Itch pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Ogechukwu Hannah Nnabude, MD
Overview
There are five main causes of itching:
- Dermal/pruritoceptive which originates in the skin,
- Neuropathic which is due to damage along the afferent pathway of a nerve,
- Neurogenic which originates centrally without the involvement of the peripheral nerves,
- Psychogenic which is associated with psychiatric disorders and phobias, and
- Mixed picture which is due to two or more causes of itching
Pathophysiology
The central chemical involved in itching is histamine, a molecule released by mast cells in the skin. Histamine is the chemical that causes itching and reddening. It binds to local nerve endings on specific receptors. Itch can originate in the peripheral nervous system (dermal or neuropathic) or in the central nervous system (neuropathic, neurogenic, or psychogenic).[1]
Dermal/Pruritoceptive
Itch originating in the skin is considered pruritoceptive and can be induced by a variety of stimuli, including mechanical, chemical, thermal, and electrical stimulation. The primary afferent neurons responsible for histamine induced itch are unmyelinated C-fibers. In human C-fiber nociceptors, the two major classes that exist are mechano-responsive nociceptors and mechano-insensitive nociceptors. Mechano-responsive nociceptors have been shown in studies to respond to mostly pain and mechano-insensitive receptors respond mostly to itch induced by histamine. However, it does not explain mechanically induced itch or when itch is produced without a flare reaction which involves no histamine. Therefore it is possible that pruritoceptive nerve fibers have different classes of fibers, which is currently unclear in current research.[2] Some classic examples that fall in this category include scabies, itching secondary to insect bites, and urticaria [3] [4] [5]. Studies have shown that itch receptors are found only on the two outermost layers of the skin, the epidermis, and the epidermal/dermal transition layers. Shelley and Arthur had verified the depth by injecting individual itch powder spicules (Mucuna pruriens) and found that maximal sensitivity was found at the basal cell layer or the innermost layer of the epidermis. Surgical removal of those skin layers removed the ability for a patient to perceive itch. Itch is never felt in muscle, joints, or inner organs, which shows that deep tissue does not contain itch signaling apparatuses.[6] Sensitivity to pruritic stimuli is not even across the skin and has a random spot distribution with a similar density to that of pain. The same substances that elicit itch upon intracutaneous injection (injection within the skin) elicit only pain when injected subcutaneously (beneath the skin). Itch is readily abolished in skin areas treated with nociceptor excitotoxin capsaicin but remains unchanged in skin areas that were rendered touch-insensitive by pretreatment with saponins, an anti-inflammatory agent. Although experimentally induced itch can still be perceived under a complete A-fiber conduction block, it is significantly diminished. Overall, itch sensation is mediated by A-delta and C nociceptors located in the topmost layer of the skin.[7]
Neuropathic
Neuropathic itch can originate at any point along the afferent pathway as a result of damage to the nervous system. They could include diseases or disorders in the central nervous system or peripheral nervous system. It is often limited to a certain point[6] Examples of itch of neuropathic origin are nostalgia paresthetica, postherpetic neuralgia, brachioradial pruritus, brain tumors, multiple sclerosis, peripheral neuropathy, and nerve irritation.[8] [9] [10] [11]
Neurogenic
Neurogenic itch, which is itch induced centrally by receptors and mediators but with no neural damage, is often associated with increased accumulation of endogenous opioids as seen in itching due to bile statsis, and possibly synthetic opioids.[6] [12] [13]
Psychogenic
Itch is also associated with some psychiatric disorders, psychological factors and phobias. Examples in this category are parasitic phobia or itching related obsessive-compulsive disorders, for example neurotic scratching.[6] [14] [15]
Mixed
This is itching brought about by two or more factors as is seen in atopic dermatitis which is a combination of neurogenic and dermal/pruritoceptive causes. [16]
Mediators, Receptors and Drugs Related to Itching
The following table shows some of the mediators, receptors and drugs related to itching [17]:
| Mediators | Receptors | Drugs |
|---|---|---|
| Histamines | Histamine receptors (H1R, H2R, and H4R) |
