Abstract
Once there was a day when all type C nonmyelinated neurons were indistinguishable. That time of histologic analysis has passed, and we have entered an era of unparalleled technological insight into the mechanisms of pain and pruritus. Since the description of the capsaicin receptor, transient receptor protein vanilloid 1 (TRPV1), in 1997, we have seen the number of related sensor ion channels, G protein–coupled receptors, and signaling proteins explode. Specific nociceptive pathways have been identified based on their sensitivity to mechanical, heat, chemical, and cold stimuli. Pruritus is now recognized to have both histamine-sensitive and histamine-independent afferent arcs. Cross-talk between C-fibre systems and myelinated neural pathways has become more complex, but through complexity, a new reality of sensory coding is emerging. A multitude of novel therapeutics have been and are in planning and production stages. These will almost certainly revolutionize our understanding and treatment of pain and itch by the end of this decade.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Smith ES, Lewin GR. Nociceptors: a phylogenetic view. J Comp Physiol A Neuroethol Sens Neural Behav Physiol. 2009;1952:1089–106.
•• Dubin AE, Patapoutian A. Nociceptors: the sensors of the pain pathway. J Clin Invest. 2010;120:3760–3772, doi: 10.1172/JCI42843. This is an excellent summary of one classification of pain-mediating sensor systems and their interactions.
Melzack R, Wall PD. Pain mechanisms: a new theory. Science. 1965;150:971–9.
Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 1997;389:816–24.
Yu FH and WA Catterall. The VGL-Chanome: a protein superfamily specialized for electrical signaling and ionic homeostatis. Science STKE. 2004;re15 www.stke.org/cgi/content/full/sigtrans;2004/253/re15.
Belmone C, Viana F. Molecular and cellular limits to somatosensory specificity. Molecular Pain. 2008;4:14.
Vay L, Gu C, McNaughton PA. The thermo-TRP ion channel family: properties and therapeutic implications. Br J Pharmacol. 2011. doi:10.1111/j.1476-5381.2011.01601.x.
O’Hanlon S, Facer P, Simpson KD, Sandhu G, Saleh HA, Anand P. Neuronal markers in allergic rhinitis: expression and correlation with sensory testing. Laryngoscope. 2007;117:1519–27.
Raap U, Braunstahl GJ. The role of neurotrophins in the pathophysiology of allergic rhinitis. Curr Opin Allergy Clin Immunol. 2010;10:8–13.
Alenmyr L, Högestätt ED, Zygmunt PM, Greiff L. TRPV1-mediated itch in seasonal allergic rhinitis. Allergy. 2009;64:807–10.
Baraniuk JN, Petrie KN, Le U, Tai CF, Park YJ, Yuta A, Ali M, Vandenbussche CJ, Nelson B. Neuropathology in rhinosinusitis. Am J Respir Crit Care Med. 2005;171:5–11.
Alenmyr L, Greiff L, Andersson M, Sterner O, Zygmunt PM, Högestätt ED. Effect of mucosal TRPV1 inhibition in allergic rhinitis. Basic Clin Pharmacol Toxicol. 2011. doi:10.1111/j.1742-7843.2011.00803.x. Epub ahead of print.
Mair N, Benetti C, Andratsch M, Leitner MG, Constantin CE, Camprubí-Robles M, Quarta S, Biasio W, Kuner R, Gibbins IL, Kress M, Haberberger RV. Genetic evidence for involvement of neuronally expressed S1P1 receptor in nociceptor sensitization and inflammatory pain. PLoS One. 2011;6:e17268.
Keh SM, Facer P, Yehia A, Sandhu G, Saleh HA, Anand P. The menthol and cold sensation receptor TRPM8 in normal human nasal mucosa and rhinitis. Rhinology. 2011;49:453–7.
•• Grace MS, Belvisi MG. TRPA1 receptors in cough. Pulm Pharmacol Ther. 2011;24:286–288. This is an excellent review of cough mechanisms and the potential role of TRPA1 receptors and nerve populations.
Uta D, Furue H, Pickering AE, Rashid MH, Mizuguchi-Takase H, Katafuchi T, Imoto K, Yoshimura M. TRPA1-expressing primary afferents synapse with a morphologically identified subclass of substantia gelatinosa neurons in the adult rat spinal cord. Eur J Neurosci. 2010;31:1960–73.
