Cannabinoid receptor type 1: Difference between revisions

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Revision as of 06:01, 24 November 2017

The cannabinoid receptor type 1, often abbreviated as CB₁, is a G protein-coupled cannabinoid receptor located primarily in the central and peripheral nervous system. It is activated by the endocannabinoid neurotransmitters anandamide and 2-arachidonoylglycerol (2-AG); by plant cannabinoids, such as the compound THC, an active ingredient of the psychoactive drug cannabis; and by synthetic analogues of THC. CB1 and THC are deactivated by the phytocannabinoid tetrahydrocannabivarin (THCV).^[1]^[2]

Structure

The CB₁ receptor shares the structure characteristic of all G-protein-coupled receptors, possessing seven transmembrane domains connected by three extracellular and three intracellular loops, an extracellular N-terminal tail, and an intracellular C-terminal tail.^[3]^[4] The receptor may exist as a homodimer or form heterodimers or other GPCR oligomers with different classes of G-protein-coupled receptors. Observed heterodimers include A_2A–CB₁, CB₁–D₂, OX₁–CB₁, while many more may only be stable enough to exist in vivo.^[5] The CB₁ receptor possesses an allosteric modulatory binding site.^[6]^[7]

Mechanism

The CB₁ receptor is a pre-synaptic heteroreceptor that modulates neurotransmitter release when activated in a dose-dependent, stereoselective and pertussis toxin-sensitive manner.^[8] The CB₁ receptor is activated by cannabinoids, generated naturally inside the body (endocannabinoids) or introduced into the body as cannabis or a related synthetic compound.

Research suggests that the majority of CB₁ receptors are coupled through G_i/o proteins. Upon activation, CB₁ receptor exhibits its effects mainly through activation of G_i, which decreases intracellular cAMP concentration by inhibiting its production enzyme, adenylate cyclase, and increases mitogen-activated protein kinase (MAP kinase) concentration. Alternatively, in some rare cases CB₁ receptor activation may be coupled to G_s proteins, which stimulate adenylate cyclase.^[5] cAMP is known to serve as a second messenger coupled to a variety of ion channels, including the positively influenced inwardly rectifying potassium channels (=Kir or IRK),^[9] and calcium channels, which are activated by cAMP-dependent interaction with such molecules as protein kinase A (PKA), protein kinase C (PKC), Raf-1, ERK, JNK, p38, c-fos, c-jun, and others.^[10] In terms of function, the inhibition of intracellular cAMP expression shortens the duration of pre-synaptic action potentials by prolonging the rectifying potassium A-type currents, which is normally inactivated upon phosphorylation by PKA. This inhibition grows more pronounced when considered with the effect of activated CB₁ receptors to limit calcium entry into the cell, which does not occur through cAMP but by a direct G-protein-mediated inhibition. As presynaptic calcium entry is a requirement for vesicle release, this function will decrease the transmitter that enters the synapse upon release.^[11] The relative contribution of each of these two inhibitory mechanisms depends on the variance of ion channel expression by cell type.

The CB₁ receptor can also be modulated by allosterically synthetic ligands^[12] in a positive^[13] and negative^[14] manner. In vivo exposure to THC impairs long-term potentiation and leads to a reduction of phosphorylated CREB.^[15]

In summary, CB₁ receptor activity has been found to be coupled to certain ion channels, in the following manner:^[5]

Positively to inwardly rectifying and A-type outward potassium channels.
Negatively to D-type outward potassium channels
Negatively to N-type and P/Q-type calcium channels.

Expression

The CB₁ receptor is encoded by the gene CNR1,^[8] located on human chromosome 6.^[11] Two transcript variants encoding different isoforms have been described for this gene.^[8] CNR1 orthologs^[16] have been identified in most mammals.

The CB₁ receptor is expressed pre-synaptically at both glutaminergic and GABAergic interneurons and, in effect, acts as a neuromodulator to inhibit release of glutamate and GABA.^[11] Repeated administration of receptor agonists may result in receptor internalization and/ or a reduction in receptor protein signalling.^[5]

The inverse agonist MK-9470 makes it possible to produce in vivo images of the distribution of CB₁ receptors in the human brain with positron emission tomography.^[17]

Brain

File:CNR1, ISH, mouse.jpg

Cnr1 is widely expressed in all major regions of the postnatal day 14 mouse brain, but is conspicuously absent in much of the thalamus. Allen Brain Atlases

CB₁ receptors are expressed most densely in the central nervous system and are largely responsible for mediating the effects of cannabinoid binding in the brain. Endocannabinoids released by a depolarized neuron bind to CB₁ receptors on pre-synaptic glutamatergic and GABAergic neurons, resulting in a respective decrease in either glutamate or GABA release. Limiting glutamate release causes reduced excitation, while limiting GABA release suppresses inhibition, a common form of short-term plasticity in which the depolarization of a single neuron induces a reduction in GABA-mediated inhibition, in effect exciting the postsynaptic cell.^[11]

Varying levels of CB₁ expression can be detected in the olfactory bulb, cortical regions (neocortex, pyriform cortex, hippocampus, and amygdala), several parts of basal ganglia, thalamic and hypothalamic nuclei, and other subcortical regions (e.g., the septal region), cerebellar cortex, and brainstem nuclei (e.g., the periaqueductal gray).^[10]

Hippocampal formation

CB₁ mRNA transcripts are abundant in GABAergic interneurons of the hippocampus, indirectly reflecting the expression of these receptors and elucidating the established effect of cannabinoids on memory. These receptors are densely located in cornu ammonis pyramidal cells, which are known to release glutamate. Cannabinoids suppress the induction of LTP and LTD in the hippocampus by inhibiting these glutamatergic neurons. By reducing the concentration of glutamate released below the threshold necessary to depolarize the postynaptic receptor NMDA,^[11] a receptor known to be directly related to the induction of LTP and LTD, cannabinoids are a crucial factor in the selectivity of memory. These receptors are highly expressed by GABAergic interneurons as well as glutamatergic principal neurons. However, a higher density is found within GABAergic cells.^[18] This means that, although synaptic strength/frequency, and thus potential to induce LTP, is lowered, net hippocampal activity is raised. In addition, CB₁ receptors in the hippocampus indirectly inhibit the release of acetylcholine. This serves as the modulatory axis opposing GABA, decreasing neurotransmitter release. Cannabinoids also likely play an important role in the development of memory through their neonatal promotion of myelin formation, and thus the individual segregation of axons.

Basal ganglia

CB₁ receptors are expressed throughout the basal ganglia and have well-established effects on movement in rodents. As in the hippocampus, these receptors inhibit the release of glutamate or GABA transmitter, resulting in decreased excitation or reduced inhibition based on the cell they are expressed in. Consistent with the variable expression of both excitatory glutamate and inhibitory GABA interneurons in both the basal ganglia's direct and indirect motor loops, synthetic cannabinoids are known to influence this system in a dose-dependent triphasic pattern. Decreased locomotor activity is seen at both higher and lower concentrations of applied cannabinoids, whereas an enhancement of movement may occur upon moderate dosages.^[11] However, these dose-dependent effects have been studied predominately in rodents, and the physiological basis for this triphasic pattern warrants future research in humans. Effects may vary based on the site of cannabinoid application, input from higher cortical centers, and whether drug application is unilateral or bilateral.

Cerebellum and neocortex

The role of the CB₁ receptor in the regulation of motor movements is complicated by the additional expression of this receptor in the cerebellum and neocortex, two regions associated with the coordination and initiation of movement. Research suggests that anandamide is synthesized by Purkinje cells and acts on presynaptic receptors to inhibit glutamate release from granule cells or GABA release from the terminals of basket cells. In the neocortex, these receptors are concentrated on local interneurons in cerebral layers II-III and V-VI.^[11] Compared to rat brains, humans express more CB₁ receptors in the cerebral cortex and amygdala and less in the cerebellum, which may help explain why motor function seems to be more compromised in rats than humans upon cannabinoid application.^[18]

Spine

Many of the documented analgesic effects of cannabinoids are based on the interaction of these compounds with CB₁ receptors on spinal cord interneurons in the superficial levels of the dorsal horn, known for its role in nociceptive processing. In particular, the CB₁ is heavily expressed in layers 1 and 2 of the spinal cord dorsal horn and in lamina 10 by the central canal. Dorsal root ganglion also express these receptors, which target a variety of peripheral terminals involved in nociception. Signals on this track are also transmitted to the periaqueductal gray (PAG) of the midbrain. Endogenous cannabinoids are believed to exhibit an analgesic effect on these receptors by limiting both GABA and glutamate of PAG cells that relate to nociceptive input processing, a hypothesis consistent with the finding that anandamide release in the PAG is increased in response to pain-triggering stimuli.^[11]

Other

CB₁ is expressed on several types of cell in pituitary gland, thyroid gland, and possibly in the adrenal gland.^[10] CB₁ is also expressed in several cells relating to metabolism, such as fat cells, muscle cells, liver cells (and also in the endothelial cells, Kupffer cells and stellate cells of the liver), and in the digestive tract.^[10] These receptor also expressed in the lungs and the kidney.

CB₁ is present on Leydig cells and human sperms. In females, it is present in the ovaries, oviducts myometrium, decidua, and placenta. It has also been implicated in the proper development of the embryo.^[10]

Function

Health and disease

Several studies have implicated the CB₁ receptor in the maintenance of homeostasis in health and disease. In a rodent neuropathic pain model, increased expression of these receptors was seen in thalamic neurons, the spinal cord, and dorsal root ganglion.^[18] Increased receptor expression has also been found in human hepatocellular carcinoma tumor samples and other human prostate cancer cells. The expression of these receptors is believed to modulate neurotransmitter release in a manner that prevents the development of excessive neuronal activity, reducing pain and other inflammatory symptoms. This finding is consistent with the localization of CB₁ receptors to the terminals of central and peripheral neurons, and the established mediation of both excitatory and inhibitory neurotransmitters acetylcholine, noradrenaline, dopamine, 5-HT, GABA, glutamate, D-aspartate, and cholecystokinin.^[18] Through its primary action as a G_i coupled receptor, CB1 inhibits production of cyclic adenosine monophosphate (cAMP), metabotropically inhibiting all NT release.

Enhanced receptor expression following disease has been found to result in a leftward shift in the log dose-response curve of cannabinol, and also an increase in the size of its maximal effects.^[18]

Anxiety response to novelty

A CB₁ receptor knock-out mouse study examined the effect that these receptors play on exploratory behavior in novel situations. Researchers selectively targeted glutamatergic and GABAergic cortical interneurons and studied results in open field, novel object, and sociability tests. Eliminating glutamatergic cannabinoid receptors led to decreased object exploration, social interactions, and increased aggressive behavior. In contrast, GABAergic cannabinoid receptor-knockout mice showed increased exploration of objects, socialization, and open field movement.^[19] These opposing effects reveal the importance of the endocannabinoid system in regulating anxiety-dependent behavior. Glutamatergic CB₁receptors not only are responsible for mediating aggression but produce anxiolytic-like function by inhibiting excessive arousal, which prevented the mice from exploring both animate and inanimate objects. In contrast, GABAergic CB₁ receptors appear to control an anxiogenic-like function by limiting inhibitory transmitter release. Taken together, these results illustrate the regulatory function of the CB₁ receptor on the organism's overall sense of arousal during novel situations and suggest that investigatory drive is associated with impulsive behavior.

