journal | author = Sharma HS, Alm P | title = Nitric oxide synthase inhibitors influence dynorphin A (1–17) immunoreactivity in the rat brain following hyperthermia | journal = Amino Acids | volume = 23 | issue = 1-3 | pages = 247–59 | year = 2002 | pmid = 12373545 | doi = 10.1007/s00726-001-0136-0 | url = | issn = }}</ref> found that subjecting rats to heat (38˚C) caused dynorphins to be upregulated in the cerebral cortex, hippocampus, cerebellum, and the brain stem.  Further, authors found that administration of nitric oxide synthase (NOS) inhibitors reduced dynorphin A1-17 levels in the brain and attenuated symptoms related to heat stress.  Sharma and Alm<ref name=Sharma/> concluded that hyperthermia increases dynorphin levels, which may cause damage and promote heat stress reaction.  They further hypothesized that [[nitric oxide]] was part of this mechanism.  Ansonoff et al.<ref name="Ansonoff">{{cite journal | author = Ansonoff MA, Zhang J, Czyzyk T, Rothman RB, Stewart J, Xu H, Zjwiony J, Siebert DJ, Yang F, Roth BL, Pintar JE | title = Antinociceptive and hypothermic effects of Salvinorin A are abolished in a novel strain of kappa-opioid receptor-1 knockout mice | journal = J. Pharmacol. Exp. Ther. | volume = 318 | issue = 2 | pages = 641–8 | year = 2006 | month = August | pmid = 16672569 | doi = 10.1124/jpet.106.101998 | url = | issn = }}</ref> found that hypothermic effects are mediated through K1 (κ-opioid receptor 1), but not K2.  The authors applied a KOR agonist to K1 knockout mice, which eliminated hypothermic response.  Thus, K2 does not appear to have a role in the hypothermic mechanism
+In addition to their role in weight control, dynorphins have been found to regulate body temperature.  Opioid peptides were first investigated in [[hyperthermia]], where it was found that MOR agonists stimulate this response when injected into the periaqueductal gray (PAG) region of the brain.<ref name=Nyberg/> Xin et al.<ref name="Xin">{{cite journal |vauthors=Xin L, Geller EB, Adler MW | title = Body temperature and analgesic effects of selective mu and kappa opioid receptor agonists microdialyzed into rat brain | journal = J. Pharmacol. Exp. Ther. | volume = 281 | issue = 1 | pages = 499–507 |date=April 1997 | pmid = 9103537 | doi = | url =  }}</ref> showed that delivery of dynorphin A<sub>1-17</sub> (a KOR agonist) through [[microdialysis]] into the PAG region induced hypothermia in rats.  The authors found that the severity of [[hypothermia]] was proportional to the dose of dynorphin A<sub>1-17</sub> administered.  Hypothermia could be prevented by administering KOR antagonist norBNI to the rat.<ref name=Xin/> Xin et al.<ref name=Xin/> hypothesized that while MOR agonists mediate hyperthermia, KOR agonists, such as dynorphin, mediate hypothermia.
+Sharma and Alm<ref name="Sharma">{{cite journal |vauthors=Sharma HS, Alm P | title = Nitric oxide synthase inhibitors influence dynorphin A (1–17) immunoreactivity in the rat brain following hyperthermia | journal = Amino Acids | volume = 23 | issue = 1–3 | pages = 247–59 | year = 2002 | pmid = 12373545 | doi = 10.1007/s00726-001-0136-0 | url =  }}</ref> found that subjecting rats to heat (38˚C) caused dynorphins to be upregulated in the cerebral cortex, hippocampus, cerebellum, and the brain stem.  Further, authors found that administration of nitric oxide synthase (NOS) inhibitors reduced dynorphin A1-17 levels in the brain and attenuated symptoms related to heat stress.  