Inflammation Research

, Volume 65, Issue 9, pp 725–736

Role of capsaicin-sensitive nerves and tachykinins in mast cell tryptase-induced inflammation of murine knees

  • Éva Borbély
  • Katalin Sándor
  • Adrienn Markovics
  • Ágnes Kemény
  • Erika Pintér
  • János Szolcsányi
  • John P. Quinn
  • Jason J. McDougall
  • Zsuzsanna Helyes
Original Research Paper

Abstract

Objective, design

Mast cell tryptase (MCT) is elevated in arthritic joints, but its direct effects are not known. Here, we investigated MCT-evoked acute inflammatory and nociceptive mechanisms with behavioural, in vivo imaging and immunological techniques.

Material and subjects

Neurogenic inflammation involving capsaicin-sensitive afferents, transient receptor potential vanilloid 1 receptor (TRPV1), substance P (SP), neurokinin A (NKA) and their NK1 tachykinin receptor were studied using gene-deleted mice compared to C57Bl/6 wildtypes (n = 5–8/group).

Treatment

MCT was administered intraarticularly or topically (20 μl, 12 μg/ml). Capsaicin-sensitive afferents were defunctionalized with the TRPV1 agonist resiniferatoxin (RTX; 30–70–100 μg/kg s.c. pretreatment).

Methods

Knee diameter was measured with a caliper, synovial perfusion with laser Doppler imaging, mechanonociception with aesthesiometry and weight distribution with incapacitance tester over 6 h. Cytokines and neuropeptides were determined with immunoassays.

Results

MCT induced synovial vasodilatation, oedema, impaired weight distribution and mechanical hyperalgesia, but cytokine or neuropeptide levels were not altered at the 6-h timepoint. Hyperaemia was reduced in RTX-treated and TRPV1-deleted animals, and oedema was absent in NK1-deficient mice. Hyperalgesia was decreased in SP/NKA- and NK1-deficient mice, weight bearing impairment in RTX-pretreated, TRPV1- and NK1-deficient animals.

Conclusions

MCT evokes synovial hyperaemia, oedema, hyperalgesia and spontaneous pain. Capsaicin-sensitive afferents and TRPV1 receptors are essential for vasodilatation, while tachykinins mediate oedema and pain.

Keywords

Capsaicin-sensitive sensory nerves Arthritis Inflammation Pain Oedema Synovial microcirculation 