Another study found that differential synthesis of anandamide and 2-AG in response to stress mediated beneficial effects of the hypothalamic-pituitary-adrenal axis. These effects were eliminated by the application of the CB₁ antagonist AM251, illustrating that this receptor is essential for modulating the function of the stress response.^[20]

Gastrointestinal activity

Inhibition of gastrointestinal activity has been observed after administration of THC or anandamide. This effect is assumed to be CB₁-mediated, since this receptor is expressed by the peptide hormone cholecystokinin, and application of the CB₁-specific inverse agonist SR 141716A (Rimonabant) blocks the effect. Another report, however, suggests that inhibition of intestinal motility may also have a CB₂-mediated component.^[21]

The CB₁ receptor inverse agonist rimonabant has been found to reduce intake of food or sweet solutions in both humans and mice. Targeting this receptor with rimonabant has been found to prevent the THC-induced enhancement of DA release in the nucleus accumbens shell from food, suggesting that these receptors may be involved in determining the hedonic value of food.^[22] In addition, CB1 facilitates ghrelin release, normally happening when the stomach is constricted In the presence of a relatively active system, overeating is promoted. This is the genesis of its appetite-stimulating effects, colloquially called "the munchies."

Cardiovascular activity

Cannabinoids are well known for their cardiovascular activity. Activation of peripheral CB1 receptors contributes to hemorrhagic and endotoxin-induced hypotension.^[23] Anandamide and 2-AG, produced by macrophages and platelets, respectively, may mediate this effect.^[23] A likely candidate for this function is the heterodimer of CB1 and adenosine 2a. Through an opposing mechanism of action (A2A elevates cAMP), together, they may serve to regulate cardiac blood supply, and thus output.

Plasticity

CB1 induction of LTD and STD have been shown in the Dorsal striatum, Amygdala, Prefrontal cortex, Ventral tegmental area, and the BNST.^[24] A recent study compared the endocannabinoid induction of LTD and STD in the bed nucleus of the stria terminalis (BNST) and striatum. Results found that both short- and long-term effects were dependent on CB₁ receptor activation in the striatum, whereas LTD induction in the BNST relied on TRPV1 receptor. Effects vary based on the endocannabinoid molecule: 2-AG was found to act on presynaptic CB₁ receptors to mediate retrograde short-term depression following activation of L-type calcium currents, whereas anandamide was synthesized after mGluR5 activation and triggered autocrine signalling that induced long-term depression.^[25] These findings demonstrate the CB₁ receptor as a direct mechanism for the brain to selectively inhibit neuronal excitability over variable time scales. By selectively internalizing different receptors, the brain may limit the production of specific endocannabinoids to favor a time scale in accordance with its needs. mGlu5 forms a heterodimer with A2A, which allows endocannabinoids to regulate their own levels, as they inhibit cAMP production, thus increase free adenosine to agonise A2A. This forms a feedback loop between the positive and negative metabotropic receptors, which can maintain a relatively similar homeostasis with any neuron connected through an electrical synapse.

Motor control

CB₁ receptors are expressed throughout motor regions of the mammalian brain, suggesting that CB₁ has a role in motor control. CB₁ activation has been shown to effect specific kinematic variables in rodents, such as the rate of applied force during lever pressing,^[26] and the amplitude (but not timing) of whisker movements.^[27]

Drug and behavioral addictions

Several recent reviews on CB1 receptors and addiction have indicated that CB1 receptor activation reinstates drug seeking behavior in addicts.^[28]^[29]^[30] In humans, this results from the influence that limbic CB1 receptors have on mesolimbic dopamine neurons, specifically dopamine receptors in the nucleus accumbens.^[30] As a consequence, CB1 receptor antagonists can reduce drug seeking behavior in some addicts.^[28]^[29]^[30]

Olfaction

The CB₁ receptor is expressed by a number of neurons that project from the anterior olfactory nucleus to the ipsilateral main olfactory bulb. However, the effects of cannabinoids on synaptic activity in these neurons has not been well-studied and its effects on olfaction warrant further research in rodents.^[11] Cannabinoids are not known to have effects on olfaction in humans. However, as with the rest of the brain, it plays a crucial role in modulation of NT release.

Use of antagonists

Selective CB₁ agonists may be used to isolate the effects of the receptor from the CB₂ receptor, as most cannabinoids and endocannabinoids bind to both receptor types.^[11] CB₁ selective antagonists are used for weight reduction and smoking cessation (see Rimonabant). A substantial number of antagonists of the CB1 receptor have been discovered and characterized. TM38837 has been developed as a CB1 receptor antagonist that is restricted to targeting only peripheral CB1 receptors.

Ligands

Agonists

Selective

Unspecified efficacy

Partial

Endogenous

2-Arachidonyl glyceryl ether

Phyto/synthetic

Full

Endogenous

2-Arachidonoylglycerol

Phyto/synthetic

Allosteric agonist

GAT228^[32]

Antagonists

Cannabigerol
Ibipinabant
Otenabant
Tetrahydrocannabivarin
Virodhamine (Endogenous CB1 antagonist and CB2 agonist)

Inverse agonists

Allosteric modulators

Lipoxin A4 – endogenous, PAM
ZCZ-011 – PAM
Pregnenolone – endogenous, NAM
Cannabidiol – NAM^[18]
Fenofibrate – NAM
GAT100 – NAM
PSNCBAM-1 – NAM
RVD-Hpα – NAM

Binding affinities

	CB₁ affinity (K_i)	Efficacy towards CB₁	CB₂ affinity (K_i)	Efficacy towards CB₂	Type	References
Anandamide	78 nM	Partial agonist	370 nM	Partial agonist	Endogenous
N-Arachidonoyl dopamine	250 nM	Agonist	12000 nM	?	Endogenous	^[33]
2-Arachidonoylglycerol	58.3 nM	Full agonist	145 nM	Full agonist	Endogenous	^[33]
2-Arachidonyl glyceryl ether	21 nM	Full agonist	480 nM	Full agonist	Endogenous
Tetrahydrocannabinol	10 nM	Partial agonist	24 nM	Partial agonist	Phytogenic	^[34]^[34]
EGCG	33.6 μM	Agonist	>50 μM	?	Phytogenic
AM-1221	52.3 nM	Agonist	0.28 nM	Agonist	Synthetic	^[35]
AM-1235	1.5 nM	Agonist	20.4 nM	Agonist	Synthetic	^[36]
AM-2232	0.28 nM	Agonist	1.48 nM	Agonist	Synthetic	^[36]
UR-144	150 nM	Full agonist	1.8 nM	Full agonist	Synthetic	^[37]
JWH-007	9.0 nM	Agonist	2.94 nM	Agonist	Synthetic	^[38]
JWH-015	383 nM	Agonist	13.8 nM	Agonist	Synthetic	^[38]
JWH-018	9.00 ± 5.00 nM	Full agonist	2.94 ± 2.65 nM	Full agonist	Synthetic	^[39]

Evolution

The CNR1 gene is used in animals as a nuclear DNA phylogenetic marker.^[16] This intronless gene has first been used to explore the phylogeny of the major groups of mammals,^[40] and contributed to reveal that placental orders are distributed into five major clades: Xenarthra, Afrotheria, Laurasiatheria, Euarchonta, and Glires. CNR1 has also proven useful at lower taxonomic levels, such as rodents,^[41]^[42] and for the identification of dermopterans as the closest primate relatives.^[43]

References

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↑ Laprairie RB, Kulkarni PM, Deschamps JR, Kelly ME, Janero DR, Cascio MG, Stevenson LA, Pertwee RG, Kenakin TP, Denovan-Wright EM, Thakur GA (February 2017). "Enantiospecific Allosteric Modulation of Cannabinoid 1 Receptor". ACS Chemical Neuroscience. doi:10.1021/acschemneuro.6b00310. PMID 28103441.
↑ ^33.0 ^33.1 Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, Greasley PJ, Hansen HS, Kunos G, Mackie K, Mechoulam R, Ross RA (December 2010). "International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂". Pharmacological Reviews. 62 (4): 588–631. doi:10.1124/pr.110.003004. PMC 2993256. PMID 21079038.
↑ ^34.0 ^34.1 "PDSP Database - UNC". Archived from the original on 8 November 2013. Retrieved 11 June 2013.
↑ WO patent 200128557, Makriyannis A, Deng H, "Cannabimimetic indole derivatives", granted 2001-06-07
↑ ^36.0 ^36.1 US patent 7241799, Makriyannis A, Deng H, "Cannabimimetic indole derivatives", granted 2007-07-10
↑ Frost JM, Dart MJ, Tietje KR, Garrison TR, Grayson GK, Daza AV, El-Kouhen OF, Yao BB, Hsieh GC, Pai M, Zhu CZ, Chandran P, Meyer MD (January 2010). "Indol-3-ylcycloalkyl ketones: effects of N1 substituted indole side chain variations on CB(2) cannabinoid receptor activity". Journal of Medicinal Chemistry. 53 (1): 295–315. doi:10.1021/jm901214q. PMID 19921781.
↑ ^38.0 ^38.1 Aung MM, Griffin G, Huffman JW, Wu M, Keel C, Yang B, Showalter VM, Abood ME, Martin BR (August 2000). "Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB(1) and CB(2) receptor binding". Drug and Alcohol Dependence. 60 (2): 133–40. doi:10.1016/S0376-8716(99)00152-0. PMID 10940540.
↑ Aung MM, Griffin G, Huffman JW, Wu M, Keel C, Yang B, Showalter VM, Abood ME, Martin BR (August 2000). "Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB(1) and CB(2) receptor binding". Drug and Alcohol Dependence. 60 (2): 133–40. doi:10.1016/s0376-8716(99)00152-0. PMID 10940540.
↑ Murphy WJ, Eizirik E, Johnson WE, Zhang YP, Ryder OA, O'Brien SJ (February 2001). "Molecular phylogenetics and the origins of placental mammals". Nature. 409 (6820): 614–8. doi:10.1038/35054550. PMID 11214319.
↑ Blanga-Kanfi S, Miranda H, Penn O, Pupko T, DeBry RW, Huchon D (April 2009). "Rodent phylogeny revised: analysis of six nuclear genes from all major rodent clades". BMC Evolutionary Biology. 9: 71. doi:10.1186/1471-2148-9-71. PMC 2674048. PMID 19341461.
↑ DeBry RW (October 2003). "Identifying conflicting signal in a multigene analysis reveals a highly resolved tree: the phylogeny of Rodentia (Mammalia)". Systematic Biology. 52 (5): 604–17. doi:10.1080/10635150390235403. PMID 14530129.
↑ Janecka JE, Miller W, Pringle TH, Wiens F, Zitzmann A, Helgen KM, Springer MS, Murphy WJ (November 2007). "Molecular and genomic data identify the closest living relative of primates". Science. 318 (5851): 792–4. Bibcode:2007Sci...318..792J. doi:10.1126/science.1147555. PMID 17975064.

External links

"Cannabinoid Receptors: CB₁". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

[1] Thomas, Adèle; Stevenson, Lesley A; Wease, Kerrie N; Price, Martin R; Baillie, Gemma; Ross, Ruth A; Pertwee, Roger G (December 2005). "Evidence that the plant cannabinoid Δ9-tetrahydrocannabivarin is a cannabinoid CB1 and CB2 receptor antagonist". British Journal of Pharmacology. 146 (7): 917–926. doi:10.1038/sj.bjp.0706414. ISSN 0007-1188. PMC 1751228. PMID 16205722.

