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Nociceptor sensitization in pain pathogenesis

Nature Medicine volume 16, pages 1248–1257 (2010)Cite this article

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Abstract

The incidence of chronic pain is estimated to be 20–25% worldwide. Few patients with chronic pain obtain complete relief from the drugs that are currently available, and more than half report inadequate relief. Underlying the challenge of developing better drugs to manage chronic pain is incomplete understanding of the heterogeneity of mechanisms that contribute to the transition from acute tissue insult to chronic pain and to pain conditions for which the underlying pathology is not apparent. An intact central nervous system (CNS) is required for the conscious perception of pain, and changes in the CNS are clearly evident in chronic pain states. However, the blockage of nociceptive input into the CNS can effectively relieve or markedly attenuate discomfort and pain, revealing the importance of ongoing peripheral input to the maintenance of chronic pain. Accordingly, we focus here on nociceptors: their excitability, their heterogeneity and their role in initiating and maintaining pain.

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Figure 1: Heterogeneity of nociceptors.
Figure 2: Activation and sensitization of nociceptors.

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References

  1. Merskey, H. & Bogduk, N. Classification of Chronic Pain (IASP, Seattle, 1994).

    Google Scholar 

  2. Staud, R., Nagel, S. & Robinson, M.E. Enhanced central pain processing of fibromyalgia patients is maintained by muscle afferent input: A randomized, double-blind, placebo-controlled study. Pain 145, 96–104 (2009).

    PubMed  PubMed Central  Google Scholar 

  3. Price, D.D. et al. Widespread hyperalgesia in irritable bowel syndrome is dynamically maintained by tonic visceral impulse input and placebo/nocebo factors: evidence from human physchophysics, animal models, and neuroimaging. Neuroimage 47, 995–1001 (2009).

    PubMed  PubMed Central  Google Scholar 

  4. Price, D.D., Zhou, O., Moshiree, B., Robinson, M.E. & Verne, G.N. Peripheral and central contributions to hyperalgesia in irritable bowel syndrome. J. Pain 7, 529–535 (2006).

    PubMed  Google Scholar 

  5. Verne, G.N., Robinson, M.E., Vase, L. & Price, D.D. Reversal of visceral and cutaneous hyperalgesia by local rectal anesthesia in irritable bowel syndrome (IBS) patients. Pain 105, 223–230 (2003).

    PubMed  Google Scholar 

  6. Gracely, R.H., Lynch, S.A. & Bennett, G.J. Painful neuropathy: altered central processing maintained dynamically by peripheral input. Pain 51, 175–194 (1992).

    CAS  PubMed  Google Scholar 

  7. Murdaca, G., Colombo, B.M. & Puppo, F. Anti–TNF-α inhibitors: a new therapeutic approach for inflammatory immune-mediated diseases: an update upon efficacy and adverse events. Int. J. Immunopathol. Pharmacol. 22, 557–565 (2009).

    CAS  PubMed  Google Scholar 

  8. Bharucha, A.E. & Linden, D.R. Linaclotide—a secretagogue and antihyperalgesic agent—what next? Neurogastroenterol. Motil. 22, 227–231 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Edvinsson, L. & Ho, T.W. CGRP receptor antagonism and migraine. Neurotherapeutics 7, 164–175 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Bessou, P. & Perl, E.R. Response of cutaneous sensory units with unmyelinated fibers to noxious stimuli. J. Neurophysiol. 32, 1025–1043 (1969).

    CAS  PubMed  Google Scholar 

  11. Kuner, R. Central mechanisms of pathological pain. Nat. Med. advance online publication doi:10.1038/nm.2231 (14 October 2010).

  12. Caterina, M.J., Gold, M.S. & Meyer, R.A. Molecular biology of nociceptors. in The Neurobiology of Pain (eds. Hunt, S. & Koltzenburg, M.) 1–33 (Oxford Univ. Press, Oxford, 2005).

    Google Scholar 

  13. Riera, C.E., Vogel, H., Simon, S.A. & le Coutre, J. Artificial sweeteners and salts producing a metallic taste sensation activate TRPV1 receptors. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R626–R634 (2007).