Nassini R, Gees M, Harrison S, De Siena G, Materazzi S, Moretto N, Failli P, Preti D, Marchetti N, Cavazzini A, Mancini F, Pedretti P, Nilius B, Patacchini R, Geppetti P. Oxaliplatin elicits mechanical and cold allodynia in rodents via TRPA1 receptor stimulation. Pain. 2011;152:1621–31.
Hori K, Ozaki N, Suzuki S, Sugiura Y. Upregulations of P2X(3) and ASIC3 involve in hyperalgesia induced by cisplatin administration in rats. Pain. 2010;149:393–405.
Willis DN, Liu B, Ha MA, Jordt SE, Morris JB. Menthol attenuates respiratory irritation responses to multiple cigarette smoke irritants. FASEB J. 2011;25:4434–44.
Deval E, Gasull X, Noël J, Salinas M, Baron A, Diochot S, Lingueglia E. Acid-sensing ion channels (ASICs): pharmacology and implication in pain. Pharmacol Ther. 2010;128:549–58.
Light AR, White AT, Hughen RW, Light KC. Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects. J Pain. 2009;10:1099–112.
•• Burnstock G, Krügel U, Abbracchio MP, Illes P. Purinergic signalling: from normal behaviour to pathological brain function. Prog Neurobiol. 2011;95:229–274. This is an excellent review of purinergic receptors and their functions in the central nervous system.
Jankowski MP, Rau KK, Soneji DJ, Ekmann KM, Anderson CE, Molliver DC, Koerber HR. Purinergic receptor P2Y1 regulates polymodal C-fiber thermal thresholds and sensory neuron phenotypic switching during peripheral inflammation. Pain. 2011 Nov 30. [Epub ahead of print].
Paruchuri S, Tashimo H, Feng C, Maekawa A, Xing W, Jiang Y, Kanaoka Y, Conley P, Boyce JA. Leukotriene E4-induced pulmonary inflammation is mediated by the P2Y12 receptor. J Exp Med. 2009;206:2543–55.
Hassenklöver T, Schwartz P, Schild D, Manzini I. Purinergic signaling regulates cell proliferation of olfactory epithelium progenitors. Stem Cells. 2009;27:2022–31.
Kim CH, Kim SS, Choi JY, Shin JH, Kim JY, Namkung W, Lee JG, Lee MG, Yoon JH. Membrane-specific expression of functional purinergic receptors in normal human nasal epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2004;287:L835–42.
Song KS, Kim HJ, Kim K, Lee JG, Yoon JH. Regulator of G-protein signaling 4 suppresses LPS-induced MUC5AC overproduction in the airway. Am J Respir Cell Mol Biol. 2009;41:40–9.
Rollins BM, Burn M, Coakley RD, Chambers LA, Hirsh AJ, Clunes MT, Lethem MI, Donaldson SH, Tarran R. A2B adenosine receptors regulate the mucus clearance component of the lung’s innate defense system. Am J Respir Cell Mol Biol. 2008;39:190–7.
Dussor G, Zylka MJ, Anderson DJ, McCleskey EW. Cutaneous sensory neurons expressing the Mrgprd receptor sense extracellular ATP and are putative nociceptors. J Neurophysiol. 2008;99:1581–9.
•• Ma Q. Labeled lines meet and talk: population coding of somatic sensations. J Clin Invest. 2010;120(11):3773–8. doi: 10.1172/JCI43426. This is an important introduction to the patterns of C-fibre interactions that code for different sensations.
Campero M, Baumann TK, Bostock H, Ochoa JL. Human cutaneous C fibres activated by cooling, heating and menthol. J Physiol. 2009;587:5633–52.
Lindstedt F, Johansson B, Martinsen S, Kosek E, Fransson P, Ingvar M. Evidence for thalamic involvement in the thermal grill illusion: an FMRI study. PLoS One. 2011;6(11):e27075.
Seifert F, Maihöfner C. Representation of cold allodynia in the human brain—a functional MRI study. NeuroImage. 2007;35:1168–80.
Krämer HH, Stenner C, Seddigh S, Bauermann T, Birklein F, Maihöfner C. Illusion of pain: pre-existing knowledge determines brain activation of ‘imagined allodynia. J Pain. 2008;9:543–51.