[2] Pertwee, R G; Thomas, A; Stevenson, L A; Ross, R A; Varvel, S A; Lichtman, A H; Martin, B R; Razdan, R K (March 2007). "The psychoactive plant cannabinoid, Δ9-tetrahydrocannabinol, is antagonized by Δ8- and Δ9-tetrahydrocannabivarin in mice in vivo". British Journal of Pharmacology. 150 (5): 586–594. doi:10.1038/sj.bjp.0707124. ISSN 0007-1188. PMC 2189766. PMID 17245367.

[pmid27851727-3] Shao Z, Yin J, Chapman K, Grzemska M, Clark L, Wang J, Rosenbaum DM (2016). "High-resolution crystal structure of the human CB1 cannabinoid receptor". Nature. doi:10.1038/nature20613. PMC 5433929. PMID 27851727.

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[pmid16570099-5] 5.0 ^5.1 ^5.2 ^5.3 Pertwee RG (April 2006). "The pharmacology of cannabinoid receptors and their ligands: an overview". International Journal of Obesity. 30 Suppl 1: S13–8. doi:10.1038/sj.ijo.0803272. PMID 16570099.

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[2AG-33] 33.0 ^33.1 Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, Greasley PJ, Hansen HS, Kunos G, Mackie K, Mechoulam R, Ross RA (December 2010). "International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂". Pharmacological Reviews. 62 (4): 588–631. doi:10.1124/pr.110.003004. PMC 2993256. PMID 21079038.

[whoa-34] 34.0 ^34.1 "PDSP Database - UNC". Archived from the original on 8 November 2013. Retrieved 11 June 2013.

[dude-35] WO patent 200128557, Makriyannis A, Deng H, "Cannabimimetic indole derivatives", granted 2001-06-07

[like-36] 36.0 ^36.1 US patent 7241799, Makriyannis A, Deng H, "Cannabimimetic indole derivatives", granted 2007-07-10

[myhandsareamazing-37] Frost JM, Dart MJ, Tietje KR, Garrison TR, Grayson GK, Daza AV, El-Kouhen OF, Yao BB, Hsieh GC, Pai M, Zhu CZ, Chandran P, Meyer MD (January 2010). "Indol-3-ylcycloalkyl ketones: effects of N1 substituted indole side chain variations on CB(2) cannabinoid receptor activity". Journal of Medicinal Chemistry. 53 (1): 295–315. doi:10.1021/jm901214q. PMID 19921781.

[puff-38] 38.0 ^38.1 Aung MM, Griffin G, Huffman JW, Wu M, Keel C, Yang B, Showalter VM, Abood ME, Martin BR (August 2000). "Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB(1) and CB(2) receptor binding". Drug and Alcohol Dependence. 60 (2): 133–40. doi:10.1016/S0376-8716(99)00152-0. PMID 10940540.

[pass-39] Aung MM, Griffin G, Huffman JW, Wu M, Keel C, Yang B, Showalter VM, Abood ME, Martin BR (August 2000). "Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB(1) and CB(2) receptor binding". Drug and Alcohol Dependence. 60 (2): 133–40. doi:10.1016/s0376-8716(99)00152-0. PMID 10940540.

[pmid11214319-40] Murphy WJ, Eizirik E, Johnson WE, Zhang YP, Ryder OA, O'Brien SJ (February 2001). "Molecular phylogenetics and the origins of placental mammals". Nature. 409 (6820): 614–8. doi:10.1038/35054550. PMID 11214319.

[pmid19341461-41] Blanga-Kanfi S, Miranda H, Penn O, Pupko T, DeBry RW, Huchon D (April 2009). "Rodent phylogeny revised: analysis of six nuclear genes from all major rodent clades". BMC Evolutionary Biology. 9: 71. doi:10.1186/1471-2148-9-71. PMC 2674048. PMID 19341461.

[pmid14530129-42] DeBry RW (October 2003). "Identifying conflicting signal in a multigene analysis reveals a highly resolved tree: the phylogeny of Rodentia (Mammalia)". Systematic Biology. 52 (5): 604–17. doi:10.1080/10635150390235403. PMID 14530129.

[pmid17975064-43] Janecka JE, Miller W, Pringle TH, Wiens F, Zitzmann A, Helgen KM, Springer MS, Murphy WJ (November 2007). "Molecular and genomic data identify the closest living relative of primates". Science. 318 (5851): 792–4. Bibcode:2007Sci...318..792J. doi:10.1126/science.1147555. PMID 17975064.