Antihistamines |
| Opioid peptides | μ-receptor, κ-receptor |
Naloxone, Naltrexone, Nalfurafine |
| Platelet-activating factor (PAF) | PAF receptor |
Rupatadine, Apafant |
| Bradykinin | Bradykinin receptors
(B1R and B2R) |
Icatibant, Bromelain |
| Leukotrienes (LTs) | Leukotriene receptors |
Zafirlukast, Pranlukast, Montelukast |
| Substance-P | NK receptor
(NKR1) |
Aprepitant, Fosaprepitant, Casopitant, Vestipitant, Orvepitant, Lanepitant, Dapitant, L-733, 060 |
| 5-Hydroxy tryptamine (5-HT) | 5-HT receptors
(5-HT2 and 5HT3) |
Paroxetine, Fluoxetine, Mirtazapine, Ondansetron |
| IL-2, IL-3, IL-4, IL-6, and IL-10 | IL-2 and IL-6 receptors |
Cyclosporine, Dupilumab, Lebrikizumab |
| Cannabinoids | Cannabinoid receptors
(CB1 and CB2 receptors) |
Palmitoylethanolamine (PEA) |
| Calcitonin gene related peptide (CGRP) | CGRP receptors
(CALCRL and RAMP1) |
Erenumab, Fremanezumab, Galcanezumab |
| Proteases | Proteases-activated receptors
(PARs, PAR1–4) |
Leupeptin, E6005, E-64, Chymostatin |
Interactions between Itch and Pain
Pain Inhibits Itch
The sensation of itch can be reduced by many painful sensations. Many studies done in the last decade have shown that itch can be inhibited by many other forms of painful stimuli, such as noxious heat, physical rubbing/scratching, noxious chemicals, and electric shock. Any stimuli that causes pain will inhibit itching.
The inhibition of itch by painful stimuli, including heat, physical stimulus, and chemical stimulus, has been shown experimentally. In an article written by Louise Ward and others, they studied the effects of noxious and non-noxious counterstimuli, such as heat, physical vibration, or chemical stimulation on skin, in healthy adults after they had experimentally induced itch (transdermal iontophoresis of histamine) and pain (with topical mustard oil) in their skin. They found that when they induced non-noxious counterstimuli, the reduction of pain and itch was reduced only for up to 20 seconds. However when they induced noxious counterstimuli, there was a significant inhibition of itch for an extended period of time but no inhibition of pain. In addition, it was found that brief noxious stimuli created an anti-itch state for more than 30 minutes. These findings show that itch is not a subliminal form of pain and that noxious counterstimulus is likely to act through a central instead of a peripheral mechanism.[18]
Painful electrical stimulation reduced histamine-induced itch for several hours at a distance up to 10 cm from the stimulated site, which suggests a central mode of action. A new method had been recently found, by Hans-Jorgen Nilsson and others, that is able to relieve itch without damaging the skin called cutaneous field stimulation (CFS). CFS consists of a flexible rubber plate with 16 needle-like electrodes placed regularly at 2-centimeter intervals in a 4 by 4 matrix used to electrically stimulate nerve fibers in the surface of the skin. The electrodes were stimulated continuously at 4 Hertz per electrode, pulse duration of 1 millisecond, intensity 0.4-0.8 milliamperes, and for 25 minutes. CFS resulted in a pricking and burning sensation that usually faded away very quickly. The burning sensation was still present during a selective block of impulse conduction of A-fibers in myelinated fibers indicating that nociceptive C-fibers are activated by CFS. In addition, a flare reaction had been noted to develop around the CFS electrodes which indicate activation of axon reflexes in nociceptive C-fibers. Itch, which was induced by transdermal iontophoresis of histamine, was inhibited within the skin area treated with CFS, and it was reduced 10 cm distally to a significant amount. CFS proves to offer a new method of combating itch by using painful electrical stimulation as it creates a long lasting inhibitory effect, does not create any significant skin injuries, and is simple to manage. It is able to activate powerful itch inhibitory mechanisms possibly routed through central mechanisms, which could normally be activated by scratching of the skin.[19]
A study done by Gil Yosipovitch, Katharine Fast, and Jeffrey Bernhard showed that noxious heat and scratching was able to inhibit or decrease itch induced by transdermal iontophoresis of histamine and most interestingly, decrease skin blood flow. Twenty-one healthy volunteers participated in their study. Baseline measurements of skin blood flow were obtained on the flexor part of the forearm and then compared with skin blood flow after various stimuli. Then transdermal iontophoresis of histamine was performed and tested with various stimuli. It is well known that skin blood flow is significantly increased during mechanical scratching, warming, and noxious heat. However it is quite interesting that this study is the first to examine the changes of blood flow by stimuli during iontophoresis of histamine and how itch is perceived in those conditions. Its examination provided an unexpected result that noxious heat and scratching has an inhibitory effect.[20]