Sharma and Alm<ref name=Sharma/> concluded that hyperthermia increases dynorphin levels, which may cause damage and promote heat stress reaction.  They further hypothesized that [[nitric oxide]] was part of this mechanism.  Ansonoff et al.<ref name="Ansonoff">{{cite journal |vauthors=Ansonoff MA, Zhang J, Czyzyk T, Rothman RB, Stewart J, Xu H, Zjwiony J, Siebert DJ, Yang F, Roth BL, Pintar JE | title = Antinociceptive and hypothermic effects of Salvinorin A are abolished in a novel strain of kappa-opioid receptor-1 knockout mice | journal = J. Pharmacol. Exp. Ther. | volume = 318 | issue = 2 | pages = 641–8 |date=August 2006 | pmid = 16672569 | doi = 10.1124/jpet.106.101998 | url =  }}</ref> found that hypothermic effects are mediated through K1 (κ-opioid receptor 1), but not K2.  The authors applied a KOR agonist to K1 knockout mice, which eliminated hypothermic response.  Thus, K2 does not appear to have a role in the hypothermic mechanism
 ==Clinical significance==
-Recent research has demonstrated that pulmonary delivery may be an effective means of distributing dynorphin derivatives.<ref>{{cite journal |author=Brugos B, Arya V, Hochhaus G |title=Stabilized dynorphin derivatives for modulating antinociceptive activity in morphine tolerant rats: effect of different routes of administration |journal=AAPS J |volume=6 |issue=4 |pages=e36 |year=2004 |pmid=15760101 |doi=10.1208/aapsj060436}}</ref>
+Dynorphin derivatives are generally considered to be of little clinical use because of their very short duration of action.<ref>{{cite journal |vauthors=Brugos B, Arya V, Hochhaus G |title=Stabilized dynorphin derivatives for modulating antinociceptive activity in morphine tolerant rats: effect of different routes of administration |journal=AAPS J |volume=6 |issue=4 |pages=e36 |year=2004 |pmid=15760101 |doi=10.1208/aapsj060436|pmc=2751232 }}</ref>
 ==References==
-{{Reflist|2}}
+{{reflist|30em}}
 ==External links==
@@ Line 76: / Line 100: @@
 {{Opioid peptides}}
+{{Opioid receptor modulators}}
 [[Category:Neurotransmitters]]
 [[Category:Kappa agonists]]
+[[Category:Opioid peptides]]
-[[de:Dynorphine]]
-[[it:Dinorfina]]
-[[nl:Dynorfine]]
-[[ja:ダイノルフィン]]
-[[fi:Dynorfiini]]

v t e Opioid receptor modulators
MOR	Agonists (abridged; see here for a full list): 3-HO-PCP 7-Acetoxymitragynine 7-Hydroxymitragynine ψ-Akuammigine α-Chlornaltrexamine α-Narcotine Acetyldihydrocodeine Acetylfentanyl Acrylfentanyl Adrenorphin (metorphamide) AH-7921 Akuammicine Akuammidine Alfentanil Anileridine Apparicine β-Endorphin BAM-12P BAM-18P BAM-22P Benzhydrocodone Benzylmorphine Bezitramide Biphalin BU08070 Buprenorphine Butorphan Butorphanol Butyrfentanyl BW-373U86 Carfentanil Casokefamide Cebranopadol Chloroxymorphamine Codeine DADLE DAMGO (DAGO) Dermorphin Desmetramadol (desmethyltramadol) Desomorphine Dextromoramide Dextropropoxyphene (propoxyphene) Dezocine Dimenoxadol Dimethylaminopivalophenone Eluxadoline Diamorphine (heroin) Dihydrocodeine Dihydroetorphine Dihydromorphine Dinalbuphine sebacate Diphenoxylate Dipipanone Dynorphin A Embutramide Endomorphin-1 Endomorphin-2 Eseroline Ethylmorphine Etorphine Fentanyl Fluorophen Frakefamide Furanylfentanyl Hemorphin-4 Herkinorin Hodgkinsine Hydrocodone Hydromorphinol Hydromorphone IBNtxA Ketamine Ketobemidone Kratom Laudanosine Lefetamine Leu-enkephalin Levacetylmethadol Levomethorphan Levorphanol Lexanopadol Loperamide Loxicodegol Matrine Meptazinol Met-enkephalin (metenkefalin) Methadone Metkefamide Metopon Mitragynine Mitragynine pseudoindoxyl Morphiceptin Morphine