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@@ Line 1: / Line 1: @@
-<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
+{{Infobox_gene}}
-{{PBB_Controls
+The '''cannabinoid receptor type 1''', often abbreviated as '''CB<sub>1</sub>''', is a [[G protein-coupled receptor|G protein-coupled]] [[cannabinoid receptor]] located primarily in the central and peripheral nervous system. It is activated by the [[endocannabinoid#Endocannabinoids|endocannabinoid]] [[neurotransmitter]]s [[anandamide]] and 2-arachidonoylglycerol ([[2-AG]]); by plant [[cannabinoid]]s, such as the compound [[tetrahydrocannabinol|THC]], an active ingredient of the [[psychoactive drug]] [[cannabis (drug)|cannabis]]; and by synthetic analogues of THC. CB1 and THC are deactivated by the phytocannabinoid [[tetrahydrocannabivarin]] (THCV).<ref>{{Cite journal|last=Thomas|first=Adèle|last2=Stevenson|first2=Lesley A|last3=Wease|first3=Kerrie N|last4=Price|first4=Martin R|last5=Baillie|first5=Gemma|last6=Ross|first6=Ruth A|last7=Pertwee|first7=Roger G|date=December 2005|title=Evidence that the plant cannabinoid Δ9-tetrahydrocannabivarin is a cannabinoid CB1 and CB2 receptor antagonist|journal=British Journal of Pharmacology|volume=146|issue=7|pages=917–926|doi=10.1038/sj.bjp.0706414|issn=0007-1188|pmc=1751228|pmid=16205722}}</ref><ref>{{Cite journal|last=Pertwee|first=R G|last2=Thomas|first2=A|last3=Stevenson|first3=L A|last4=Ross|first4=R A|last5=Varvel|first5=S A|last6=Lichtman|first6=A H|last7=Martin|first7=B R|last8=Razdan|first8=R K|date=March 2007|title=The psychoactive plant cannabinoid, Δ9-tetrahydrocannabinol, is antagonized by Δ8- and Δ9-tetrahydrocannabivarin in mice in vivo|journal=British Journal of Pharmacology|volume=150|issue=5|pages=586–594|doi=10.1038/sj.bjp.0707124|issn=0007-1188|pmc=2189766|pmid=17245367}}</ref>
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-<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
-{{GNF_Protein_box
- | image =
- | image_source =
- | PDB =
- | Name = Cannabinoid receptor 1 (brain)
- | HGNCid = 2159
- | Symbol = CNR1
- | AltSymbols =; CANN6; CB-R; CB1; CB1A; CB1K5; CNR
- | OMIM = 114610
- | ECnumber =
- | Homologene = 7273
- | MGIid = 104615
- | GeneAtlas_image1 = PBB_GE_CNR1_213436_at_tn.png
- | GeneAtlas_image2 =
- | GeneAtlas_image3 =
- | Function = {{GNF_GO|id=GO:0004872 |text = receptor activity}} {{GNF_GO|id=GO:0004949 |text = cannabinoid receptor activity}}
- | Component = {{GNF_GO|id=GO:0005886 |text = plasma membrane}} {{GNF_GO|id=GO:0005887 |text = integral to plasma membrane}}
- | Process = {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007187 |text = G-protein signaling, coupled to cyclic nucleotide second messenger}} {{GNF_GO|id=GO:0007610 |text = behavior}}
- | Orthologs = {{GNF_Ortholog_box
-    | Hs_EntrezGene = 1268
-    | Hs_Ensembl = ENSG00000118432
-    | Hs_RefseqProtein = NP_057167
-    | Hs_RefseqmRNA = NM_016083
-    | Hs_GenLoc_db =
-    | Hs_GenLoc_chr = 6
-    | Hs_GenLoc_start = 88906302
-    | Hs_GenLoc_end = 88932385
-    | Hs_Uniprot = P21554
-    | Mm_EntrezGene = 12801
-    | Mm_Ensembl = ENSMUSG00000044288
-    | Mm_RefseqmRNA = NM_007726
-    | Mm_RefseqProtein = NP_031752
-    | Mm_GenLoc_db =
-    | Mm_GenLoc_chr = 4
-    | Mm_GenLoc_start = 34253206
-    | Mm_GenLoc_end = 34277444
-    | Mm_Uniprot = Q99NU3
-  }}
-}}
-The '''cannabinoid receptor type 1''', also known '''CB<sub>1</sub>''', is a [[G protein-coupled receptor|G protein-coupled]] [[cannabinoid receptor]] that is found in the [[brain]] and is activated by the [[psychoactive drug]] [[cannabis (drug)|cannabis]] and its active compound [[tetrahydrocannabinol|THC]] and by a group of [[endocannabinoid#Endocannabinoids|endocannabinoid]] [[neurotransmitter]]s including [[anandamide]].
-== Expression ==
+==Structure==
+The CB<sub>1</sub> receptor shares the structure characteristic of all G-protein-coupled receptors, possessing seven transmembrane domains connected by three extracellular and three intracellular loops, an extracellular N-terminal tail, and an intracellular C-terminal tail.<ref name="pmid27851727">{{cite journal |vauthors=Shao Z, Yin J, Chapman K, Grzemska M, Clark L, Wang J, Rosenbaum DM |title=High-resolution crystal structure of the human CB1 cannabinoid receptor |journal=Nature |volume= |issue= |pages= |year=2016 |pmid=27851727 |pmc=5433929 |doi=10.1038/nature20613 |url=}}</ref><ref name="pmid27768894">{{cite journal |vauthors=Hua T, Vemuri K, Pu M, Qu L, Han GW, Wu Y, Zhao S, Shui W, Li S, Korde A, Laprairie RB, Stahl EL, Ho JH, Zvonok N, Zhou H, Kufareva I, Wu B, Zhao Q, Hanson MA, Bohn LM, Makriyannis A, Stevens RC, Liu ZJ |title=Crystal Structure of the Human Cannabinoid Receptor CB1 |journal=Cell |volume=167 |issue=3 |pages=750–762.e14 |year=2016 |pmid=27768894 |doi=10.1016/j.cell.2016.10.004 |url=}}</ref> The receptor may exist as a [[homodimer]] or form [[heterodimer]]s or other [[GPCR oligomer]]s with different [[G protein–coupled receptor#Classification|classes of G-protein-coupled receptors]]. Observed heterodimers include A<sub>2A</sub>–CB<sub>1</sub>, CB<sub>1</sub>–D<sub>2</sub>, OX<sub>1</sub>–CB<sub>1</sub>, while many more may only be stable enough to exist in vivo.<ref name="pmid16570099">{{cite journal | vauthors = Pertwee RG | title = The pharmacology of cannabinoid receptors and their ligands: an overview | journal = International Journal of Obesity | volume = 30 Suppl 1 | pages = S13-8 | date = April 2006 | pmid = 16570099 | doi = 10.1038/sj.ijo.0803272 }}</ref> The CB<sub>1</sub> receptor possesses an [[allosteric modulator]]y [[binding site]].<ref name="pmid24076101">{{cite journal | vauthors = Nickols HH, Conn PJ | title = Development of allosteric modulators of GPCRs for treatment of CNS disorders | journal = Neurobiology of Disease | volume = 61 | issue =  | pages = 55–71 | date = January 2014 | pmid = 24076101 | pmc = 3875303 | doi = 10.1016/j.nbd.2013.09.013 }}</ref><ref name="pmid27879006">{{cite journal | vauthors = Nguyen T, Li JX, Thomas BF, Wiley JL, Kenakin TP, Zhang Y | title = Allosteric Modulation: An Alternate Approach Targeting the Cannabinoid CB1 Receptor | journal = Medicinal Research Reviews | volume =  37| issue =  | date = November 2016 | pmid = 27879006 | doi = 10.1002/med.21418 | pages=441–474}}</ref>
-The CB<sub>1</sub> receptor is encoded by the gene or ''CNR1''.<ref name="entrez">{{cite web | title = Entrez Gene: CNR1 cannabinoid receptor 1 (brain)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1268| accessdate = }}</ref> Two transcript variants encoding different isoforms have been described for this gene.<ref name="entrez">{{cite web | title = Entrez Gene: CNR1 cannabinoid receptor 1 (brain)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1268| accessdate = }}</ref>
+==Mechanism==
+The CB<sub>1</sub> receptor is a pre-synaptic [[heteroreceptor]] that modulates neurotransmitter release when activated in a dose-dependent, stereoselective and pertussis toxin-sensitive manner.<ref name="entrez" /> The CB<sub>1</sub> receptor is activated by [[cannabinoids]], generated naturally inside the body ([[Cannabinoids#Endocannabinoids|endocannabinoids]]) or introduced into the body as [[cannabis (drug)|cannabis]] or a related [[Chemical synthesis|synthetic]] compound.
-=== Brain ===
+Research suggests that the majority of CB<sub>1</sub> receptors are coupled through G<sub>i/o</sub> proteins. Upon activation, CB<sub>1</sub> receptor exhibits its effects mainly through activation of [[Gi alpha subunit|G<sub>i</sub>]], which decreases intracellular cAMP concentration by inhibiting its production [[enzyme]], [[adenylate cyclase]], and increases [[mitogen-activated protein kinase]] (MAP kinase) concentration. Alternatively, in some rare cases CB<sub>1</sub> receptor activation may be coupled to [[Gs alpha subunit|G<sub>s</sub>]] proteins, which stimulate [[adenylate cyclase]].<ref name="pmid16570099" /> cAMP is known to serve as a second messenger coupled to a variety of ion channels, including the positively influenced [[Inward-rectifier potassium ion channel|inwardly rectifying potassium channels]] (=Kir or IRK),<ref name="pmid16109430">{{cite journal | vauthors = Demuth DG, Molleman A | title = Cannabinoid signalling | journal = Life Sciences | volume = 78 | issue = 6 | pages = 549–63 | date = January 2006 | pmid = 16109430 | doi = 10.1016/j.lfs.2005.05.055 }}</ref> and [[calcium channel]]s, which are activated by cAMP-dependent interaction with such molecules as [[protein kinase A]] (PKA), [[protein kinase C]] (PKC), [[C-Raf|Raf-1]], [[Extracellular signal-regulated kinases|ERK]], [[JNK]], [[p38 mitogen-activated protein kinases|p38]], [[c-fos]], [[c-jun]], and others.<ref name="endocrino" /> In terms of function, the inhibition of intracellular cAMP expression shortens the duration of pre-synaptic action potentials by  prolonging the rectifying potassium A-type currents, which is normally inactivated upon phosphorylation by PKA. This inhibition grows more pronounced when considered with the effect of activated CB<sub>1</sub> receptors to limit calcium entry into the cell, which does not occur through cAMP but by a direct G-protein-mediated inhibition. As presynaptic calcium entry is a requirement for vesicle release, this function will decrease the transmitter that enters the synapse upon release.<ref name="pmid11316486">{{cite journal | vauthors = Elphick MR, Egertová M | title = The neurobiology and evolution of cannabinoid signalling | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 356 | issue = 1407 | pages = 381–408 | date = March 2001 | pmid = 11316486 | pmc = 1088434 | doi = 10.1098/rstb.2000.0787 }}</ref> The relative contribution of each of these two inhibitory mechanisms depends on the variance of ion channel expression by cell type.
-CB<sub>1</sub> receptors are thought to be the most widely [[gene expression|expressed]] G protein-coupled receptors in the brain. This is key to endocannabinoid-mediated [[depolarization-induced suppression of inhibition]], a very common form of short-term [[synaptic plasticity|plasticity]] in which the depolarization of a single neuron induces a reduction in [[GABA]]-mediated neurotransmission. Endocannabinoids released from the depolarized neuron bind to CB<sub>1</sub> receptors in the pre-synaptic neuron and cause a reduction in GABA release. Varying levels of CB<sub>1</sub> expression can be detected in the [[olfactory bulb]], [[Cerebral cortex|cortical]] regions ([[neocortex]], [[Piriform cortex|pyriform cortex]], [[hippocampus]], and [[amygdala]]), several parts of [[basal ganglia]], [[thalamus|thalamic]] and [[hypothalamus|hypothalamic]] nuclei and other subcortical regions (''e.g.'' the [[septal nuclei|septal region]]), [[cerebellar cortex]], and [[brainstem]] nuclei (''e.g.'' the [[periaqueductal gray]]).<ref name="endocrino">{{cite journal | author = Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R | title = The emerging role of the endocannabinoid system in endocrine regulation and energy balance | journal = Endocr. Rev. | volume = 27 | issue = 1 | pages = 73–100 | year = 2006 | pmid = 16306385 | doi = 10.1210/er.2005-0009 | issn = }}</ref>