Abbreviations

CGRP

Calcitonin gene-related peptide

IL-1β

Interleukin-1β

MCT

Mast cell tryptase

NK1

Tachykinin NK1 receptor

NKA

Neurokinin A

PAR2

Protease-activated receptor 2

TRPV1

Transient receptor potential vanilloid 1

RTX

Resiniferatoxin

SP

Substance P

Tac1

Preprotachykinin 1 gene

Tacr1

Tachykinin NK1 receptor encoding gene

TNFα

Tumour necrosis factor α

References

  1. 1.
    Gaber MA, Seliet IA, Ehsan NA, Megahed MA. Mast cells and angiogenesis in wound healing. Anal Quant Cytopathol Histpathol. 2014;36:32–40.PubMedGoogle Scholar
  2. 2.
    Ossovskaya VS, Bunnett NW. Protease-activated receptors: contribution to physiology and disease. Physiol Rev. 2004;84:579–621.CrossRefPubMedGoogle Scholar
  3. 3.
    McDougall JJ, Muley MM. The role of proteases in pain. Handb Exp Pharmacol. 2015;227:239–60. doi:10.1007/978-3-662-46450-2_12.CrossRefPubMedGoogle Scholar
  4. 4.
    Douaiher J, Succar J, Lancerotto L, Gurish MF, Orgill DP, Hamilton MJ, Krilis SA, Stevens RL. Development of mast cells and importance of their tryptase and chymase serine proteases in inflammation and wound healing. Adv Immunol. 2014;122:211–52. doi:10.1016/B978-0-12-800267-4.00006-7.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Hollenberg MD, Compton SJ. International union of pharmacology. XXVIII. Proteinase-activated receptors. Pharmacol Rev. 2002;54:203–17.CrossRefPubMedGoogle Scholar
  6. 6.
    Kobayashi Y, Okunishi H. Mast cells as a target of rheumatoid arthritis treatment. Jpn J Pharmacol. 2002;90:7–11.CrossRefPubMedGoogle Scholar
  7. 7.
    DeBruin EJ, Gold M, Lo BC, Snyder K, Cait A, Lasic N, Lopez M, McNagny KM, Hughes MR. Mast cells in human health and disease. Methods Mol Biol. 2015;1220:93–119. doi:10.1007/978-1-4939-1568-2_7.CrossRefPubMedGoogle Scholar
  8. 8.
    Shin K, Nigrovic PA, Crish J, Boilard E, McNeil HP, Larabee KS, Adachi R, Gurish MF, Gobezie R, Stevens RL, Lee DM. Mast cells contribute to autoimmune inflammatory arthritis via their tryptase/heparin complexes. J Immunol. 2009;182:647–56.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Caughey GH. Mast cell proteases as pharmacological targets. Eur J Pharmacol. 2015. doi:10.1016/j.ejphar.2015.04.045.
  10. 10.
    Szolcsanyi J. Capsaicin-sensitive sensory nerve terminals with local and systemic efferent functions: facts and scopes of an unorthodox neuroregulatory mechanism. Prog Brain Res. 1996;113:343–59.CrossRefPubMedGoogle Scholar
  11. 11.
    Karimian SM, McDougall JJ, Ferrell WR. Neuropeptidergic and autonomic control of the vasculature of the rat knee joint revealed by laser Doppler perfusion imaging. Exp Physiol. 1995;80:341–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Keeble J, Russell F, Curtis B, Starr A, Pinter E, Brain SD. Involvement of transient receptor potential vanilloid 1 in the vascular and hyperalgesic components of joint inflammation. Arthritis Rheum. 2005;52:3248–56.CrossRefPubMedGoogle Scholar
  13. 13.
    Szabó Á, Helyes Z, Sándor K, Bite A, Pintér E, Németh J, Bánvölgyi Á, Bölcskei K, Elekes K, Szolcsányi J. Role of transient receptor potential vanilloid 1 receptors in adjuvant-induced chronic arthritis: In vivo study using gene-deficient mice. J Pharmacol Exp Ther. 2005;314:111–9. doi:10.1124/jpet.104.082487.CrossRefPubMedGoogle Scholar
  14. 14.
    Kissin EY, Freitas CF, Kissin I. The effects of intraarticular resiniferatoxin in experimental knee-joint arthritis. Anesth Analg. 2005;101:1433–9.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Helyes Z, Szabó A, Németh J, Jakab B, Pintér E, Bánvölgyi A, Kereskai L, Kéri G, Szolcsányi J. Antiinflammatory and analgesic effect of somatostatin released from capsaicin-sensitive sensory nerve terminals in Freund’s adjuvant-induced chronic arthritis model of the rat. Arthritis Rheum. 2004;50:1677–85.CrossRefPubMedGoogle Scholar