Nalbuphine NalBzOH Nalmexone Naltalimide Neopine NFEPP Nicocodeine Nicodicodeine Nicomorphine NKTR-181 Norketamine Octreotide Oliceridine OM-3-MNZ Oripavine Oxycodone Oxymorphazone Oxymorphonazine Oxymorphone Oxymorphone phenylhydrazone OxyPNPH Papaver somniferum (opium) Pentazocine Pericine Pethidine (meperidine) Phenazocine Phencyclidine Piminodine Piritramide PL-017 Prodine Propiram PZM21 Racemethorphan Racemorphan Remifentanil Salsolinol SC-17599 Sinomenine Sufentanil Tapentadol Tetrahydropapaveroline TH-030418 Thebaine Thienorphine Tianeptine Tilidine Tramadol Trimebutine TRIMU 5 TRV734 Tubotaiwine U-47700 Valorphin Viminol Xorphanol PAMs: BMS-986121 BMS-986122 Antagonists: (3S,4S)-Picenadol 2-(S)-N,N-(R)-Viminol 3CS-nalmefene 4-Caffeoyl-1,5-quinide 4′-Hydroxyflavanone 4',7-Dihydroxyflavone 6β-Naltrexol 6β-Naltrexol-d4 18-MC α-Gliadin β-Chlornaltrexamine β-Funaltrexamine Akuammine Alvimopan AM-251 Apigenin AT-076 Axelopran Bevenopran Catechin Catechin gallate Clocinnamox CTAP CTOP Cyclofoxy Cyprodime Diacetylnalorphine Diprenorphine ECG EGC Epicatechin Eptazocine Gemazocine Ginsenoside R Hyperoside Ibogaine Levallorphan Lobeline LY-255582 LY-2196044 Methocinnamox Methylnaltrexone Methylsamidorphan chloride Naldemedine Nalmefene Nalodeine (N-allylnorcodeine) Nalorphine Nalorphine dinicotinate Naloxazone Naloxegol Naloxol Naloxonazine Naloxone Naltrexazone Naltrexonazine Naltrexone Naltrindole Naringenin Noribogaine Oxilorphan Pawhuskin A Rimonabant Quadazocine Samidorphan Taxifolin Unknown/unsorted: Cannabidiol Coronaridine Cyproterone acetate Dihydroakuuamine Tabernanthine Tetrahydrocannabinol
DOR	Agonists: 3CS-nalmefene 6'-GNTI 7-SIOM ADL-5747 (PF-04856881) ADL-5859 Alazocine (SKF-10047) Amoxapine AR-M100390 (ARM390) AZD2327 β-Endorphin BAM-18P Biphalin BU-48 Butorphan Butorphanol BW-373U86 Casokefamide Cebranopadol Codeine Cyclazocine DADLE Deltorphin A Deltorphin I Deltorphin II Desmethylclozapine Desmetramadol (desmethyltramadol) Dezocine Diamorphine (heroin) Dihydroetorphine Dihydromorphine DPDPE DPI-221 DPI-3290 DSLET Ethylketazocine Etorphine Fentanyl FIT Fluorophen Hemorphin-4 Hydrocodone Hydromorphone Ibogaine Isomethadone JNJ-20788560 KNT-127 Kratom Laudanosine Leu-enkephalin Levomethorphan Levorphanol Lexanopadol Lofentanil Met-enkephalin (metenkefalin) Metazocine Metkefamide Mitragynine Mitragynine pseudoindoxyl Morphine N-Phenethyl-14-ethoxymetopon Norbuprenorphine NalBzOH Oripavine Oxycodone Oxymorphone Pethidine (meperidine) Proglumide Racemethorphan Racemorphan RWJ-394674 Samidorphan SB-235863 SNC-80 SNC-162 TAN-67 (SB-205,607) TH-030418 Thebaine Thiobromadol (C-8813) Tonazocine Tramadol TRV250 Xorphanol Zenazocine Antagonists: 4',7-Dihydroxyflavone 5'-NTII 6β-Naltrexol 6β-Naltrexol-d4 α-Santolol β-Chlornaltrexamine Apigenin AT-076 Axelopran Bevenopran BNTX Catechin Catechin gallate Clocinnamox Diacetylnalorphine Diprenorphine ECG EGC Eluxadoline Epicatechin ICI-154129 ICI-174864 LY-255582 LY-2196044 Methylnaltrexone Methylnaltrindole N-Benzylnaltrindole Nalmefene Nalorphine Naltrexone Naltriben Naltrindole Naloxone Naringenin Noribogaine Pawhuskin A Quadazocine SDM25N SoRI-9409 Taxifolin Thienorphine Unknown/unsorted: 18-MC Cannabidiol Coronaridine Cyproterone acetate Tabernanthine Tetrahydrocannabinol
