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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 2/2011

01-04-2011 | Review

Update on peripheral mechanisms of pain: beyond prostaglandins and cytokines

Authors: Hans-Georg Schaible, Andrea Ebersberger, Gabriel Natura

Published in: Arthritis Research & Therapy | Issue 2/2011

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Abstract

The peripheral nociceptor is an important target of pain therapy because many pathological conditions such as inflammation excite and sensitize peripheral nociceptors. Numerous ion channels and receptors for inflammatory mediators were identified in nociceptors that are involved in neuronal excitation and sensitization, and new targets, beyond prostaglandins and cytokines, emerged for pain therapy. This review addresses mechanisms of nociception and focuses on molecules that are currently favored as new targets in drug development or that are already targeted by new compounds at the stage of clinical trials - namely the transient receptor potential V1 receptor, nerve growth factor, and voltage-gated sodium channels - or both.
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Literature
1.
Breivik H, Beverly C, Ventafridda V, Cohen R, Gallacher D: Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain. 2006, 10: 287-333. 10.1016/j.ejpain.2005.06.009.CrossRefPubMed
2.
Gold MS, Gebhart GF: Nociceptor sensitization in pain pathogenesis. Nat Med. 2010, 16: 1248-1257. 10.1038/nm.2235.CrossRefPubMed
3.
4.
Belmonte C, Cervero E, (Eds): Neurobiology of Nociceptors. 1996, Oxford: Oxford University Press
5.
6.
Schaible H-G, Del Rosso A, Matucci-Cerinic M: Neurogenic aspects of inflammation. Rheum Dis Clin North Am. 2005, 31: 77-101. 10.1016/j.rdc.2004.09.004.CrossRefPubMed
7.
Schmidt R, Schmelz M, Forster C, Ringkamp M, Torebjork E, Handwerker H: Novel classes of responsive and unresponsive C nociceptors in human skin. J Neurosci. 1995, 15: 333-341.PubMed
8.
Cervero F: Spinal cord hyperexcitablity and its role in pain and hyperalgesia. Exp Brain Res. 2009, 196: 129-137. 10.1007/s00221-009-1789-2.CrossRefPubMed
9.
Sandkuhler J: Models and mechanisms of hyperalgesia and allodynia. Physiol Rev. 2009, 89: 707-758. 10.1152/physrev.00025.2008.CrossRefPubMed
10.
Devor M: Ectopic discharge in Aβ afferents as a source of neuropathic pain. Exp Brain Res. 2009, 196: 115-128. 10.1007/s00221-009-1724-6.CrossRefPubMed
11.
Janig W, Grossmann L, Gorodetskaya N: Mechano- and thermosensitivity of regenerating cutaneous afferent nerve fi bers. Exp Brain Res. 2009, 196: 101-114. 10.1007/s00221-008-1673-5.CrossRefPubMed
12.
Wu G, Ringkamp M, Hartke TV, Murinson BB, Campbell JN, Griffin JW, Meyer RA: Early onset of spontaneous activity in uninjured C-fiber nociceptors after injury to neighbouring nerve fi bers. J Neurosci. 2001, 21: RC140-1-5PubMed
13.
14.
Sommer C, Kress M: Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in infl ammatory and neuropathic hyperalgesia. Neurosci Lett. 2004, 361: 184-187. 10.1016/j.neulet.2003.12.007.CrossRefPubMed
15.
Janig W, Levine JD, Michaelis M: Interactions of sympathetic and primary afferent neurons following nerve injury and tissue trauma. The Polymodal Receptor: A Gateway to Pathological Pain. Progress in Brain Research. Edited by: Kumazawa T, Kruger L, Mizumura K. 1996, Amsterdam: Elsevier Science, 113: 161-184.CrossRef
16.
Bondeson J, Blom AB, Wainwright S: The role of synovial macrophages and macrophage-produced mediators in driving inflammatory and destructive responses in osteoarthritis. Arthritis Rheum. 2010, 62: 647-657.CrossRefPubMed
17.