  16. 16.
    Borbély É, Botz B, Bölcskei K, Kenyér T, Kereskai L, Kiss T, Szolcsányi J, Pintér E, Csepregi JZ, Mócsai A, Helyes Z. Capsaicin-sensitive sensory nerves exert complex regulatory functions in the serum-transfer mouse model of autoimmune arthritis. Brain Behav Immun. 2015;45:50–9. doi:10.1016/j.bbi.2014.12.012.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Engler A, Aeschlimann A, Simmen BR, Michel BA, Gay RE, Gay S, Sprott H. Expression of transient receptor potential vanilloid 1 (TRPV1) in synovial fibroblasts from patients with osteoarthritis and rheumatoid arthritis. Biochem Biophys Res Commun. 2007;359:884–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Lam FY, Ferrell WR. Specific neurokinin receptors mediate plasma extravasation in the rat knee joint. Br J Pharmacol. 1991;103:1263–7.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Keeble JE, Brain SD. A role for substance P in arthritis? Neurosci Lett. 2004;361:176–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Makino A, Sakai A, Ito H, Suzuki H. Involvement of tachykinins and NK1 receptor in the joint inflammation with collagen type II-specific monoclonal antibody-induced arthritis in mice. J Nippon Med Sch. 2012;79:129–38.CrossRefPubMedGoogle Scholar
  21. 21.
    Millward-Sadler SJ, Mackenzie A, Wright MO, Lee HS, Elliot K, Gerrard L, Fiskerstrand CE, Salter DM, Quinn JP. Tachykinin expression in cartilage and function in human articular chondrocyte mechanotransduction. Arthritis Rheum. 2003;48:146–56.CrossRefPubMedGoogle Scholar
  22. 22.
    Howard MR, Millward-Sadler SJ, Vasilliou AS, Salter DM, Quinn JP. Mechanical stimulation induces preprotachykinin gene expression in osteoarthritic chondrocytes which is correlated with modulation of the transcription factor neuron restrictive silence factor. Neuropeptides. 2008;42:681–6.CrossRefPubMedGoogle Scholar
  23. 23.
    Opolka A, Straub RH, Pasoldt A, Grifka J, Grässel S. Substance P and norepinephrine modulate murine chondrocyte proliferation and apoptosis. Arthritis Rheum. 2012;64:729–39. doi:10.1002/art.33449.CrossRefPubMedGoogle Scholar
  24. 24.
    Larsson J, Ekblom A, Henriksson K, Lundeberg T, Theodorsson E. Concentration of substance P, neurokinin A, calcitonin gene related peptide, neuropeptide Y and vasoactive intestinal polypeptide in synovial fluid from knee joints in patients suffering from rheumatoid arthritis. Scand J Rheumatol. 1991;20:326–35.CrossRefPubMedGoogle Scholar
  25. 25.
    Origuchi T, Iwamoto N, Kawashiri SY, Fujikawa K, Aramaki T, Tamai M, Arima K, Nakamura H, Yamasaki S, Ida H, Kawakami A, Ueki Y, Matsuoka N, Nakashima M, Mizokami A, Kawabe Y, Mine M, Fukuda T, Eguchi K. Reduction in serum levels of substance P in patients with rheumatoid arthritis by etanercept, a tumor necrosis factor inhibitor. Mod Rheumatol. 2011;21:244–50. doi:10.1007/s10165-010-0384-5.CrossRefPubMedGoogle Scholar
  26. 26.
    Ferrell WR, Lockhart JC, Kelso EB, Dunning L, Plevin R, Meek SE, Smith AJ, Hunter GD, McLean JS, McGarry F, Ramage R, Jiang L, Kanke T, Kawagoe J. Essential role for proteinase-activated receptor-2 in arthritis. J Clin Invest. 2003;111:35–41.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Steinhoff M, Corvera CU, Thoma MS, Kong W, McAlpine BE, Caughey GH, Ansel JC, Bunnett NW. Proteinase-activated receptor-2 in human skin: tissue distribution and activation of keratinocytes by mast cell tryptase. Exp Dermatol. 1999;8:282–94.CrossRefPubMedGoogle Scholar
  28. 28.
    Steinhoff M, Vergnolle N, Young SH, Tognetto M, Amadesi S, Ennes HS, Trevisani M, Hollenberg MD, Wallace JL, Caughey GH, Mitchell SE, Williams LM, Geppetti P, Mayer EA, Bunnett NW. Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat Med. 2000;6:151–8.CrossRefPubMedGoogle Scholar
  29. 29.