+The CB<sub>1</sub> receptor can also be modulated by [[allosteric]]ally synthetic ligands<ref name="pmid16113085">{{cite journal | vauthors = Price MR, Baillie GL, Thomas A, Stevenson LA, Easson M, Goodwin R, McLean A, McIntosh L, Goodwin G, Walker G, Westwood P, Marrs J, Thomson F, Cowley P, Christopoulos A, Pertwee RG, Ross RA | title = Allosteric modulation of the cannabinoid CB1 receptor | journal = Molecular Pharmacology | volume = 68 | issue = 5 | pages = 1484–95 | date = November 2005 | pmid = 16113085 | doi = 10.1124/mol.105.016162 }}</ref>  in a positive<ref name="pmid19226282">{{cite journal | vauthors = Navarro HA, Howard JL, Pollard GT, Carroll FI | title = Positive allosteric modulation of the human cannabinoid (CB) receptor by RTI-371, a selective inhibitor of the dopamine transporter | journal = British Journal of Pharmacology | volume = 156 | issue = 7 | pages = 1178–84 | date = April 2009 | pmid = 19226282 | pmc = 2697692 | doi = 10.1111/j.1476-5381.2009.00124.x }}</ref> and negative<ref name="pmid17592509">{{cite journal | vauthors = Horswill JG, Bali U, Shaaban S, Keily JF, Jeevaratnam P, Babbs AJ, Reynet C, Wong Kai In P | title = PSNCBAM-1, a novel allosteric antagonist at cannabinoid CB1 receptors with hypophagic effects in rats | journal = British Journal of Pharmacology | volume = 152 | issue = 5 | pages = 805–14 | date = November 2007 | pmid = 17592509 | pmc = 2190018 | doi = 10.1038/sj.bjp.0707347 }}</ref> manner. ''[[In vivo]]'' exposure to [[THC]] impairs [[long-term potentiation]] and leads to a reduction of phosphorylated [[CREB]].<ref name="neurochem">{{cite journal | vauthors = Fan N, Yang H, Zhang J, Chen C | title = Reduced expression of glutamate receptors and phosphorylation of CREB are responsible for in vivo Δ<sup>9</sup>-THC exposure-impaired hippocampal synaptic plasticity | journal = Journal of Neurochemistry | volume = 112 | issue = 3 | pages = 691–702 | date = February 2010 | pmid = 19912468 | pmc = 2809144 | doi = 10.1111/j.1471-4159.2009.06489.x }}</ref>
-=== Other ===
+In summary, CB<sub>1</sub> receptor activity has been found to be coupled to certain ion channels, in the following manner:<ref name="pmid16570099" />
+* Positively to inwardly rectifying and A-type outward potassium channels.
+* Negatively to D-type outward potassium channels
+* Negatively to N-type and P/Q-type calcium channels.
-CB<sub>1</sub> is expressed on several cell types of the [[pituitary gland]], in the [[thyroid gland]], and most likely in the [[adrenal gland]].<ref name="endocrino" /> CB<sub>1</sub> is also expressed in several cells relating to metabolism, such as [[Adipocyte|fat cells]], [[Muscle fiber|muscle cells]], [[Hepatocyte|liver cells]] (and also in the [[Endothelium|endothelial cells]], [[Kupffer cell]]s and [[Hepatic stellate cell|stellate cells]] of the [[liver]]), and in the [[Gastrointestinal tract|digestive tract]].<ref name="endocrino" /> It is also expressed in the [[lungs]] and the [[kidney]].
+==Expression==
+The CB<sub>1</sub> receptor is encoded by the gene ''CNR1,''<ref name="entrez">{{cite web |title=Entrez Gene: CNR1 cannabinoid receptor 1 (brain) |url=https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1268 |accessdate=}}</ref> located on human chromosome 6.<ref name="pmid11316486" /> Two transcript variants encoding different isoforms have been described for this gene.<ref name="entrez" /> CNR1 [[orthologs]]<ref name="OrthoMaM">{{cite web |title=OrthoMaM phylogenetic marker: CNR1 coding sequence |url=http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000118432_CNR1.xml}}</ref> have been identified in most [[mammals]].
-CB<sub>1</sub> is present on [[Leydig cells]] and human [[Spermatozoon|sperms]]. In [[females]], it is present in the [[ovarium|ovaries]], [[oviduct]]s [[myometrium]], [[decidua]] and [[placenta]]. It is probably important also for the [[embryo]].<ref name="endocrino" />
+The CB<sub>1</sub> receptor is expressed pre-synaptically at both glutaminergic and GABAergic interneurons and, in effect, acts as a [[neuromodulator]] to inhibit release of [[glutamate]] and [[GABA]].<ref name="pmid11316486" /> Repeated administration of receptor agonists may result in receptor internalization and/ or a reduction in receptor protein signalling.<ref name="pmid16570099" />
-=== Neuroimaging ===
+The [[inverse agonist]] [[MK-9470]] makes it possible to produce ''in vivo'' images of the distribution of CB<sub>1</sub> receptors in the human brain with [[positron emission tomography]].<ref name="pmid17535893">{{cite journal | vauthors = Burns HD, Van Laere K, Sanabria-Bohórquez S, Hamill TG, Bormans G, Eng WS, Gibson R, Ryan C, Connolly B, Patel S, Krause S, Vanko A, Van Hecken A, Dupont P, De Lepeleire I, Rothenberg P, Stoch SA, Cote J, Hagmann WK, Jewell JP, Lin LS, Liu P, Goulet MT, Gottesdiener K, Wagner JA, de Hoon J, Mortelmans L, Fong TM, Hargreaves RJ | title = [18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 23 | pages = 9800–5 | date = June 2007 | pmid = 17535893 | pmc = 1877985 | doi = 10.1073/pnas.0703472104 | bibcode = 2007PNAS..104.9800B }}</ref>
-The [[inverse agonist]] [[MK-9470]] makes it possible to produce ''in vivo'' images of the distribution of CB<sub>1</sub> receptors in the human brain with [[positron emission tomography]].<ref name="pmid17535893">{{cite journal | author = Burns HD, Van Laere K, Sanabria-Bohórquez S, Hamill TG, Bormans G, Eng WS, Gibson R, Ryan C, Connolly B, Patel S, Krause S, Vanko A, Van Hecken A, Dupont P, De Lepeleire I, Rothenberg P, Stoch SA, Cote J, Hagmann WK, Jewell JP, Lin LS, Liu P, Goulet MT, Gottesdiener K, Wagner JA, de Hoon J, Mortelmans L, Fong TM, Hargreaves RJ | title = [18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 104 | issue = 23 | pages = 9800–5 | year = 2007 | pmid = 17535893 | doi = 10.1073/pnas.0703472104 | issn = }}</ref>
+===Brain===
+[[File:CNR1, ISH, mouse.jpg|thumbnail|left|[http://developingmouse.brain-map.org/data/Cnr1/100015330.html?ispopup=true Cnr1] is widely expressed in all major regions of the postnatal day 14 mouse brain, but is conspicuously absent in much of the thalamus. [[Allen Brain Atlas]]es]]
+CB<sub>1</sub> receptors are expressed most densely in the central nervous system and are largely responsible for mediating the effects of cannabinoid binding in the brain.  Endocannabinoids released by a depolarized neuron bind to CB<sub>1</sub> receptors on pre-synaptic glutamatergic and GABAergic neurons, resulting in a respective decrease in either glutamate or GABA release. Limiting glutamate release causes reduced excitation, while limiting GABA release suppresses inhibition, a common form of short-term [[synaptic plasticity|plasticity]] in which the depolarization of a single neuron induces a reduction in [[GABA]]-mediated inhibition, in effect exciting the postsynaptic cell.<ref name="pmid11316486" />
+Varying levels of CB<sub>1</sub> expression can be detected in the [[olfactory bulb]], [[Cerebral cortex|cortical]] regions ([[neocortex]], [[Piriform cortex|pyriform cortex]], [[hippocampus]], and [[amygdala]]), several parts of [[basal ganglia]], [[thalamus|thalamic]] and [[hypothalamus|hypothalamic]] nuclei, and other subcortical regions (e.g., the [[septal nuclei|septal region]]), [[cerebellar cortex]], and [[brainstem]] nuclei (e.g., the [[periaqueductal gray]]).<ref name="endocrino">{{cite journal | vauthors = Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R | title = The emerging role of the endocannabinoid system in endocrine regulation and energy balance | journal = Endocrine Reviews | volume = 27 | issue = 1 | pages = 73–100 | date = February 2006 | pmid = 16306385 | doi = 10.1210/er.2005-0009 }}</ref>
+====Hippocampal formation====
+CB<sub>1</sub> mRNA transcripts are abundant in GABAergic interneurons of the hippocampus, indirectly reflecting the expression of these receptors and elucidating the established effect of cannabinoids on memory. These receptors are densely located in [[CA1-CA4|cornu ammonis]] pyramidal cells, which are known to release glutamate. Cannabinoids suppress the induction of LTP and LTD in the hippocampus by inhibiting these glutamatergic neurons. By reducing the concentration of glutamate released below the threshold necessary to depolarize the postynaptic receptor [[NMDA receptor|NMDA]],<ref name="pmid11316486" /> a receptor known to be directly related to the induction of LTP and LTD, cannabinoids are a crucial factor in the selectivity of memory.
+These receptors are highly expressed by GABAergic interneurons as well as glutamatergic principal neurons. However, a higher density is found within GABAergic cells.<ref name="pmid17828291">{{cite journal | vauthors = Pertwee RG | title = The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ<sup>9</sup>-tetrahydrocannabinol, cannabidiol and Δ<sup>9</sup>-tetrahydrocannabivarin | journal = British Journal of Pharmacology | volume = 153 | issue = 2 | pages = 199–215 | date = January 2008 | pmid = 17828291 | pmc = 2219532 | doi = 10.1038/sj.bjp.0707442 }}</ref> This means that, although synaptic strength/frequency, and thus potential to induce LTP, is lowered, net hippocampal activity is raised. In addition, CB<sub>1</sub> receptors in the hippocampus indirectly inhibit the release of [[acetylcholine]]. This serves as the modulatory axis opposing GABA, decreasing neurotransmitter release. Cannabinoids also likely play an important role in the development of memory through their neonatal promotion of [[myelin]] formation, and thus the individual segregation of axons.
+====Basal ganglia====
+CB<sub>1</sub> receptors are expressed throughout the [[basal ganglia]] and have well-established effects on movement in rodents. As in the hippocampus, these receptors inhibit the release of glutamate or GABA transmitter, resulting in decreased excitation or reduced inhibition based on the cell they are expressed in. Consistent with the variable expression of both excitatory glutamate and inhibitory GABA interneurons in both the basal ganglia's direct and indirect motor loops, synthetic cannabinoids are known to influence this system in a dose-dependent triphasic pattern. Decreased locomotor activity is seen at both higher and lower concentrations of applied cannabinoids, whereas an enhancement of movement may occur upon moderate dosages.<ref name="pmid11316486" />  However, these dose-dependent effects have been studied predominately in rodents, and the physiological basis for this triphasic pattern warrants future research in humans. Effects may vary based on the site of cannabinoid application, input from higher cortical centers, and whether drug application is unilateral or bilateral.
+====Cerebellum and neocortex====
+The role of the CB<sub>1</sub> receptor in the regulation of motor movements is complicated by the additional expression of this receptor in the [[cerebellum]] and [[neocortex]], two regions associated with the coordination and initiation of movement. Research suggests that anandamide is synthesized by Purkinje cells and acts on presynaptic receptors to inhibit glutamate release from granule cells or GABA release from the terminals of basket cells. In the neocortex, these receptors are concentrated on local interneurons in cerebral layers II-III and V-VI.<ref name="pmid11316486" /> Compared to rat brains, humans express more CB<sub>1</sub> receptors in the cerebral cortex and amygdala and less in the cerebellum, which may help explain why motor function seems to be more compromised in rats than humans upon cannabinoid application.<ref name="pmid17828291" />
+===Spine===
+Many of the documented analgesic effects of cannabinoids are based on the interaction of these compounds with CB<sub>1</sub> receptors on [[spinal cord]] interneurons in the superficial levels of the [[Posterior horn of spinal cord|dorsal horn]], known for its role in nociceptive processing. In particular, the CB<sub>1</sub> is heavily expressed in layers 1 and 2 of the spinal cord dorsal horn and in lamina 10 by the central canal. Dorsal root ganglion also express these receptors, which target a variety of peripheral terminals involved in nociception. Signals on this track are also transmitted to the [[periaqueductal gray]] (PAG) of the midbrain. Endogenous cannabinoids are believed to exhibit an analgesic effect on these receptors by limiting both GABA and glutamate of PAG cells that relate to nociceptive input processing, a hypothesis consistent with the finding that anandamide release in the PAG is increased in response to pain-triggering stimuli.<ref name="pmid11316486" />