Im H-J, Kim J-S, Li X, Kotwal N, Sumner DR, van Wijnen AJ, Davis FJ, Yan D, Levine B, Henry JL, Desevre J, Krin JS: Alteration of sensory neurons and spinal response to an experimental osteoarthritis pain model. Arthritis Rheum. 2010, 62: 2995-3005. 10.1002/art.27608.PubMedCentralCrossRefPubMed
18.
Nakajima T, Ohtori S, Inoue G, Koshi T, Yamamoto J, Takahashi K, Harada Y: The characteristics of dorsal-root-ganglia and sensory innervation of the hip in rats. J Bone Joint Surg Br. 2008, 90: 254-257.CrossRefPubMed
19.
Jimenez-Andrade JM, Mantyh WG, Bloom AP, Xu H, Ferng AS, Dussor G, Vanderah TW, Mantyh PW: A phenotypically restricted set of primary afferent nerve fibres innervate the bone versus skin: therapeutic opportunity for treating skeletal pain. Bone. 2010, 46: 306-313. 10.1016/j.bone.2009.09.013.PubMedCentralCrossRefPubMed
20.
21.
Schaible H-G, Richter F, Ebersberger A, Boettger MK, Vanegas H, Natura G, Vazquez E, Segond von Banchet G: Joint pain. Exp Brain Res. 2009, 196: 153-162. 10.1007/s00221-009-1782-9.CrossRefPubMed
22.
Bielefeldt K, Gebhart GF: Visceral pain: basic mechanisms. Wall and Melzack's Textbook of Pain. Edited by: McMahon SB, Koltzenburg M. 2006, Edinburgh: Elsevier Churchill Livingstone, 721-736.CrossRef
23.
St Pierre M, Reeh PW, Zimmermann K: Differential role of TRPV channel block on polymodal activation of rat cutaneous nociceptors in vitro. Exp Brain Res. 2009, 196: 31-44. 10.1007/s00221-009-1808-3.CrossRefPubMed
24.
Hucho T, Levine JD: Signaling pathways in sensitization: toward a nociceptor cell biology. Neuron. 2007, 55: 365-376. 10.1016/j.neuron.2007.07.008.CrossRefPubMed
25.
Linley JE, Rose K, Ooi L, Gamper N: Understanding inflammatory pain: ion channels contributing to acute and chronic nociception. Pflügers Arch. 2010, 459: 657-669. 10.1007/s00424-010-0784-6.CrossRefPubMed
26.
McCleskey EW, Gold MS: Ion channels of nociception. Annu Rev Physiol. 1999, 61: 835-856. 10.1146/annurev.physiol.61.1.835.CrossRefPubMed
27.
Mizumura K, Sugiura T, Katanosaka K, Banik RK, Kozaki Y: Excitation and sensitization of nociceptors by bradykinin: what do we know?. Exp Brain Res. 2009, 196: 53-65. 10.1007/s00221-009-1814-5.CrossRefPubMed
28.
Schaible H-G, Segond von Banchet G, Boettger MK, Bräuer R, Gajda M, Richter F, Hensellek S, Brenn D, Natura G: The role of proinflammatory cytokines in the generation and maintenance of joint pain. Ann N Y Acad Sci. 2010, 1193: 60-69. 10.1111/j.1749-6632.2009.05301.x.CrossRefPubMed
29.
Üceyler N, Schäfers M, Sommer C: Mode of action of cytokines on nociceptive neurons. Exp Brain Res. 2009, 196: 67-78. 10.1007/s00221-009-1755-z.CrossRefPubMed
30.
Stein C, Clark JD, Oh U, Vasko MR, Wilcox GL, Overland AC, Vanderah TW, Spencer RH: Peripheral mechanisms of pain and analgesia. Brain Res Rev. 2009, 60: 90-113. 10.1016/j.brainresrev.2008.12.017.PubMedCentralCrossRefPubMed
31.
Levine JD, Alessandri-Haber N: TRP channels: targets for the relief of pain. Biochim Biophys Acta. 2007, 1772: 989-1003.CrossRefPubMed
32.
Szabo A, Helyes z, Sandor K, Bite A, Pinter E, Nemeth J, Banvolgyi A, Bolcskei K, Elekes K, Szolcsanyi J: Role of transient receptor potential vanilloid 1 receptors in adjuvant-induced chronic arthritis: in vivo study using genedeficient mice. J Pharmacol Exp Ther. 2005, 314: 111-119. 10.1124/jpet.104.082487.CrossRefPubMed
33.
Belmonte C, Brock JA, Viana F: Converting cold into pain. Exp Brain Res. 2009, 196: 13-30. 10.1007/s00221-009-1797-2.CrossRefPubMed
34.
Mense S: Algesic agents exciting muscle nociceptors. Exp Brain Res. 2009, 196: 89-100. 10.1007/s00221-008-1674-4.CrossRefPubMed
35.