    Amadesi S, Nie J, Vergnolle N, Cottrell GS, Grady EF, Trevisani M, Manni C, Geppetti P, McRoberts JA, Ennes H, Davis JB, Mayer EA, Bunnett NW. Protease-activated receptor 2 sensitizes the capsaicin receptor transient receptor potential vanilloid receptor 1 to induce hyperalgesia. J Neurosci. 2004;24:4300–12.CrossRefPubMedGoogle Scholar
  30. 30.
    Dai Y, Moriyama T, Higashi T, Togashi K, Kobayashi K, Yamanaka H, Tominaga M, Noguchi K. Proteinase-activated receptor 2-mediated potentiation of transient receptor potential vanilloid subfamily 1 activity reveals a mechanism for proteinase-induced inflammatory pain. J Neurosci. 2004;24:4293–9.CrossRefPubMedGoogle Scholar
  31. 31.
    McIntosh KA, Plevin R, Ferrell WR, Lockhart JC. The therapeutic potential of proteinase-activated receptors in arthritis. Curr Opin Pharmacol. 2007;7:334–8.CrossRefPubMedGoogle Scholar
  32. 32.
    Russell FA, McDougall JJ. Proteinase activated receptor (PAR) involvement in mediating arthritis pain and inflammation. Inflamm Res. 2009;58:119–26. doi:10.1007/s00011-009-8087-0.CrossRefPubMedGoogle Scholar
  33. 33.
    Helyes Z, Sándor K, Borbély E, Tékus V, Pintér E, Elekes K, Tóth DM, Szolcsányi J, McDougall JJ. Involvement of transient receptor potential vanilloid 1 receptors in protease-activated receptor-2-induced joint inflammation and nociception. Eur J Pain. 2010;14:351–8. doi:10.1016/j.ejpain.2009.07.005.CrossRefPubMedGoogle Scholar
  34. 34.
    Zimmer A, Zimmer AM, Baffi J, Usdin T, Reynolds K, König M, Palkovits M, Mezey E. Hypoalgesia in mice with a targeted deletion of the tachykinin 1 gene. Proc Natl Acad Sci USA. 1998;95:2630–5.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    De Felipe C, Herrero JF, O’Brien JA, Palmer JA, Doyle CA, Smith AJ, Laird JM, Belmonte C, Cervero F, Hunt SP. Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature. 1998;392:394–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Gonzalez MI, Field MJ, Hughes J, Singh L. Evaluation of selective NK(1) receptor antagonist CI-1021 in animal models of inflammatory and neuropathic pain. J Pharmacol Exp Ther. 2000;294:444–50.PubMedGoogle Scholar
  37. 37.
    Starr A, Graepel R, Keeble J, Schmidhuber S, Clark N, Grant A, Shah AM, Brain SD. A reactive oxygen species-mediated component in neurogenic vasodilatation. Cardiovasc Res. 2008;78:139–47.CrossRefPubMedGoogle Scholar
  38. 38.
    Hirsch S, Corradini L, Just S, Arndt K, Doods H. The CGRP receptor antagonist BIBN4096BS peripherally alleviates inflammatory pain in rats. Pain. 2013;154:700–7.CrossRefPubMedGoogle Scholar
  39. 39.
    Elekes K, Helyes Z, Németh J, Sándor K, Pozsgai G, Kereskai L, Börzsei R, Pintér E, Szabó A, Szolcsányi J. Role of capsaicin-sensitive afferents and sensory neuropeptides in endotoxin-induced airway inflammation and consequent bronchial hyperreactivity in the mouse. Regul Pept. 2007;141(1–3):44–54.CrossRefPubMedGoogle Scholar
  40. 40.
    Helyes Z, Németh J, Pintér E, Szolcsányi J. Inhibition by nociceptin of neurogenic inflammation and the release of SP and CGRP from sensory nerve terminals. Br J Pharmacol. 1997;121:613–5.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Szolcsányi J. Hot target on nociceptors: perspectives, caveats and unique features. Br J Pharmacol. 2008;155:1142–4. doi:10.1038/bjp.2008.374.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Sándor K, Bölcskei K, McDougall JJ, Schuelert N, Reglodi D, Elekes K, Petho G, Pintér E, Szolcsányi J, Helyes Z. Divergent peripheral effects of pituitary adenylate cyclase-activating polypeptide-38 on nociception in rats and mice. Pain. 2009;141:143–50. doi:10.1016/j.pain.2008.10.028.CrossRefPubMedGoogle Scholar
  43. 43.
    McDougall JJ, Barin AK, McDougall CM. Loss of vasomotor responsiveness to the mu-opioid receptor ligand endomorphin-1 in adjuvant monoarthritic rat knee joints. Am J Physiol Regul Integr Comp Physiol. 2004;286:R634–41.CrossRefPubMedGoogle Scholar