+===Other===
+CB<sub>1</sub> is expressed on several types of cell in [[pituitary gland]], [[thyroid gland]], and possibly in the [[adrenal gland]].<ref name="endocrino" /> CB<sub>1</sub> is also expressed in several cells relating to metabolism, such as [[Adipocyte|fat cells]], [[Muscle fiber|muscle cells]], [[Hepatocyte|liver cells]] (and also in the [[Endothelium|endothelial cells]], [[Kupffer cell]]s and [[Hepatic stellate cell|stellate cells]] of the [[liver]]), and in the [[Gastrointestinal tract|digestive tract]].<ref name="endocrino" /> These receptor also expressed in the [[lungs]] and the [[kidney]].
+CB<sub>1</sub> is present on [[Leydig cells]] and human [[Spermatozoon|sperms]]. In [[females]], it is present in the [[ovarium|ovaries]], [[oviduct]]s [[myometrium]], [[decidua]], and [[placenta]]. It has also been implicated in the proper development of the [[embryo]].<ref name="endocrino" />
 == Function ==
-=== Liver ===
+===Health and disease===
+Several studies have implicated the CB<sub>1</sub> receptor in the maintenance of homeostasis in health and disease. In a rodent neuropathic pain model, increased expression of these receptors was seen in thalamic neurons, the spinal cord, and dorsal root ganglion.<ref name="pmid17828291" /> Increased receptor expression has also been found in human [[hepatocellular]] [[carcinoma]] tumor samples and other human [[prostate cancer]] cells. The expression of these receptors is believed to modulate neurotransmitter release  in a manner that prevents the development of excessive neuronal activity, reducing pain and other inflammatory symptoms. This finding is consistent with the localization of CB<sub>1</sub> receptors to the terminals of central and peripheral neurons, and the established mediation of both excitatory and inhibitory neurotransmitters [[acetylcholine]], [[noradrenaline]], [[dopamine]], [[5-HT]], [[GABA]], [[glutamate]], [[D-aspartate]], and [[cholecystokinin]].<ref name="pmid17828291" /> Through its primary action as a G<sub>i</sub> coupled receptor, CB1 inhibits production of [[cyclic adenosine monophosphate]] (cAMP), metabotropically inhibiting all NT release.
+Enhanced receptor expression following disease has been found to result in a leftward shift in the log dose-response curve of cannabinol, and also an increase in the size of its maximal effects.<ref name="pmid17828291" />
+===Anxiety response to novelty===
+A CB<sub>1</sub> receptor knock-out mouse study examined the effect that these receptors play on exploratory behavior in novel situations. Researchers selectively targeted glutamatergic and GABAergic cortical interneurons and studied results in open field, novel object, and sociability tests. Eliminating glutamatergic cannabinoid receptors led to decreased object exploration, social interactions, and increased aggressive behavior. In contrast, GABAergic cannabinoid receptor-knockout mice showed increased exploration of objects, socialization, and open field movement.<ref>{{cite journal | vauthors = Häring M, Kaiser N, Monory K, Lutz B | title = Circuit specific functions of cannabinoid CB1 receptor in the balance of investigatory drive and exploration | journal = PLoS One | volume = 6 | issue = 11 | pages = e26617 | year = 2011 | pmid = 22069458 | pmc = 3206034 | doi = 10.1371/journal.pone.0026617 | editor1-last = Burgess | bibcode = 2011PLoSO...626617H | editor1-first = Harold A. }}</ref> These opposing effects reveal the importance of the endocannabinoid system in regulating anxiety-dependent behavior. Glutamatergic CB<sub>1</sub>receptors not only are responsible for mediating aggression but produce anxiolytic-like function by inhibiting excessive arousal, which prevented the mice from exploring both animate and inanimate objects. In contrast, GABAergic CB<sub>1</sub> receptors appear to control an anxiogenic-like function by limiting inhibitory transmitter release. Taken together, these results illustrate the regulatory function of the CB<sub>1</sub> receptor on the organism's overall sense of arousal during novel situations and suggest that investigatory drive is associated with impulsive behavior.
+Another study found that differential synthesis of anandamide and 2-AG in response to stress mediated beneficial effects of the [[hypothalamic-pituitary-adrenal axis]]. These effects were eliminated by the application of the CB<sub>1</sub> antagonist [[AM251]], illustrating that this receptor is essential for modulating the function of the stress response.<ref>{{cite journal | vauthors = Hill MN, McLaughlin RJ, Bingham B, Shrestha L, Lee TT, Gray JM, Hillard CJ, Gorzalka BB, Viau V | title = Endogenous cannabinoid signaling is essential for stress adaptation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 20 | pages = 9406–11 | date = May 2010 | pmid = 20439721 | pmc = 2889099 | doi = 10.1073/pnas.0914661107 | bibcode = 2010PNAS..107.9406H }}</ref>
+===Gastrointestinal activity===
+Inhibition of [[Gastrointestinal tract|gastrointestinal]] activity has been observed after administration of [[THC]] or [[anandamide]]. This effect is assumed to be CB<sub>1</sub>-mediated, since this receptor is expressed by the [[peptide hormone]] [[cholecystokinin]], and application of the CB<sub>1</sub>-specific inverse agonist SR 141716A ([[Rimonabant]]) blocks the effect. Another report, however, suggests that inhibition of [[intestine|intestinal]] [[motility]] may also have a [[Cannabinoid receptor 2 (macrophage)|CB<sub>2</sub>]]-mediated component.<ref name="pmid15249429">{{cite journal | vauthors = Mathison R, Ho W, Pittman QJ, Davison JS, Sharkey KA | title = Effects of cannabinoid receptor-2 activation on accelerated gastrointestinal transit in lipopolysaccharide-treated rats | journal = British Journal of Pharmacology | volume = 142 | issue = 8 | pages = 1247–54 | date = August 2004 | pmid = 15249429 | pmc = 1575196 | doi = 10.1038/sj.bjp.0705889 }}</ref>
+The CB<sub>1</sub> receptor [[inverse agonist]] [[rimonabant]] has been found to reduce intake of food or sweet solutions in both humans and mice. Targeting this receptor with rimonabant has been found to prevent the THC-induced enhancement of DA release in the [[nucleus accumbens]] shell from food, suggesting that these receptors may be involved in determining the hedonic value of food.<ref>{{cite journal | vauthors = De Luca MA, Solinas M, Bimpisidis Z, Goldberg SR, Di Chiara G | title = Cannabinoid facilitation of behavioral and biochemical hedonic taste responses | journal = Neuropharmacology | volume = 63 | issue = 1 | pages = 161–8 | date = July 2012 | pmid = 22063718 | pmc = 3705914 | doi = 10.1016/j.neuropharm.2011.10.018 }}</ref> In addition, CB1 facilitates [[ghrelin]] release, normally happening when the stomach is constricted In the presence of a relatively active system, overeating is promoted. This is the genesis of its appetite-stimulating effects, colloquially called "the munchies."
+===Cardiovascular activity===
+Cannabinoids are well known for their [[Circulatory system|cardiovascular]] activity.<!--This needs to be expanded--> Activation of peripheral CB1 receptors contributes to [[Bleeding|hemorrhagic]] and [[endotoxin]]-induced [[hypotension]].<ref name="Varga">{{cite journal | vauthors = Varga K, Wagner JA, Bridgen DT, Kunos G | title = Platelet- and macrophage-derived endogenous cannabinoids are involved in endotoxin-induced hypotension | journal = FASEB Journal | volume = 12 | issue = 11 | pages = 1035–44 | date = August 1998 | pmid = 9707176 }}</ref> Anandamide and 2-AG, produced by macrophages and [[platelet]]s, respectively, may mediate this effect.<ref name="Varga" /> A likely candidate for this function is the heterodimer of CB1 and adenosine 2a. Through an opposing mechanism of action (A2A elevates cAMP), together, they may serve to regulate cardiac blood supply, and thus output.
+===Plasticity===
+CB1 induction of LTD and STD have been shown in the Dorsal striatum, Amygdala, Prefrontal cortex, Ventral tegmental area, and the BNST.<ref>{{cite journal | vauthors = Sidhpura N, Parsons LH | title = Endocannabinoid-mediated synaptic plasticity and addiction-related behavior | journal = Neuropharmacology | volume = 61 | issue = 7 | pages = 1070–87 | date = December 2011 | pmid = 21669214 | doi = 10.1016/j.neuropharm.2011.05.034 | pmc=3176941}}</ref> A recent study compared the endocannabinoid induction of LTD and STD in the bed nucleus of the stria terminalis (BNST) and striatum.  Results found that both short- and long-term effects were dependent on CB<sub>1</sub> receptor activation in the striatum, whereas LTD induction in the BNST relied on [[TRPV1]] receptor. Effects vary based on the endocannabinoid molecule: 2-AG was found to act on presynaptic CB<sub>1</sub> receptors to mediate retrograde [[short-term depression]] following activation of L-type calcium currents, whereas anandamide was synthesized after mGluR5 activation and triggered [[autocrine signalling]] that induced [[long-term depression]].<ref>{{cite journal | vauthors = Puente N, Cui Y, Lassalle O, Lafourcade M, Georges F, Venance L, Grandes P, Manzoni OJ | title = Polymodal activation of the endocannabinoid system in the extended amygdala | journal = Nature Neuroscience | volume = 14 | issue = 12 | pages = 1542–7 | date = November 2011 | pmid = 22057189 | doi = 10.1038/nn.2974 }}</ref>  These findings demonstrate the CB<sub>1</sub> receptor as a direct mechanism for the brain to selectively inhibit neuronal excitability over variable time scales. By selectively internalizing different receptors, the brain may limit the production of specific endocannabinoids to favor a time scale in accordance with its needs. mGlu5 forms a heterodimer with A2A, which allows endocannabinoids to regulate their own levels, as they inhibit cAMP production, thus increase free adenosine to agonise A2A. This forms a feedback loop between the positive and negative metabotropic receptors, which can maintain a relatively similar homeostasis with any neuron connected through an electrical synapse.
+===Motor control===
+CB<sub>1</sub> receptors are expressed throughout motor regions of the mammalian brain, suggesting that CB<sub>1</sub> has a role in motor control. CB<sub>1</sub> activation has been shown to effect specific kinematic variables in rodents, such as the rate of applied force during lever pressing,<ref name="McLaughlin">{{cite journal | vauthors = Mclaughlin PJ, Delevan CE, Carnicom S, Robinson JK, Brener J | title = Fine motor control in rats is disrupted by delta-9-tetrahydrocannabinol | journal = Pharmacology, Biochemistry, and Behavior | volume = 66 | issue = 4 | pages = 803–9 | date = August 2000 | pmid = 10973519 | doi = 10.1016/S0091-3057(00)00281-1 }}</ref> and the amplitude (but not timing) of whisker movements.<ref name="Pietr">{{cite journal | vauthors = Pietr MD, Knutsen PM, Shore DI, Ahissar E, Vogel Z | title = Cannabinoids reveal separate controls for whisking amplitude and timing in rats | journal = Journal of Neurophysiology | volume = 104 | issue = 5 | pages = 2532–42 | date = November 2010 | pmid = 20844105 | doi = 10.1152/jn.01039.2009 }}</ref>
+===Drug and behavioral addictions===