    CAS  PubMed  Google Scholar 

  14. Robinson, D.R. & Gebhart, G.F. Inside information—the unique features of visceral sensation. Mol. Interv. 8, 242–253 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Snider, W.D. & McMahon, S.B. Tackling pain at the source: New ideas about nociceptors. Neuron 20, 629–632 (1998).

    CAS  PubMed  Google Scholar 

  16. Hökfelt, T. et al. Phenotype regulation in dorsal root ganglion neurons after nerve injury: focus on peptides and their receptors. in Molecular Neurobiology of Pain: Progress in Pain Research and Management Vol. 9 (ed. Borsook, D.) 115–143 (IASP, Seattle, 1997).

    Google Scholar 

  17. Elitt, C.M. et al. Artemin overexpression in skin enhances expression of TRPV1 and TRPA1 in cutaneous sensory neurons and leads to behavioral sensitivity to heat and cold. J. Neurosci. 26, 8578–8587 (2006).

    CAS  PubMed  Google Scholar 

  18. Kruger, L. Morphological features of thin sensory afferent fibers: a new interpretation of 'nociceptor' function. Prog. Brain Res. 74, 253–257 (1988).

    CAS  PubMed  Google Scholar 

  19. Richardson, J.D. & Vasko, M.R. Cellular mechanisms of neurogenic inflammation. J. Pharmacol. Exp. Ther. 302, 839–845 (2002).

    CAS  PubMed  Google Scholar 

  20. Willis, W.D. Jr . Dorsal root potentials and dorsal root reflexes: a double-edged sword. Exp. Brain Res. 124, 395–421 (1999).

    CAS  PubMed  Google Scholar 

  21. Lewis, T. Experiments relating to cutaneous hyperalgesia and its spread through somatic fibers. Clin. Sci. 2, 373–423 (1935).

    Google Scholar 

  22. Shakhanbeh, J. & Lynn, B. Morphine inhibits antidromic vasodilatation without affecting the excitability of C-polymodal nociceptors in the skin of the rat. Brain Res. 607, 314–318 (1993).

    CAS  PubMed  Google Scholar 

  23. Lynn, B. & Carpenter, S.E. Primary afferent units from the hairy skin of the rat hind limb. Brain Res. 238, 29–43 (1982).

    CAS  PubMed  Google Scholar 

  24. Gebhart, G.F. & Bielefeldt, K. Visceral pain. in The Senses: A Comprehensive Reference (eds. Bushnell, M.C. & Basbaum, A.I.) 543–570 (Academic, San Diego, 2008).

    Google Scholar 

  25. Schaible, H.G. & Schmidt, R.F. Responses of fine medial articular nerve afferents to passive movements of knee joints. J. Neurophysiol. 49, 1118–1126 (1983).

    CAS  PubMed  Google Scholar 

  26. Meyer, R.A., Davis, K.D., Cohen, R.H., Treede, R.D. & Campbell, J.N. Mechanically insensitive afferents (MIAs) in cutaneous nerves of monkey. Brain Res. 561, 252–261 (1991).

    CAS  PubMed  Google Scholar 

  27. Braz, J.M., Nassar, M.A., Wood, J.N. & Basbaum, A.I. Parallel “pain” pathways arise from subpopulations of primary afferent nociceptor. Neuron 47, 787–793 (2005).

    CAS  PubMed  Google Scholar 

  28. Patel, L. & Lindley, C. Aprepitant—a novel NK1-receptor antagonist. Expert Opin. Pharmacother. 4, 2279–2296 (2003).

    CAS  PubMed  Google Scholar 

  29. Ritter, A.M. & Mendell, L.M. Somal membrane properties of physiologically identified sensory neurons in the rat: effects of nerve growth factor. J. Neurophysiol. 68, 2033–2041 (1992).

    CAS  PubMed  Google Scholar 

  30. Kirchhoff, C., Leah, J.D., Jung, S. & Reeh, P.W. Excitation of cutaneous senory nerve endings in the rat by 4-aminopyridine and tetraethylammonium. J. Neurophysiol. 67, 125–131 (1992).

