Abstract
This chapter is an overview of published observations from our laboratory on the psychophysics and neurobiology of the persistent itch and pain of allergic contact dermatitis (ACD). ACD is a clinically significant problem with many features characteristic of other pruritic disorders. Our approach was to produce ACD experimentally in humans and in the mouse. The goal was to use the mouse as an animal model for investigating the peripheral neural mechanisms of itch and pain of ACD in humans. Humans and mice were each sensitized by cutaneous topical application of squaric acid dibutyl ester, a hapten not encountered in the environment. Subsequent challenge at another cutaneous site produced local inflammation (“ACD”) with humans reporting persistent itch (lasting up to a week) and mice exhibiting persistent itch- and pain-like behaviors directed toward the ACD site. Enhanced mechanically evoked itch and pain in surrounding skin in humans were reversibly blocked by numbing the ACD site with cold, suggesting dependence on ongoing activity from the site. In mice, in vivo recordings revealed spontaneous activity in a subset of pruriceptive, mechanoheat-sensitive nociceptors with unmyelinated axons innervating the ACD site. These and a larger subpopulation of acutely dissociated small-diameter neurons innervating the ACD site exhibited an upregulation of the receptor CXCR3 and excitatory responses to one of its ligands, the chemokine CXCL10 (IP-10) that contributes to the pathogenesis of ACD. Preliminary findings point to possible therapeutic targets that could be investigated in inflammatory itch disorders in humans.
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References
Alikhan A, Maibach HI. Allergic contact dermatitis. Chem Immunol Allergy. 2014;100:97–100.
Bartoshuk LM, Duffy VB, Green BG, Hoffman HJ, Ko CW, Lucchina LA, Marks LE, Snyder DJ, Weiffenbach JM. Valid across-group comparisons with labeled scales: the gLMS versus magnitude matching. Physiol Behav. 2004;82:109–14.
Bhangoo S, Ren D, Miller RJ, Henry KJ, Lineswala J, Hamdouchi C, Li B, Monahan PE, Chan DM, Ripsch MS, White FA. Delayed functional expression of neuronal chemokine receptors following focal nerve demyelination in the rat: a mechanism for the development of chronic sensitization of peripheral nociceptors. Mol pain. 2007;3:38.
Christensen AD, Haase C. Immunological mechanisms of contact hypersensitivity in mice. APMIS. 2012;120:1–27.
Davidson S, Zhang X, Khasabov SG, Moser HR, Honda CN, Simone DA, Giesler Jr GJ. Pruriceptive spinothalamic tract neurons: physiological properties and projection targets in the primate. J Neurophysiol. 2012;108:1711–23.
Fu K, Qu L, Shimada SG, Nie H, LaMotte RH. Enhanced scratching elicited by a pruritogen and an algogen in a mouse model of contact hypersensitivity. Neurosci Lett. 2014;579:190–4.
Green BG, Dalton P, Cowart B, Shaffer G, Rankin K, Higgins J. Evaluating the ’Labeled Magnitude Scale’ for measuring sensations of taste and smell. Chem Senses. 1996;21:323–34.
Han L, Ma C, Liu Q, Weng HJ, Cui Y, Tang Z, Kim Y, Nie H, Qu L, Patel KN, Li Z, McNeil B, He S, Guan Y, Xiao B, LaMotte RH, Dong X. A subpopulation of nociceptors specifically linked to itch. Nat Neurosci. 2013;16:174–82.
Hosogi M, Schmelz M, Miyachi Y, Ikoma A. Bradykinin is a potent pruritogen in atopic dermatitis: a switch from pain to itch. Pain. 2006;126:16–23.
Imamachi N1, Park GH, Lee H, Anderson DJ, Simon MI, Basbaum AI, Han SK. TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms. Proc Natl Acad Sci U S A. 2009;106(27):11330–5.
Jin X, Gereau RW. Acute p38-mediated modulation of tetrodotoxin-resistant sodium channels in mouse sensory neurons by tumor necrosis factor-alpha. J Neurosci. 2006;26:246–55.
Johanek LM, Meyer RA, Friedman RM, Greenquist KW, Shim B, Borzan J, Hartke T, LaMotte RH, Ringkamp M. A role for polymodal C-fiber afferents in nonhistaminergic itch. J Neurosci. 2008;28:7659–69.
LaMotte RH, Shimada SG, Green BG, Zelterman D. Pruritic and nociceptive sensations and dysesthesias from a spicule of cowhage. J Neurophysiol. 2009;101:1430–43.
LaMotte RH, Dong X, Ringkamp M. Sensory neurons and circuits mediating itch. Nat Rev Neurosci. 2014;15:19–31.