KOR	Agonists: 3CS-nalmefene 6'-GNTI 8-CAC 18-MC 14-Methoxymetopon β-Chlornaltrexamine β-Funaltrexamine Adrenorphin (metorphamide) Akuuamicine Alazocine (SKF-10047) Allomatrine Apadoline Asimadoline BAM-12P BAM-18P BAM-22P Big dynorphin Bremazocine BRL-52537 Butorphan Butorphanol BW-373U86 Cebranopadol Ciprefadol CR665 Cyclazocine Cyclorphan Cyprenorphine Desmetramadol (desmethyltramadol) Diamorphine (heroin) Diacetylnalorphine Difelikefalin Dihydroetorphine Dihydromorphine Dinalbuphine sebacate Diprenorphine Dynorphin A Dynorphin B (rimorphin) Eluxadoline Enadoline Eptazocine Erinacine E Ethylketazocine Etorphine Fedotozine Fentanyl Gemazocine GR-89696 GR-103545 Hemorphin-4 Herkinorin HS665 Hydromorphone HZ-2 Ibogaine ICI-199,441 ICI-204,448 Ketamine Ketazocine Laudanosine Leumorphin (dynorphin B-29) Levallorphan Levomethorphan Levorphanol Lexanopadol Lofentanil LPK-26 Lufuradom Matrine MB-1C-OH Menthol Metazocine Metkefamide Mianserin Mirtazapine Morphine Moxazocine MR-2034 N-MPPP Nalbuphine NalBzOH Nalfurafine Nalmefene Nalodeine (N-allylnorcodeine) Nalorphine Naltriben Niravoline Norbuprenorphine Norbuprenorphine-3-glucuronide Noribogaine Norketamine Oripavine Oxilorphan Oxycodone Pentazocine Pethidine (meperidine) Phenazocine Proxorphan Racemethorphan Racemorphan RB-64 Salvinorin A (salvia) Salvinorin B ethoxymethyl ether Salvinorin B methoxymethyl ether Samidorphan Spiradoline (U-62,066) TH-030418 Thienorphine Tifluadom Tricyclic antidepressants (e.g., amitriptyline, desipramine, imipramine, nortriptyline) U-50,488 U-54,494A U-69,593 Xorphanol Antagonists: 4′-Hydroxyflavanone 4',7-Dihydroxyflavone 5'-GNTI 6'-GNTI 6β-Naltrexol 6β-Naltrexol-d4 β-Chlornaltrexamine Buprenorphine/samidorphan Amentoflavone ANTI Apigenin Arodyne AT-076 Axelopran AZ-MTAB Binaltorphimine BU09059 Buprenorphine Catechin Catechin gallate CERC-501 (LY-2456302) Clocinnamox Cyclofoxy Dezocine DIPPA EGC ECG Epicatechin Hyperoside JDTic LY-255582 LY-2196044 LY-2444296 LY-2459989 LY-2795050 MeJDTic Methylnaltrexone ML190 ML350 MR-2266 N-Fluoropropyl-JDTic Naloxone Naltrexone Naltrindole Naringenin Norbinaltorphimine Noribogaine Pawhuskin A PF-4455242 RB-64 Quadazocine Taxifolin UPHIT Zyklophin Unknown/unsorted: Akuammicine Akuammine Coronaridine Cyproterone acetate Dihydroakuuamine Ibogamine Tabernanthine
NOP	Agonists: (Arg14,Lys15)Nociceptin ((pF)Phe⁴)Nociceptin(1-13)NH₂ (Phe¹Ψ(CH₂-NH)Gly²)Nociceptin(1-13)NH₂ Ac-RYYRWK-NH₂ Ac-RYYRIK-NH₂ BU08070 Buprenorphine Cebranopadol Dihydroetorphine Etorphine JNJ-19385899 Levomethorphan Levorphanol Levorphanol Lexanopadol MCOPPB MT-7716 NNC 63-0532 Nociceptin (orphanin FQ) Nociceptin (1-11) Nociceptin (1-13)NH₂ Norbuprenorphine Racemethorphan Racemorphan Ro64-6198 Ro65-6570 SCH-221510 SCH-486757 SR-8993 SR-16435 TH-030418 Antagonists: (Nphe¹)Nociceptin(1-13)NH₂ AT-076 BAN-ORL-24 BTRX-246040 (LY-2940094) J-113397 JTC-801 NalBzOH Nociceptin (1-7) Nocistatin SB-612111 SR-16430 Thienorphine Trap-101 UFP-101
Unsorted	β-Casomorphins Amidorphin BAM-20P Cytochrophin-4 Deprolorphin Gliadorphin (gluteomorphin) Gluten exorphins Hemorphins Kava constituents MEAGL MEAP NEM Neoendorphins Nepetalactone (catnip) Peptide B Peptide E Peptide F Peptide I Rubiscolins Soymorphins
Others	Enkephalinase inhibitors: Amastatin BL-2401 Candoxatril D -Phenylalanine Dexecadotril (retorphan) Ecadotril (sinorphan) Kelatorphan Racecadotril (acetorphan) RB-101 RB-120 RB-3007 Opiorphan Selank Semax Spinorphin Thiorphan Tynorphin Ubenimex (bestatin) Propeptides: β-Lipotropin (proendorphin) Prodynorphin Proenkephalin Pronociceptin Proopiomelanocortin (POMC) Others: Kyotorphin (met-enkephalin releaser/degradation stabilizer)
See also: Receptor/signaling modulators • Signaling peptide/protein receptor modulators