Boettger MK, Schwier C, Bär KJ. Sad mood increases pain sensitivity upon thermal grill illusion stimulation: implications for central pain processing. Pain. 2011;152:123–30.
Braat JP, Mulder PG, Fokkens WJ, van Wijk RG, Rijntjes E. Intranasal cold dry air is superior to histamine challenge in determining the presence and degree of nasal hyperreactivity in nonallergic noninfectious perennial rhinitis. Am J Respir Crit Care Med. 1998;157:1748–55.
Nakaya M, Takeuchi N, Kondo K. Immunohistochemical localization of histamine receptor subtypes in human inferior turbinates. Ann Otol Rhinol Laryngol. 2004;113:552–7.
Andrew D, Craig AD. Spinothalamic lamina 1 neurons selectively sensitive to histamine: a central neural pathway for itch. Nat Neurosci. 2001;4:72–7.
Vaughan RP, Szewczyk Jr MT, Lanosa MJ, Desesa CR, Gianutsos G, Morris JB. Adenosine sensory transduction pathways contribute to activation of the sensory irritation response to inspirited irritant vapors. Toxicol Sci. 2006;93:411–21.
Gao Z, Li JD, Sinoway LI, Li J. Effect of muscle interstitial pH on P2X and TRPV1 receptor-mediated pressor response. J Appl Physiol. 2007;102:2288–93.
Wilson SR, Gerhold KA, Bifolck-Fisher A, Liu Q, Patel KN, Dong X, Bautista DM. TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch. Nat Neurosci. 2011;14:595–602.
Johanek LM, Meyer RA, Hartke T, Hobelmann JG, Maine DN, LaMotte RH, Ringkamp M. Psychophysical and physiological evidence for parallel afferent pathways mediating the sensation of itch. J Neurosci. 2007;27:7490–7.
Shelley WB, Arthur RP. Studies on cowhage (Mucuna pruriens) and its pruritogenic proteinase, mucunain. AMA Arch Derm. 1955;72:399–406.
Handwerker HO. Microneurography of pruritus. Neurosci Lett. 2010;19(470):193–6.
• Davidson S, Giesler GJ. The multiple pathways for itch and their interactions with pain. Trends Neurosci. 2010;33:550–558. This is a useful distillation of pruritic mechanisms to two pathways and demonstration of the interactions of pain and itch systems.
Swain MG. Gastrin-releasing peptide and pruritus: more than just scratching the surface. J Hepatol. 2008;48:681–3.
Baraniuk JN, Lundgren JD, Goff J, Peden D, Merida M, Shelhamer J, Kaliner M. Gastrin-releasing peptide in human nasal mucosa. J Clin Invest. 1990;85:998–1005.
• Ständer S, Raap U, Weisshaar E, Schmelz M, Mettang T, Handwerker H, Luger TA. Pathogenesis of pruritus. J Dtsch Dermatol Ges. 2011;9(6):456–63. doi:10.1111/j.1610-0387.2011.07585.x. This is a comprehensive examination of mechanisms of itch, including newer potential pathways.
Rieker J, Steinhoff M, Hoffmann TK, Ruzicka T, Zlotnik A, Homey B. IL-31: a new link between T cells and pruritus in atopic skin inflammation. J Allergy Clin Immunol. 2006;117:411–7.
Melzack R, Casey KL. Sensory, motivational and central control determinants of chronic pain: a new conceptual model. In: Kenshalo DR, editor. The skin senses: proceedings of the first international symposium on the skin senses. Springfield: Thomas; 1968.
Turk DC, Rudy TE. Toward an empirically derived taxonomy of chronic pain patients: integration of psychological assessment data. J Consult Clin Psychol. 1988;56:233–8.
Acknowledgments
The figures are used with the permission of the copyright holder. Support was provided by Congressionally Directed Medical Research Program awards W81XWH-07-1-0618 and W81XWH-09-1-0526, and the Georgetown University–Howard University Clinical and Translational Science Award.
Disclosure
No potential conflicts of interest relevant to this article were reported.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Baraniuk, J.N. Rise of the Sensors: Nociception and Pruritus. Curr Allergy Asthma Rep 12, 104–114 (2012). https://doi.org/10.1007/s11882-012-0245-8
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11882-012-0245-8