    CAS  PubMed  Google Scholar 

  31. Baumann, T.K., Chaudhary, P. & Martenson, M.E. Background potassium channel block and TRPV1 activation contribute to proton depolarization of sensory neurons from humans with neuropathic pain. Eur. J. Neurosci. 19, 1343–1351 (2004).

    PubMed  Google Scholar 

  32. Harriott, A.M. & Gold, M.S. Contribution of primary afferent channels to neuropathic pain. Curr. Pain Headache Rep. 13, 197–207 (2009).

    PubMed  PubMed Central  Google Scholar 

  33. Viana, F., de la Pena, E. & Belmonte, C. Specificity of cold thermotransduction is determined by differential ionic channel expression. Nat. Neurosci. 5, 254–260 (2002).

    CAS  PubMed  Google Scholar 

  34. Zimmermann, K. et al. Sensory neuron sodium channel Nav1.8 is essential for pain at low temperatures. Nature 447, 855–858 (2007).

    CAS  PubMed  Google Scholar 

  35. Zhao, J. et al. Small RNAs control sodium channel expression, nociceptor excitability and pain thresholds. J. Neurosci. 30, 10860–10871 (2010).

    CAS  PubMed  Google Scholar 

  36. Del Camino, D. et al. TRPA1 contributes to cold hypersensitivity. J. Neurosci. (in the press).

  37. Kremeyer, B. et al. A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome. Neuron 66, 671–680 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Woodbury, C.J. et al. Nociceptors lacking TRPV1 and TRPV2 have normal heat responses. J. Neurosci. 24, 6410–6415 (2004).

    CAS  PubMed  Google Scholar 

  39. Tsunozaki, M. & Bautista, D.M. Mammalian somatosensory mechanotransduction. Curr. Opin. Neurobiol. 19, 362–369 (2009).

    CAS  PubMed  Google Scholar 

  40. Kwan, K.Y., Glazer, J.M., Corey, D.P., Rice, F.L. & Stucky, C.L. TRPA1 modulates mechanotransduction in cutaneous sensory neurons. J. Neurosci. 29, 4808–4819 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Price, M.P. et al. The DRASIC cation channel contributes to the detection of cutaneous touch and acid stimuli in mice. Neuron 32, 1071–1083 (2001).

    CAS  PubMed  Google Scholar 

  42. Patel, A.J. & Honore, E. Properties and modulation of mammalian 2P domain K+ channels. Trends Neurosci. 24, 339–346 (2001).

    CAS  PubMed  Google Scholar 

  43. Maingret, F., Fosset, M., Lesage, F., Lazdunski, M. & Honore, E. TRAAK is a mammalian neuronal mechano-gated K+ channel. J. Biol. Chem. 274, 1381–1387 (1999).

    CAS  PubMed  Google Scholar 

  44. Cummins, T.R. et al. A novel persistent tetrodotoxin-resistant sodium current in SNS-null and wild-type small primary sensory neurons. J. Neurosci. 19, RC43 (1999).

    CAS  PubMed  Google Scholar 

  45. Gold, M.S. & Caterina, M.J. Molecular biology of nociceptor transduction. in The Senses: A Comprehensive Reference Vol. 5 (eds. Basbaum, A.I. & Bushnell, M.C.) 43–74 (Academic, San Diego, 2008).

    Google Scholar 

  46. Waxman, S.G. Channel, neuronal and clinical function in sodium channelopathies: from genotype to phenotype. Nat. Neurosci. 10, 405–409 (2007).

    CAS  PubMed  Google Scholar 

  47. Reimann, F. et al. Pain perception is altered by a nucleotide polymorphism in SCN9A. Proc. Natl. Acad. Sci. USA 107, 5148–5153 (2010).

    CAS  PubMed  Google Scholar 

  48. Liu, B. et al. The acute nociceptive signals induced by bradykinin in rat sensory neurons are mediated by inhibition of M-type K+ channels and activation of Ca2+-activated Cl− channels. J. Clin. Invest. 120, 1240–1252 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Alves, D.P. et al. Additive antinociceptive effect of the combination of diazoxide, an activator of ATP-sensitive K+ channels, and sodium nitroprusside and dibutyryl-cGMP. Eur. J. Pharmacol. 489, 59–65 (2004).