Rush AM, Cummins TR, Waxman SG: Multiple sodium channels and their roles in electrogenesis within dorsal root ganglion neurons. J Physiol. 2007, 579: 1-14. 10.1113/jphysiol.2006.121483.PubMedCentralCrossRefPubMed
36.
Pinto V, Derkach VA, Safronov BV: Role of TTX-sensitive and TTX-resistant sodium channels in Aδ and C-fiber conduction and synaptic transmission. J Neurophysiol. 2008, 99: 617-628. 10.1152/jn.00944.2007.CrossRefPubMed
37.
Wada A, Wanke E, Gullo F, Schiavon E: Voltage-dependent Nav1.7 sodium channels: multiple roles in adrenal chromaffin cells and peripheral nervous system. Acta Physiol (Oxf). 2008, 192: 221-231.CrossRef
38.
McMahon SB, Bennet DLH, Bevan S: Inflammatory mediators and modulators. Wall and Melzack's Textbook of Pain. Edited by: McMahon SB, Koltzenburg M. 2006, Edinburgh: Elsevier Churchill Livingstone, 49-72.CrossRef
39.
Segond von Banchet G, Boettger MK, Fischer N, Bräuer R, Schaible H-G: Experimental arthritis causes tumor necrosis factor-α dependent infiltration of macrophages in rat dorsal root ganglia which correlates with pain-related behavior. Pain. 2009, 145: 151-159. 10.1016/j.pain.2009.06.002.CrossRefPubMed
40.
Inglis JJ, Notley CA, Essex D, Wilson AW, Feldmann M, Anand P, Williams R: Collagen-induced arthritis as a model of hyperalgesia: functional and cellular analysis of the analgesic actions of tumor necrosis factor blockade. Arthritis Rheum. 2007, 56: 4015-4023. 10.1002/art.23063.CrossRefPubMed
41.
Lane NE, Schnitzer TJ, Birbara CA, Mokhtarani M, Shelton DL, Smith MD, Brown MT: Tanezumab for the treatment of pain from osteoarthritis of the knee. N Engl J Med. 2010, 363: 1521-1531. 10.1056/NEJMoa0901510.CrossRefPubMed
42.
Bennett D: NGF, sensitization of nociceptors. Encyclopedia of Pain. Edited by: Schmidt RF, Willis WD. 2007, Berlin: Springer, 2: 1338-1342.CrossRef
43.
Bär K-J, Schurigt U, Scholze A, Segond von Banchet G, Stopfel N, Bräuer R, Halbhuber K-J, Schaible H-G: The expression and localisation of somatostatin receptors in dorsal root ganglion neurons of normal and monoarthritic rats. Neuroscience. 2004, 127: 197-206. 10.1016/j.neuroscience.2004.04.051.CrossRefPubMed
44.
Agarwal N, Pacher P, Tegeder I, Amaya F, Constantin CE, Brenner GJ, Rubino T, Michalski CW, Marsicano G, Monory K, Mackie K, Marian C, Batkai S, Parolaro D, Fischer MJ, Reeh P, Kunos G, Kress M, Lutz B, Woolf CJ, Kuner R: Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. Nat Neurosci. 2007, 10: 870-879. 10.1038/nn1916.PubMedCentralCrossRefPubMed
45.
Kress M, Kuner R: Mode of action of cannabinoids on nociceptive nerve endings. Exp Brain Res. 2009, 196: 79-88. 10.1007/s00221-009-1762-0.CrossRefPubMed
46.
Helyes Z, Szabó A, Németh J, Jakab B, Pintér E, Bánvölgyi Á, Kereskai L, Kéri G, Szolcsányi J: Anti-inflammatory and analgesic effects of somatostatin released from capsaicin-sensitive sensory nerve terminals in a Freund's adjuvant-induced chronic arthritis model in the rat. Arthritis Rheum. 2004, 50: 1677-1685. 10.1002/art.20184.CrossRefPubMed
47.
Treede RD, Kenshalo DR, Gracely RH, Jones A: The cortical representation of pain. Pain. 1999, 79: 105-111. 10.1016/S0304-3959(98)00184-5.CrossRefPubMed
48.
49.
Willis WD: The role of TRPV1 receptors in pain evoked by noxious thermal and chemical stimuli. Exp Brain Res. 2009, 196: 5-11. 10.1007/s00221-009-1760-2.CrossRefPubMed
Metadata
Title
Update on peripheral mechanisms of pain: beyond prostaglandins and cytokines
Authors
Hans-Georg Schaible
Andrea Ebersberger
Gabriel Natura
Publication date
01-04-2011
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 2/2011
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/ar3305

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