Liu Q, Sikand P, Ma C, Tang Z, Han L, Li Z, Sun S, LaMotte RH, Dong X. Mechanisms of itch evoked by beta-alanine. J Neurosci. 2012;32(42):14532–7.
Ma C, Nie H, Gu Q, Sikand P, LaMotte RH. In vivo responses of cutaneous C-mechanosensitive neurons in mouse to punctate chemical stimuli that elicit itch and nociceptive sensations in humans. J Neurophysiol. 2012;107(1):357–63.
Micali G, Cicero RL, Nasca MR, Sapuppo A. Treatment of alopecia areata with squaric acid dibutyl ester. Int J Dermatol. 1996;35:52–6.
Namer B, Carr R, Johanek LM, Schmelz M, Handwerker HO, Ringkamp M. Separate peripheral pathways for pruritus in man. J Neurophysiol. 2008;100:2062–9.
Pall PS, Hurwitz OE, King BA, LaMotte RH. Psychophysical measurements of itch and nociceptive sensations in an experimental model of allergic contact dermatitis. J Pain. 2015;16(8):741–9.
Qu L, Fan N, Ma C, Wang T, Han L, Fu K, Wang Y, Shimada SG, Dong X, LaMotte RH. Enhanced excitability of MRGPRA3- and MRGPRD-positive nociceptors in a model of inflammatory itch and pain. Brain. 2014;137:1039–50.
Qu L, Fu K, Yang J, Shimada SG, LaMotte RH. CXCR3 chemokine receptor signaling mediates itch in experimental allergic contact dermatitis. Pain. 2015;156(9):1737–46.
Schmelz M, Schmidt R, Bickel A, Handwerker HO, Torebjork HE. Specific C-receptors for itch in human skin. J Neurosci. 1997;17:8003–8.
Shubayev VI, Myers RR. Axonal transport of TNF-alpha in painful neuropathy: distribution of ligand tracer and TNF receptors. J Neuroimmunol. 2001;114:48–56.
Sikand P, Dong X, LaMotte RH. BAM8-22 peptide produces itch and nociceptive sensations in humans independent of histamine release. J Neurosci. 2011;31(20):7563–7.
Silverberg NB, Lim JK, Paller AS, Mancini AJ. Squaric acid immunotherapy for warts in children. J Am Acad Dermatol. 2000;42:803–8.
Steain M, Gowrishankar K, Rodriguez M, Slobedman B, Abendroth A. Upregulation of CXCL10 in human dorsal root ganglia during experimental and natural varicella-zoster virus infection. J Virol. 2011;85:626–31.
Strong JA, Xie W, Coyle DE, Zhang JM. Microarray analysis of rat sensory ganglia after local inflammation implicates novel cytokines in pain. PLoS One. 2012;7(7):e40779.
Torebjork HE, LaMotte RH, Robinson CJ. Peripheral neural correlates of the magnitude of cutaneous pain and hyperalgesia: simultaneous recordings in humans of sensory judgments of pain and evoked responses in nociceptors with C-fibers. J Neurophysiol. 1984;51:325–39.
Van Raemdonck K, Van den Steen PE, Liekens S, Van Damme J, Struyf S. CXCR3 ligands in disease and therapy. Cytokine Growth Factor Rev. 2015;26(3):311–27.
Wang T, Hurwitz O, Shimada SG, Qu L, Fu K, Zhang P, Ma C, LaMotte RH. Chronic compression of the dorsal root ganglion enhances mechanically evoked pain behavior and the activity of cutaneous nociceptors in mice. PLoS One. 2015;10(9):e0137512.
Wooten M, Weng HJ, Hartke TV, Borzan J, Klein AH, Turnquist B, Dong X, Meyer RA, Ringkamp M. Three functionally distinct classes of C-fibre nociceptors in primates. Nat Commun. 2014;5:4122.
Ziegler EA, Magerl W, Meyer RA, Treede RD. Secondary hyperalgesia to punctate mechanical stimuli. Central sensitization to A-fibre nociceptor input. Brain J Neurol. 1999;122(Pt 12):2245–57.
Zylka MJ, Rice FL, Anderson DJ. Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron. 2005;45(1):17–25.
Acknowledgment
Funding provided by NIH grants NS047399 and NS014624 (RHL PI). The author declares no competing interests. The author thanks each of his colleagues who co-authored the cited research studies from our laboratory.
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LaMotte, R.H. (2016). Allergic Contact Dermatitis: A Model of Inflammatory Itch and Pain in Human and Mouse. In: Ma, C., Huang, Y. (eds) Translational Research in Pain and Itch. Advances in Experimental Medicine and Biology, vol 904. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-7537-3_2
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DOI: https://doi.org/10.1007/978-94-017-7537-3_2
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