    CAS  PubMed  Google Scholar 

  50. Steranka, L.R., Burch, R.M., Vavrek, R.J., Stewart, J.M. & Enna, S.J. Multiple bradykinin receptors: results of studies using a novel class of receptor antagonists. Adv. Exp. Med. Biol. 236, 111–127 (1988).

    CAS  PubMed  Google Scholar 

  51. Russell, F.A., Veldhoen, V.E., Tchitchkan, D. & McDougall, J.J. Proteinase-activated receptor-4 (PAR4) activation leads to sensitization of rat joint primary afferents via a bradykinin B2 receptor–dependent mechanism. J. Neurophysiol. 103, 155–163 (2010).

    CAS  PubMed  Google Scholar 

  52. Schaible, H.G., Ebersberger, A. & Von Banchet, G.S. Mechanisms of pain in arthritis. Ann. NY Acad. Sci. 966, 343–354 (2002).

    CAS  PubMed  Google Scholar 

  53. Mousa, S.A. Morphological correlates of immune-mediated peripheral opioid analgesia. Adv. Exp. Med. Biol. 521, 77–87 (2003).

    CAS  PubMed  Google Scholar 

  54. Tfelt-Hansen, P., De Vries, P. & Saxena, P.R. Triptans in migraine: a comparative review of pharmacology, pharmacokinetics and efficacy. Drugs 60, 1259–1287 (2000).

    CAS  PubMed  Google Scholar 

  55. Potrebic, S., Ahn, A.H., Skinner, K., Fields, H.L. & Basbaum, A.I. Peptidergic nociceptors of both trigeminal and dorsal root ganglia express serotonin 1D receptors: implications for the selective antimigraine action of triptans. J. Neurosci. 23, 10988–10997 (2003).

    CAS  PubMed  Google Scholar 

  56. Dao, T.T., Lund, J.P., Remillard, G. & Lavigne, G.J. Is myofascial pain of the temporal muscles relieved by oral sumatriptan? A cross-over pilot study. Pain 62, 241–244 (1995).

    CAS  PubMed  Google Scholar 

  57. Harriott, A.M. & Gold, M.S. Serotonin type 1D receptors (5HTR) are differentially distributed in nerve fibres innervating craniofacial tissues. Cephalalgia 28, 933–944 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Carlton, S.M. & Hargett, G.L. Colocalization of metabotropic glutamate receptors in rat dorsal root ganglion cells. J. Comp. Neurol. 501, 780–789 (2007).

    CAS  PubMed  Google Scholar 

  59. Hucho, T.B., Dina, O.A. & Levine, J.D. Epac mediates a cAMP-to-PKC signaling in inflammatory pain: an isolectin B4+ neuron-specific mechanism. J. Neurosci. 25, 6119–6126 (2005).

    CAS  PubMed  Google Scholar 

  60. Lewin, G.R. & Mendell, L.M. Nerve growth factor and nociception. Trends Neurosci. 16, 353–359 (1993).

    CAS  PubMed  Google Scholar 

  61. Amir, R. et al. The role of sodium channels in chronic inflammatory and neuropathic pain. J. Pain 7, S1–S29 (2006).

    CAS  PubMed  Google Scholar 

  62. Rukwied, R. et al. NGF induces non-inflammatory localized and lasting mechanical and thermal hypersensitivity in human skin. Pain 148, 407–413 (2010).

    CAS  PubMed  Google Scholar 

  63. Hefti, F.F. et al. Novel class of pain drugs based on antagonism of NGF. Trends Pharmacol. Sci. 27, 85–91 (2006).

    CAS  PubMed  Google Scholar 

  64. Schaible, H.G. et al. The role of proinflammatory cytokines in the generation and maintenance of joint pain. Ann. NY Acad. Sci. 1193, 60–69 (2010).