+Several recent reviews on CB1 receptors and addiction have indicated that CB1 receptor activation reinstates drug seeking behavior in addicts.<ref name="pmid15992935">{{cite journal | vauthors = De Vries TJ, Schoffelmeer AN | title = Cannabinoid CB1 receptors control conditioned drug seeking | journal = Trends in Pharmacological Sciences | volume = 26 | issue = 8 | pages = 420–6 | date = August 2005 | pmid = 15992935 | doi = 10.1016/j.tips.2005.06.002 }}</ref><ref name="pmid18482432">{{cite journal | vauthors = Wiskerke J, Pattij T, Schoffelmeer AN, De Vries TJ | title = The role of CB1 receptors in psychostimulant addiction | journal = Addiction Biology | volume = 13 | issue = 2 | pages = 225–38 | date = June 2008 | pmid = 18482432 | doi = 10.1111/j.1369-1600.2008.00109.x }}</ref><ref name="pmid23108546" />
+In humans, this results from the influence that [[limbic system|limbic]] CB1 receptors have on [[mesolimbic pathway|mesolimbic]] dopamine neurons, specifically [[dopamine receptor]]s in the [[nucleus accumbens]].<ref name="pmid23108546">{{cite journal | vauthors = Melis M, Pistis M | title = Hub and switches: endocannabinoid signalling in midbrain dopamine neurons | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 367 | issue = 1607 | pages = 3276–85 | date = December 2012 | pmid = 23108546 | pmc = 3481525 | doi = 10.1098/rstb.2011.0383 }}</ref> As a consequence, [[Cannabinoid receptor antagonist|CB1 receptor antagonists]] can reduce drug seeking behavior in some addicts.<ref name="pmid15992935" /><ref name="pmid18482432" /><ref name="pmid23108546" />
+===Olfaction===
+The CB<sub>1</sub> receptor is expressed by a number of neurons that project from the [[anterior olfactory nucleus]] to the [[ipsilateral]] main [[olfactory bulb]]. However, the effects of cannabinoids on synaptic activity in these neurons has not been well-studied and its effects on olfaction warrant further research in rodents.<ref name="pmid11316486" /> Cannabinoids are not known to have effects on olfaction in humans. However, as with the rest of the brain, it plays a crucial role in modulation of NT release.
+==Use of antagonists==
+Selective CB<sub>1</sub> agonists may be used to isolate the effects of the receptor from the CB<sub>2</sub> receptor, as most cannabinoids and endocannabinoids bind to both receptor types.<ref name="pmid11316486" />
+[[Cannabinoid receptor antagonist|CB<sub>1</sub> selective antagonists]] are used for weight reduction and [[smoking cessation]] (see [[Rimonabant]]). A substantial number of antagonists of the CB1 receptor have been discovered and characterized. [[TM38837]] has been developed as a CB1 receptor antagonist that is restricted to targeting only peripheral CB1 receptors. <!--What does this have to do with CB1 antagonists?: Activation of CB<sub>1</sub> provides neuroprotection after brain injury.<ref name="pmid11586361">{{Cite pmid|11586361}}</ref> -->
+== Ligands ==
+=== Agonists ===
+* [[Minocycline]]<ref name="pmid23960212">{{cite journal |title=CB1 and CB2 cannabinoid receptor antagonists prevent minocycline-induced neuroprotection following traumatic brain injury in mice |date=2015-01-01 |journal=Cereb Cortex. |doi=10.1093/cercor/bht202 |url=https://academic.oup.com/cercor/article-lookup/doi/10.1093/cercor/bht202 |volume=25 |issue=1 |pages=35–45 |pmid=23960212 |author=Lopez-Rodriguez AB, et al.}}</ref>
+*[[Dronabinol]]
+==== Selective ====
+* [[Epigallocatechin]]
+* [[Epicatechin]]
+* [[Kavain]]
+* [[Yangonin]]
+==== Unspecified efficacy ====
+* [[N-Arachidonoyl dopamine]]
+* [[Cannabinol]]
+* [[HU-210]]
+* [[11-Hydroxy-THC]]
+* [[Levonantradol]]
-In the liver, activation of the CB<sub>1</sub> receptor is known to increase de novo [[lipogenesis]],<ref name="pmid15864349">{{cite journal | author = Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Bátkai S, Harvey-White J, Mackie K, Offertáler L, Wang L, Kunos G | title = Endocannabinoid activation at hepatic CB<sub>1</sub> receptors stimulates fatty acid synthesis and contributes to diet-induced obesity | journal = J. Clin. Invest. | volume = 115 | issue = 5 | pages = 1298–305 | year = 2005 | pmid = 15864349 | doi = 10.1172/JCI200523057 | issn = }}</ref> Activation of presynaptic CB<sub>1</sub> receptors is also known to inhibit sympathetic innervation of blood vessels and contributes to the suppression of the neurogenic vasopressor response in [[septic shock]].<ref name="pmid15159284">{{cite journal | author = Godlewski G, Malinowska B, Schlicker E | title = Presynaptic cannabinoid CB<sub>1</sub> receptors are involved in the inhibition of the neurogenic vasopressor response during septic shock in pithed rats | journal = Br. J. Pharmacol. | volume = 142 | issue = 4 | pages = 701–8 | year = 2004 | pmid = 15159284 | doi = 10.1038/sj.bjp.0705839 | issn = }}</ref>
+==== Partial ====
-=== Gastrointestinal activity ===
+=====Endogenous=====
+* [[2-Arachidonyl glyceryl ether]]
-Inhibition of [[Gastrointestinal tract|gastrointestinal]] activity has been observed after administration of Δ<sup>9</sup>-THC, or of [[anandamide]]. This effect has been assumed to be CB<sub>1</sub>-mediated since the specific CB<sub>1</sub> antagonist SR 141716A ([[Rimonabant]]) blocks the effect. Another report, however, suggests that inhibition of [[intestine|intestinal]] [[motility]] may also have a CB<sub>2</sub>-mediated component.<ref name="pmid15249429">{{cite journal | author = Mathison R, Ho W, Pittman QJ, Davison JS, Sharkey KA | title = Effects of cannabinoid receptor-2 activation on accelerated gastrointestinal transit in lipopolysaccharide-treated rats | journal = Br. J. Pharmacol. | volume = 142 | issue = 8 | pages = 1247–54 | year = 2004 | pmid = 15249429 | doi = 10.1038/sj.bjp.0705889 | issn = }}</ref>
+=====Phyto/synthetic=====
+* [[JWH-073]]
+* [[Tetrahydrocannabinol]]
-=== Cardiovascular activity ===
+==== Full ====
-Cannabinoids are well known for their [[Circulatory system|cardiovascular]] activity. Activation of peripheral CB1 receptors contributes to [[Bleeding|hemorrhagic]] and [[endotoxin]]-induced [[hypotension]]. Anandamide and 2-AG, produced by macrophages and [[platelet]]s respectively, may mediate this effect.
+=====Endogenous=====
+* [[2-Arachidonoylglycerol]]
-=== Pain ===
+=====Phyto/synthetic=====
+* [[AM-2201]]
+* [[CP 55,940]]
+* [[JWH-018]]
+* [[WIN 55,212-2]]
-Anandamide attenuates the early phase or the late phase of [[Pain and nociception|pain]] behavior produced by [[Formaldehyde|formalin]]-induced chemical damage. This effect is produced by interaction with CB<sub>1</sub> (or CB<sub>1</sub>-like) receptors, located on peripheral endings of [[sensory neuron]]s involved in pain transmission. Palmitylethanolamide, which like anandamide is present in the [[skin]], also exhibits peripheral antinociceptive activity during the late phase of pain behavior. Palmitylethanolamide, however does not bind to either CB<sub>1</sub> or CB<sub>2</sub>. Its analgetic activity is blocked by the specific CB<sub>2</sub> antagonist SR 144528, though not by the specific CB<sub>1</sub> antagonist SR 141716A. Hence a CB<sub>2</sub>-like receptor was postulated.
+==== Allosteric agonist ====
+* GAT228<ref name="pmid28103441">{{cite journal | vauthors = Laprairie RB, Kulkarni PM, Deschamps JR, Kelly ME, Janero DR, Cascio MG, Stevenson LA, Pertwee RG, Kenakin TP, Denovan-Wright EM, Thakur GA | title = Enantiospecific Allosteric Modulation of Cannabinoid 1 Receptor | journal = ACS Chemical Neuroscience | volume =  | issue =  | date = February 2017 | pmid = 28103441 | doi = 10.1021/acschemneuro.6b00310 }}</ref>
-== Use of antagonists ==
+=== Antagonists ===
+* [[Cannabigerol]]
+* [[Ibipinabant]]
+* [[Otenabant]]
+* [[Tetrahydrocannabivarin]]
+* [[Virodhamine]] (Endogenous CB1 antagonist and CB2 agonist)
-CB<sub>1</sub> selective antagonists are used for weight reduction and smoking cessation (see [[Rimonabant]]). Activation of CB<sub>1</sub> provides neuroprotection after brain injury.<ref name="pmid11586361">{{cite journal | author = Panikashvili D, Simeonidou C, Ben-Shabat S, Hanus L, Breuer A, Mechoulam R, Shohami E | title = An endogenous cannabinoid (2-AG) is neuroprotective after brain injury | journal = Nature | volume = 413 | issue = 6855 | pages = 527–31 | year = 2001 | pmid = 11586361 | doi = 10.1038/35097089 | issn = }}</ref>
+=== Inverse agonists===
+* [[Rimonabant]]
+* [[Taranabant]]
-== Mechanism ==
+=== Allosteric modulators ===
+{{div col|colwidth=20em}}
+* [[Lipoxin|Lipoxin A4]] – endogenous, PAM
+* [[ZCZ-011]] – PAM
+* [[Pregnenolone]] – endogenous, NAM
+* [[Cannabidiol]] – NAM<ref name="pmid17828291"/>
+* [[Fenofibrate]] – NAM
+* [[GAT100]] – NAM
+* [[PSNCBAM-1]] – NAM
+* [[RVD-Hpα]] – NAM
+{{Div col end}}
-Cannabinoid receptors are activated by [[cannabinoids]], generated naturally inside the body ([[Endocannabinoids#Endogenous Cannabinoids|endocannabinoids]]) or introduced into the body as [[cannabis (drug)|cannabis]] or a related [[Chemical synthesis|synthetic]] compound. They are activated in a dose-dependent, stereoselective and pertussis toxin-sensitive manner<ref name="entrez" />.
+==Binding affinities==
+{| class="wikitable sortable" style="font-size: smaller; text-align: center; width: auto;"
+|-
+! style="width: 12em"|
+! CB<sub>1</sub> affinity (K<sub>i</sub>)
+! Efficacy towards CB<sub>1</sub>
+! CB<sub>2</sub> affinity (K<sub>i</sub>)
+! Efficacy towards CB<sub>2</sub>
+! Type
+! References
-After the receptor is engaged, multiple [[intracellular]] [[signal transduction]] pathways are activated. At first, it was thought that cannabinoid receptors mainly activated the [[G protein]] [[Gi alpha subunit|G<sub>i</sub>]], which inhibits the [[enzyme]] [[adenylate cyclase]] (and thereby the production of the [[second messenger]] molecule [[cyclic AMP]]), and positively influenced [[Inward-rectifier potassium ion channel|inwardly rectifying potassium channels]] (=Kir or IRK).<ref name="pmid16109430">{{cite journal | author = Demuth DG, Molleman A | title = Cannabinoid signalling | journal = Life Sci. | volume = 78 | issue = 6 | pages = 549–63 | year = 2006 | pmid = 16109430 | doi = 10.1016/j.lfs.2005.05.055 | issn = }}</ref> However, a much more complex picture has appeared in different cell types, implicating other [[potassium ion channels]], [[calcium channel]]s, [[protein kinase A]] and [[protein kinase C|C]], [[C-Raf|Raf-1]], [[ERK]], [[JNK]], [[p38]], [[c-fos]], [[c-jun]] and many more<ref name="endocrino" />
+|-
+! '''[[Anandamide]]'''
+| 78 nM
+| Partial agonist
+| 370 nM
+| Partial agonist
+| Endogenous
+|
+|-
+! [[N-Arachidonoyl dopamine]]
+| 250 nM
+| Agonist
+| 12000 nM
+| ?
+| Endogenous
+| <ref name="2AG">{{cite journal | vauthors = Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, Greasley PJ, Hansen HS, Kunos G, Mackie K, Mechoulam R, Ross RA | title = International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂ | journal = Pharmacological Reviews | volume = 62 | issue = 4 | pages = 588–631 | date = December 2010 | pmid = 21079038 | doi = 10.1124/pr.110.003004 | pmc=2993256}}</ref>
+|-
+! [[2-Arachidonoylglycerol]]
+| 58.3 nM
+| Full agonist
+| 145 nM
+| Full agonist
+| Endogenous
+| <ref name="2AG" />
+|-
+! [[2-Arachidonyl glyceryl ether]]
+| 21 nM
+| Full agonist
+| 480 nM
+| Full agonist
+| Endogenous
+|
+|-
+!  '''[[Tetrahydrocannabinol]]'''
+|  10 nM
+|  Partial agonist
+|  24 nM
+|  Partial agonist
+|  Phytogenic
+| <ref name="whoa">{{cite web |title=PDSP Database - UNC |url=http://pdsp.med.unc.edu/pdsp.php? |accessdate=11 June 2013 |deadurl=yes |archiveurl=https://web.archive.org/web/20131108013656/http://pdsp.med.unc.edu/pdsp.php |archivedate=8 November 2013 |df= }}</ref><ref name="whoa" />
+|-
+! [[EGCG]]
+| 33.6 μM
+| Agonist
+| >50 μM
+| ?
+| Phytogenic
+|
+|-
+!  [[AM-1221]]
+|  52.3 nM
+|  Agonist
+|  0.28 nM
+|  Agonist
+|  Synthetic
+| <ref name="dude">{{Ref patent2 |country=WO |number=200128557 |status=granted |title=Cannabimimetic indole derivatives |pubdate=2001-04-26 |gdate=2001-06-07 |pridate=1999-10-18 |inventor=Makriyannis A, Deng H}}</ref>