A negative correlation was found between pain sensitivity and itch sensitivity. In a study done by Amanda Green and others, they aimed to determine itch-related genetic factors, and establish a more useful animal model for itch. They looked at 11 different inbred mouse strains and compared their scratching behavior in response to two itch inducing agents, histamine and chloroquine. Every strain revealed an inverted-U shape dose response relationship from chloroquine, indicating that moderate dosages produced more scratching than at higher dosages. An explanation is that higher dosage produces more pain and the presence of pain inhibits pain thereby lowering the amount of overall scratching. Another notable result was that histamine-induced scratching occurred in female mice on average 23% more than males. Finally, it was found that mice having strains sensitive to pain were resistant to itch and vice versa.[21]
Peripheral Sensitization
Inflammatory mediators such as bradykinin, serotonin (5-HT) and prostaglandins, released during a painful or pruritic inflammatory condition not only activates pruriceptors but also causes acute sensitization of the nociceptors. In addition, expression of neuro growth factors (NGF) can cause structural changes in of nociceptors such as sprouting. NGF is high in injured or inflamed tissue. Increased NGF is also found in atopic dermatitis, a hereditary and non-contagious skin disease with chronic inflammation.[22] NGF is known to up-regulate neuropeptides, especially substance P. Substance P has been found to have an important role in inducing pain however there is no confirmation that substance P directly causes acute sensitization. Instead substance P may contribute to itch by increasing neuronal sensitization and may the affect release of mast cells, which contain many granules rich in histamine, during long-term interaction.[2]
Central Sensitization
Noxious input to the [[spinal cord] is known to produce central sensitization, which consists of allodynia, exaggeration of pain, and punctuate hyperalgesia, extreme sensitivity to pain. Two types of mechanical hyperalgesia can occur: 1) touch that is normally painless in the uninjured surroundings of a cut or tear can trigger painful sensations (touch-evoked hyperalgesia), and 2) a slightly painful pin prick stimulation is perceived as more painful around a focused area of inflammation (punctuate hyperalgesia). Touch-evoked hyperalgesia requires continuous firing of primary afferent nociceptors, and punctuate hyperalgesia does not require continuous firing which means it can persist for hours after a trauma and can be stronger than normally experienced. In addition, it was found that patients with neuropathic pain, histamine ionophoresis resulted in a sensation of burning pain rather than itch, which would be induced in normal healthy patients. This shows that there is spinal hypersensitivity to C-fiber input in chronic pain.[2]
References
- ↑ Yosipovitch, G., Greaves, M.W., Schmelz, M. (2003). Itch. The Lancet, 361(9358), 690-694.
- ↑ 2.0 2.1 2.2 Ikoma, A., Steinhoff, M., Stander, S., Yosipovitch, G., Schmelz, M. (2006). The neurobiology of itch. Nature Reviews Neuroscience, 7(7), 535-547.
- ↑ Jovanović M, Poljacki M, Mimica-Dukić N, Boza P, Vujanović Lj, Duran V | display-authors=etal (2004) Sesquiterpene lactone mix patch testing supplemented with dandelion extract in patients with allergic contact dermatitis, atopic dermatitis and non-allergic chronic inflammatory skin diseases. Contact Dermatitis 51 (3):101-10. DOI:10.1111/j.0105-1873.2004.00413.x PMID: 15479198
- ↑ Jovanović M, Mimica-Dukić N, Poljacki M, Boza P (2003) Erythema multiforme due to contact with weeds: a recurrence after patch testing. Contact Dermatitis 48 (1):17-25. DOI:10.1034/j.1600-0536.2003.480104.x PMID: 12641574
- ↑ Jovanovic M, Oliwiecki S, Beck MH (1992) Occupational contact urticaria from beef associated with hand eczema. Contact Dermatitis 27 (3):188-9. DOI:10.1111/j.1600-0536.1992.tb05253.x PMID: 1451468
- ↑ 6.0 6.1 6.2 6.3 ,Twycross R., Greaves, M.W., Handwerker, H., Jones, E.A., Libretto, S.E., Szepietowski, J.C., Zylicz, Z. (2003). Itch: scratching more than the surface. Q J Med, 96, 7-26.