    CAS  PubMed  Google Scholar 

  65. Abbadie, C. et al. Chemokines and pain mechanisms. Brain Res. Brain Res. Rev. 60, 125–134 (2009).

    CAS  Google Scholar 

  66. Ren, K. & Dubner, R. Interactions between the immune and nervous systems in pain. Nat. Med. advance online publication doi:10.1038/nm.2234 (14 October 2010).

  67. Fehrenbacher, J.C. et al. Rapid pain modulation with nuclear receptor ligands. Brain Res. Brain Res. Rev. 60, 114–124 (2009).

    CAS  Google Scholar 

  68. Walder, R.Y. et al. ASIC1 and ASIC3 play different roles in the development of hyperalgesia after inflammatory muscle injury. J. Pain 11, 210–218 (2010).

    CAS  PubMed  Google Scholar 

  69. Shinoda, M., Feng, B. & Gebhart, G.F. Peripheral and central P2X receptor contributions to colon mechanosensitivity and hypersensitivity in the mouse. Gastroenterology 137, 2096–2104 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Vaughn, A.H. & Gold, M.S. Ionic mechanisms underlying inflammatory mediator–induced sensitization of dural afferents. J. Neurosci. 30, 7878–7888 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Backonja, M.M. & Stacey, B. Neuropathic pain symptoms relative to overall pain rating. J. Pain 5, 491–497 (2004).

    PubMed  Google Scholar 

  72. Janig, W., Grossmann, L. & Gorodetskaya, N. Mechano- and thermosensitivity of regenerating cutaneous afferent nerve fibers. Exp. Brain Res. 196, 101–114 (2009).

    PubMed  Google Scholar 

  73. McLachlan, E.M., Janig, W., Devor, M. & Michaelis, M. Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia. Nature 363, 543–546 (1993).

    CAS  PubMed  Google Scholar 

  74. Rush, A.M. et al. A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc. Natl. Acad. Sci. USA 103, 8245–8250 (2006).

    CAS  PubMed  Google Scholar 

  75. Sengupta, J.N. & Gebhart, G.F. Mechanosensitive afferent fibers in the gastrointestinal and lower urinary tracts. in Visceral Pain, Progress in Pain Research and Management Vol. 5 (ed. Gebhart, G.F.) 75–98 (IASP, Seattle, 1995).

    Google Scholar 

  76. Page, A.J. et al. Different contributions of ASIC channels 1a, 2 and 3 in gastrointestinal mechanosensory function. Gut 54, 1408–1415 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Dubreuil, A.S. et al. Role of T-type calcium current in identified D-hair mechanoreceptor neurons studied in vitro. J. Neurosci. 24, 8480–8484 (2004).

    CAS  PubMed  Google Scholar 

  78. Honore, P. et al. A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a novel transient receptor potential type V1 receptor antagonist, relieves pathophysiological pain associated with inflammation and tissue injury in rats. J. Pharmacol. Exp. Ther. 314, 410–421 (2005).

    CAS  PubMed  Google Scholar 

  79. Alessandri-Haber, N., Dina, O.A., Chen, X. & Levine, J.D. TRPC1 and TRPC6 channels cooperate with TRPV4 to mediate mechanical hyperalgesia and nociceptor sensitization. J. Neurosci. 29, 6217–6228 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Brierley, S.M. et al. The ion channel TRPA1 is required for normal mechanosensation and is modulated by algesic stimuli. Gastroenterology 137, 2084–2095 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Maingret, F., Patel, A.J., Lesage, F., Lazdunski, M. & Honore, E. Mechano- or acid stimulation, two interactive modes of activation of the TREK-1 potassium channel. J. Biol. Chem. 274, 26691–26696 (1999).

    CAS  PubMed  Google Scholar 

  82. Alloui, A. et al. TREK-1, a K+ channel involved in polymodal pain perception. EMBO J. 25, 2368–2376 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Burnstock, G. Purinergic mechanosensory transduction and visceral pain. Mol. Pain 5, 69 (2009).

    PubMed  PubMed Central  Google Scholar 

  84. Noël, J. et al. The mechano-activated K+ channels TRAAK and TREK-1 control both warm and cold perception. EMBO J. 28, 1308–1318 (2009).