+|-
+!  [[AM-1235]]
+|  1.5 nM
+|  Agonist
+|  20.4 nM
+|  Agonist
+|  Synthetic
+| <ref name="like">{{Ref patent2 |country=US |number=7241799 |status=granted |title=Cannabimimetic indole derivatives |pubdate=2004-11-05 |gdate=2007-07-10 |pridate=2004-11-05 |inventor=Makriyannis A, Deng H |assign1=}}</ref>
+|-
+!  [[AM-2232]]
+|  0.28 nM
+|  Agonist
+|  1.48 nM
+|  Agonist
+|  Synthetic
+|  <ref name="like" />
+|-
+!  [[UR-144]]
+|  150 nM
+|  Full agonist
+|  1.8 nM
+|  Full agonist
+|  Synthetic
+| <ref name="myhandsareamazing">{{cite journal | vauthors = Frost JM, Dart MJ, Tietje KR, Garrison TR, Grayson GK, Daza AV, El-Kouhen OF, Yao BB, Hsieh GC, Pai M, Zhu CZ, Chandran P, Meyer MD | title = Indol-3-ylcycloalkyl ketones: effects of N1 substituted indole side chain variations on CB(2) cannabinoid receptor activity | journal = Journal of Medicinal Chemistry | volume = 53 | issue = 1 | pages = 295–315 | date = January 2010 | pmid = 19921781 | doi = 10.1021/jm901214q }}</ref>
+|-
+!  [[JWH-007]]
+|  9.0 nM
+|  Agonist
+|  2.94 nM
+|  Agonist
+|  Synthetic
+|  <ref name="puff">{{cite journal | vauthors = Aung MM, Griffin G, Huffman JW, Wu M, Keel C, Yang B, Showalter VM, Abood ME, Martin BR | title = Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB(1) and CB(2) receptor binding | journal = Drug and Alcohol Dependence | volume = 60 | issue = 2 | pages = 133–40 | date = August 2000 | pmid = 10940540 | doi = 10.1016/S0376-8716(99)00152-0 }}</ref>
+|-
+!  [[JWH-015]]
+|  383 nM
+|  Agonist
+|  13.8 nM
+|  Agonist
+|  Synthetic
+| <ref name="puff" />
+|-
+!  [[JWH-018]]
+|  9.00 ± 5.00 nM
+|  Full agonist
+|  2.94 ± 2.65 nM
+|  Full agonist
+|  Synthetic
+| <ref name="pass">{{cite journal | vauthors = Aung MM, Griffin G, Huffman JW, Wu M, Keel C, Yang B, Showalter VM, Abood ME, Martin BR | title = Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB(1) and CB(2) receptor binding | journal = Drug and Alcohol Dependence | volume = 60 | issue = 2 | pages = 133–40 | date = August 2000 | pmid = 10940540 | doi = 10.1016/s0376-8716(99)00152-0 }}</ref>
+|-
+|}
+==Evolution==
+The '''CNR1''' gene is used in animals as a [[nuclear DNA]] phylogenetic marker.<ref name="OrthoMaM" /> This intronless gene has first been used to explore the phylogeny of the major groups of [[mammals]],<ref name="pmid11214319">{{cite journal | vauthors = Murphy WJ, Eizirik E, Johnson WE, Zhang YP, Ryder OA, O'Brien SJ | title = Molecular phylogenetics and the origins of placental mammals | journal = Nature | volume = 409 | issue = 6820 | pages = 614–8 | date = February 2001 | pmid = 11214319 | doi = 10.1038/35054550 }}</ref> and contributed to reveal that [[placental]] orders are distributed into five major clades: [[Xenarthra]], [[Afrotheria]], [[Laurasiatheria]], [[Euarchonta]], and [[Glires]].  CNR1 has also proven useful at lower [[taxonomic]] levels, such as [[rodents]],<ref name="pmid19341461">{{cite journal | vauthors = Blanga-Kanfi S, Miranda H, Penn O, Pupko T, DeBry RW, Huchon D | title = Rodent phylogeny revised: analysis of six nuclear genes from all major rodent clades | journal = BMC Evolutionary Biology | volume = 9 | pages = 71 | date = April 2009 | pmid = 19341461 | pmc = 2674048 | doi = 10.1186/1471-2148-9-71 }}</ref><ref name="pmid14530129">{{cite journal | vauthors = DeBry RW | title = Identifying conflicting signal in a multigene analysis reveals a highly resolved tree: the phylogeny of Rodentia (Mammalia) | journal = Systematic Biology | volume = 52 | issue = 5 | pages = 604–17 | date = October 2003 | pmid = 14530129 | doi = 10.1080/10635150390235403 }}</ref> and for the identification of [[dermoptera]]ns as the closest primate relatives.<ref name="pmid17975064">{{cite journal | vauthors = Janecka JE, Miller W, Pringle TH, Wiens F, Zitzmann A, Helgen KM, Springer MS, Murphy WJ | title = Molecular and genomic data identify the closest living relative of primates | journal = Science | volume = 318 | issue = 5851 | pages = 792–4 | date = November 2007 | pmid = 17975064 | doi = 10.1126/science.1147555 | bibcode = 2007Sci...318..792J }}</ref>
-Separation between the therapeutically undesirable psychotropic effects, and the clinically desirable ones however, has not been reported with [[agonists]] that bind to cannabinoid receptors. THC, as well as the two major [[endogenous]] compounds identified so far that bind to the cannabinoid receptors ([[anandamide]] and [[2-arachidonylglycerol]]) produce most of their effects by binding to both the CB<sub>1</sub> and CB<sub>2</sub> cannabinoid receptors.{{Fact|date=January 2008}}
-<!-- The PBB_Summary template is not automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
-{{PBB_Summary
-| section_title =
-| summary_text =
-}}
 == See also ==
+* [[Discovery and development of Cannabinoid Receptor 1 Antagonists]]
 * [[Cannabinoid receptor]]
+* [[Cannabinoid receptor type 2]] (CB<sub>2</sub>)
 == References ==
 {{reflist|2}}
-== Further reading ==
+== External links ==
-{{refbegin | 2}}
+* {{cite web |url=http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2205 |title=Cannabinoid Receptors: CB<sub>1</sub> |accessdate= |authorlink= |date= |format= |work=IUPHAR Database of Receptors and Ion Channels |publisher=International Union of Basic and Clinical Pharmacology |pages= |quote=}}
-{{PBB_Further_reading
-| citations =
-* {{cite journal | author=Oddi S, Spagnuolo P, Bari M, ''et al.'' |title=Differential modulation of type 1 and type 2 cannabinoid receptors along the neuroimmune axis. |journal=Int. Rev. Neurobiol. |volume=82 |issue= |pages= 327-37 |year= 2007 |pmid= 17678969 |doi= 10.1016/S0074-7742(07)82017-4 }}
-* {{cite journal | author=Gérard CM, Mollereau C, Vassart G, Parmentier M |title=Molecular cloning of a human cannabinoid receptor which is also expressed in testis. |journal=Biochem. J. |volume=279 ( Pt 1) |issue= |pages= 129-34 |year= 1991 |pmid= 1718258 |doi= }}
-* {{cite journal | author=Hoehe MR, Caenazzo L, Martinez MM, ''et al.'' |title=Genetic and physical mapping of the human cannabinoid receptor gene to chromosome 6q14-q15. |journal=New Biol. |volume=3 |issue= 9 |pages= 880-5 |year= 1991 |pmid= 1931832 |doi= }}
-* {{cite journal | author=Matsuda LA, Lolait SJ, Brownstein MJ, ''et al.'' |title=Structure of a cannabinoid receptor and functional expression of the cloned cDNA. |journal=Nature |volume=346 |issue= 6284 |pages= 561-4 |year= 1990 |pmid= 2165569 |doi= 10.1038/346561a0 }}
-* {{cite journal | author=Gérard C, Mollereau C, Vassart G, Parmentier M |title=Nucleotide sequence of a human cannabinoid receptor cDNA. |journal=Nucleic Acids Res. |volume=18 |issue= 23 |pages= 7142 |year= 1991 |pmid= 2263478 |doi= }}
-* {{cite journal | author=Shire D, Carillon C, Kaghad M, ''et al.'' |title=An amino-terminal variant of the central cannabinoid receptor resulting from alternative splicing. |journal=J. Biol. Chem. |volume=270 |issue= 8 |pages= 3726-31 |year= 1995 |pmid= 7876112 |doi= }}
-* {{cite journal | author=Bonaldo MF, Lennon G, Soares MB |title=Normalization and subtraction: two approaches to facilitate gene discovery. |journal=Genome Res. |volume=6 |issue= 9 |pages= 791-806 |year= 1997 |pmid= 8889548 |doi= }}
-* {{cite journal | author=Kenney SP, Kekuda R, Prasad PD, ''et al.'' |title=Cannabinoid receptors and their role in the regulation of the serotonin transporter in human placenta. |journal=Am. J. Obstet. Gynecol. |volume=181 |issue= 2 |pages= 491-7 |year= 1999 |pmid= 10454705 |doi= }}
-* {{cite journal | author=Porcella A, Maxia C, Gessa GL, Pani L |title=The human eye expresses high levels of CB1 cannabinoid receptor mRNA and protein. |journal=Eur. J. Neurosci. |volume=12 |issue= 3 |pages= 1123-7 |year= 2000 |pmid= 10762343 |doi= }}
-* {{cite journal | author=Mukhopadhyay S, Howlett AC |title=CB1 receptor-G protein association. Subtype selectivity is determined by distinct intracellular domains. |journal=Eur. J. Biochem. |volume=268 |issue= 3 |pages= 499-505 |year= 2001 |pmid= 11168387 |doi= }}
-* {{cite journal | author=Murphy WJ, Eizirik E, Johnson WE, ''et al.'' |title=Molecular phylogenetics and the origins of placental mammals. |journal=Nature |volume=409 |issue= 6820 |pages= 614-8 |year= 2001 |pmid= 11214319 |doi= 10.1038/35054550 }}
-* {{cite journal | author=Nong L, Newton C, Friedman H, Klein TW |title=CB1 and CB2 receptor mRNA expression in human peripheral blood mononuclear cells (PBMC) from various donor types. |journal=Adv. Exp. Med. Biol. |volume=493 |issue= |pages= 229-33 |year= 2002 |pmid= 11727770 |doi= }}
-* {{cite journal | author=Leroy S, Griffon N, Bourdel MC, ''et al.'' |title=Schizophrenia and the cannabinoid receptor type 1 (CB1): association study using a single-base polymorphism in coding exon 1. |journal=Am. J. Med. Genet. |volume=105 |issue= 8 |pages= 749-52 |year= 2002 |pmid= 11803524 |doi= }}
-* {{cite journal | author=Schmidt LG, Samochowiec J, Finckh U, ''et al.'' |title=Association of a CB1 cannabinoid receptor gene (CNR1) polymorphism with severe alcohol dependence. |journal=Drug and alcohol dependence |volume=65 |issue= 3 |pages= 221-4 |year= 2002 |pmid= 11841893 |doi= }}
-* {{cite journal | author=Lastres-Becker I, Cebeira M, de Ceballos ML, ''et al.'' |title=Increased cannabinoid CB1 receptor binding and activation of GTP-binding proteins in the basal ganglia of patients with Parkinson's syndrome and of MPTP-treated marmosets. |journal=Eur. J. Neurosci. |volume=14 |issue= 11 |pages= 1827-32 |year= 2002 |pmid= 11860478 |doi= }}
-* {{cite journal | author=Petrelli A, Gilestro GF, Lanzardo S, ''et al.'' |title=The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met. |journal=Nature |volume=416 |issue= 6877 |pages= 187-90 |year= 2002 |pmid= 11894096 |doi= 10.1038/416187a }}
-* {{cite journal | author=Huang SM, Bisogno T, Trevisani M, ''et al.'' |title=An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 12 |pages= 8400-5 |year= 2002 |pmid= 12060783 |doi= 10.1073/pnas.122196999 }}
-* {{cite journal | author=Ujike H, Takaki M, Nakata K, ''et al.'' |title=CNR1, central cannabinoid receptor gene, associated with susceptibility to hebephrenic schizophrenia. |journal=Mol. Psychiatry |volume=7 |issue= 5 |pages= 515-8 |year= 2002 |pmid= 12082570 |doi= 10.1038/sj.mp.4001029 }}
-* {{cite journal | author=Ho BY, Current L, Drewett JG |title=Role of intracellular loops of cannabinoid CB(1) receptor in functional interaction with G(alpha16). |journal=FEBS Lett. |volume=522 |issue= 1-3 |pages= 130-4 |year= 2002 |pmid= 12095632 |doi= }}
-* {{cite journal | author=Matias I, Pochard P, Orlando P, ''et al.'' |title=Presence and regulation of the endocannabinoid system in human dendritic cells. |journal=Eur. J. Biochem. |volume=269 |issue= 15 |pages= 3771-8 |year= 2002 |pmid= 12153574 |doi= }}
-}}
-{{refend}}
 {{NLM content}}
 {{G protein-coupled receptors}}
+{{Cannabinoidergics}}
+{{DEFAULTSORT:Cannabinoid Receptor Type 1}}
 [[Category:G protein coupled receptors]]

Cannabinoid receptor type 1: Difference between revisions

Revision as of 06:01, 24 November 2017

Structure

Mechanism

Expression

Brain

Hippocampal formation

Basal ganglia

Cerebellum and neocortex

Spine

Other

Function

Health and disease

Anxiety response to novelty

Gastrointestinal activity

Cardiovascular activity

Plasticity

Motor control

Drug and behavioral addictions

Olfaction

Use of antagonists

Ligands

Agonists

Selective

Unspecified efficacy

Partial

Endogenous

Phyto/synthetic

Full

Endogenous

Phyto/synthetic

Allosteric agonist

Antagonists

Inverse agonists

Allosteric modulators

Binding affinities

Evolution

See also

References

External links

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