- ↑ Schmelz, M., Schmidt, R., Bickel, A., Handwerker, H.O., Torebjork, H.E. (1997). Specific C-Receptors for Itch in Human Skin. The Journal of Neuroscience, 17(20), 8003-8008.
- ↑ Bernhard, J.D. (2005). Itch and pruritus: what are they, and how should itches be classified? Dermatologic Therapy, 18, 288-291.
- ↑ Bernhard JD (2005). "Itch and pruritus: what are they, and how should itches be classified?". Dermatol Ther. 18 (4): 288–91. doi:10.1111/j.1529-8019.2005.00040.x. PMID 16296999.
- ↑ Berny-Moreno J., Szepietowski J. C. Neuropathic itch caused by nerve root compression: brachioradial pruritus and notalgia paresthetica/Neuropatski pruritus (svrab) prouzrokovan kompresijom nervnih korenova-brahioradijalni pruritus inostalgija parestetika. Serbian Journal of Dermatology and Venerology. 2013;1(2):68–72.
- ↑ Yosipovitch G., Greaves M., Fleischer A., McGlone F. Itch: basic mechanisms and therapy. New York, NY, USA: Marcel Dekker; 2004.
- ↑ Jones EA, Bergasa NV (1999). "The pruritus of cholestasis". Hepatology. 29 (4): 1003–6. doi:10.1002/hep.510290450. PMID 10094938.
- ↑ Kremer AE, Bolier R, van Dijk R, Oude Elferink RP, Beuers U (2014). "Advances in pathogenesis and management of pruritus in cholestasis". Dig Dis. 32 (5): 637–45. doi:10.1159/000360518. PMID 25034299.
- ↑ Yosipovitch G, Samuel LS (2008). "Neuropathic and psychogenic itch". Dermatol Ther. 21 (1): 32–41. doi:10.1111/j.1529-8019.2008.00167.x. PMID 18318883.
- ↑ Arnold LM, Auchenbach MB, McElroy SL (2001). "Psychogenic excoriation. Clinical features, proposed diagnostic criteria, epidemiology and approaches to treatment". CNS Drugs. 15 (5): 351–9. doi:10.2165/00023210-200115050-00002. PMID 11475941.
- ↑ Jovanović M (2014). "Current concepts of pathophysiology, epidemiology and classification of pruritus". Srp Arh Celok Lek. 142 (1–2): 106–12. doi:10.2298/sarh1402106j. PMID 24684042.
- ↑ Schmoldt A, Benthe HF, Haberland G (1975). "Digitoxin metabolism by rat liver microsomes". Biochem Pharmacol. 24 (17): 1639–41. PMID doi.org/10.1155/2018/9625936 Check
|pmid=value (help). - ↑ Ward, L., Wright E., McMahon S.B. (1996). A comparison of the effects of noxious and innocuous counterstimuli on experimentally induced itch and pain. Pain, 64, 129-138.
- ↑ Nilsson, H., Levinsson, A., Schouenborg, J. (1997). Cutaneous field stimulation (CFS): a new powerful method to combat itch. Pain, 71, 49-55.
- ↑ Yosipovitch, G., Fast, K., Bernhard, J.D. (2005). Noxious Heat and Scratching Decrease Histamine-Induced Itch and Skin Blood Flow. Journal of Investigative Dermatology, 125, 1268-1272.
- ↑ Green, A.D., Young, K.K., Lehto, S.G., Smith, S.B., Mogil, J.S. (2006). Influence of genotype, dose and sex on pruritogen-induced scratching behavior in the mouse. Pain, 124, 50-58.
- ↑ Rukweid, R., Lischetzki, G., Mcglone, F., Heyer, G., Schmelz, M. (2000). Mast cell mediators other than histamine induce pruritus in atopic dermatitis patients: a dermal microdialysis study. British Journal of Dermatology, 142(6), 1114-1120.