    PubMed  PubMed Central  Google Scholar 

  85. Bautista, D.M. et al. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124, 1269–1282 (2006).

    CAS  PubMed  Google Scholar 

  86. Karashima, Y. et al. TRPA1 acts as a cold sensor in vitro and in vivo. Proc. Natl. Acad. Sci. USA 106, 1273–1278 (2009).

    CAS  PubMed  Google Scholar 

  87. Kwan, K.Y. et al. TRPA1 contributes to cold, mechanical and chemical nociception but is not essential for hair-cell transduction. Neuron 50, 277–289 (2006).

    CAS  PubMed  Google Scholar 

  88. Bautista, D.M. et al. The menthol receptor TRPM8 is the principal detector of environmental cold. Nature 448, 204–208 (2007).

    CAS  PubMed  Google Scholar 

  89. McKemy, D.D., Neuhausser, W.M. & Julius, D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416, 52–58 (2002).

    CAS  Google Scholar 

  90. Peier, A.M. et al. A heat-sensitive TRP channel expressed in keratinocytes. Science 296, 2046–2049 (2002).

    CAS  PubMed  Google Scholar 

  91. Güler, A.D. et al. Heat-evoked activation of the ion channel, TRPV4. J. Neurosci. 22, 6408–6414 (2002).

    PubMed  Google Scholar 

  92. Burnstock, G. Purinergic receptors and pain. Curr. Pharm. Des. 15, 1717–1735 (2009).

    CAS  PubMed  Google Scholar 

  93. Camilleri, M. Review article: new receptor targets for medical therapy in irritable bowel syndrome. Aliment. Pharmacol. Ther. 31, 35–46 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Rau, K.K., Johnson, R.D. & Cooper, B.Y. Nicotinic AChR in subclassified capsaicin-sensitive and -insensitive nociceptors of the rat DRG. J. Neurophysiol. 93, 1358–1371 (2005).

    CAS  PubMed  Google Scholar 

  95. Carlton, S.M. & Coggeshall, R.E. Inflammation-induced changes in peripheral glutamate receptor populations. Brain Res. 820, 63–70 (1999).

    CAS  PubMed  Google Scholar 

  96. Price, T.J., Cervero, F., Gold, M.S., Hammond, D.L. & Prescott, S.A. Chloride regulation in the pain pathway. Brain Res. Brain Res. Rev. 60, 149–170 (2009).

    CAS  Google Scholar 

  97. Michaelis, M., Blenk, K.H., Vogel, C. & Janig, W. Distribution of sensory properties among axotomized cutaneous C-fibres in adult rats. Neuroscience 94, 7–10 (1999).

    CAS  PubMed  Google Scholar 

  98. Howe, J.F., Loeser, J.D. & Calvin, W.H. Mechanosensitivity of dorsal root ganglia and chronically injured axons: a physiological basis for the radicular pain of nerve root compression. Pain 3, 25–41 (1977).

    CAS  PubMed  Google Scholar 

  99. Kohno, T. et al. Peripheral axonal injury results in reduced mu opioid receptor pre- and post-synaptic action in the spinal cord. Pain 117, 77–87 (2005).

    CAS  PubMed  Google Scholar 

  100. Tsuzuki, K. et al. Differential regulation of P2X3 mRNA expression by peripheral nerve injury in intact and injured neurons in the rat sensory ganglia. Pain 91, 351–360 (2001).

    CAS  PubMed  Google Scholar 

  101. Birder, L.A. & Perl, E.R. Expression of α2-adrenergic receptors in rat primary afferent neurones after peripheral nerve injury or inflammation. J. Physiol. (Lond.) 515, 533–542 (1999).

    CAS  Google Scholar 

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Acknowledgements

The authors are supported by National Institutes of Health awards NS019912 (G.F.G.), NS035790 (G.F.G.), DE018252 (M.S.G.) and NS063010 (M.S.G.).

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  1. Department of Anesthesiology, Center for Pain Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Michael S Gold & Gerald F Gebhart

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Gold, M., Gebhart, G. Nociceptor sensitization in pain pathogenesis. Nat Med 16, 1248–1257 (2010). https://doi.org/10.1038/nm.2235

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