  44. 44.
    Andersen RK, Lund JP, Puil E. Enkephalin and substance P effects related to trigeminal pain. Can J Physiol Pharmacol. 1978;56:216–22.CrossRefPubMedGoogle Scholar
  45. 45.
    Garret C, Carruette A, Fardin V, Moussaoui S, Peyronel JF, Blanchard JC, Laduron PM. Pharmacological properties of a potent and selective nonpeptide substance P antagonist. Proc Natl Acad Sci USA. 1991;88:10208–12.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Davis AJ, Perkins MN. Substance P and capsaicin-induced mechanical hyperalgesia in the rat knee joint; the involvement of bradykinin B1 and B2 receptors. Br J Pharmacol. 1996;118:2206–12.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Li X, Kim JS, van Wijnen AJ, Im HJ. Osteoarthritic tissues modulate functional properties of sensory neurons associated with symptomatic OA pain. Mol Biol Rep. 2011;38:5335–9. doi:10.1007/s11033-011-0684-7.CrossRefPubMedGoogle Scholar
  48. 48.
    McDougall JJ, Hanesch U, Pawlak M, Schmidt RF. Participation of NK1 receptors in nociceptin-induced modulation of rat knee joint mechanosensitivity. Exp Brain Res. 2001;137:249–53.CrossRefPubMedGoogle Scholar
  49. 49.
    Russell FA, Schuelert N, Veldhoen VE, Hollenberg MD, McDougall JJ. Activation of PAR(2) receptors sensitizes primary afferents and causes leukocyte rolling and adherence in the rat knee joint. Br J Pharmacol. 2012;167:1665–78. doi:10.1111/j.1476-5381.2012.02120.x.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Chu KL, Chandran P, Joshi SK, Jarvis MF, Kym PR, McGaraughty S. TRPV1-related modulation of spinal neuronal activity and behavior in a rat model of osteoarthritic pain. Brain Res. 2011;1369:158–66. doi:10.1016/j.brainres.2010.10.101.CrossRefPubMedGoogle Scholar
  51. 51.
    Hughes KH, Wijekoon EP, Valcour JE, Chia EW, McGuire JJ. Effects of chronic in vivo treatments with protease-activated receptor 2 agonist on endothelium function and blood pressures in mice. Can J Physiol Pharmacol. 2013;91:295–305. doi:10.1139/cjpp-2012-0266.CrossRefPubMedGoogle Scholar
  52. 52.
    Vesey DA, Suen JY, Seow V, Lohman RJ, Liu L, Gobe GC, Johnson DW, Fairlie DP. PAR2-induced inflammatory responses in human kidney tubular epithelial cells. Am J Physiol Renal Physiol. 2013;304:F737–50. doi:10.1152/ajprenal.00540.2012.CrossRefPubMedGoogle Scholar
  53. 53.
    Wernersson S, Pejler G. Mast cell secretory granules: armed for battle. Nat Rev Immunol. 2014;14:478–94. doi:10.1038/nri3690.CrossRefPubMedGoogle Scholar
  54. 54.
    de Souza Junior DA, Santana AC, da Silva EZ, Oliver C, Jamur MC. The role of mast cell specific chymases and tryptases in tumor angiogenesis. Biomed Res Int. 2015;2015:142359. doi:10.1155/2015/142359.
  55. 55.
    Camargo LL, Denadai-Souza A, Yshii LM, Mesquita FP, Soares AG, Lima C, Schenka A, Grant A, Fernandes E, Muscará MN, Costa SK. Peripheral Neurokinin-1 receptors contribute to kaolin-induced acute monoarthritis in rats. Neuro Immuno Modulation. 2015;22:373–84. doi:10.1159/000381549.Google Scholar
  56. 56.
    Borbély E, Hajna Z, Sándor K, Kereskai L, Tóth I, Pintér E, Nagy P, Szolcsányi J, Quinn J, Zimmer A, Stewart J, Paige C, Berger A, Helyes Z. Role of tachykinin 1 and 4 gene-derived neuropeptides and the neurokinin 1 receptor in adjuvant-induced chronic arthritis of the mouse. PLoS One. 2013;8:e61684. doi:10.1371/journal.pone.0061684.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Jancsó-Gábor A, Szolcsányi J. Neurogenic inflammatory responses. J Dent Res. 1972;51:264–9.CrossRefPubMedGoogle Scholar
  58. 58.
    Rosa AC, Fantozzi R. The role of histamine in neurogenic inflammation. Br J Pharmacol. 2013;170:38–45. doi:10.1111/bph.12266.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Baylie RL, Brayden JE. TRPV channels and vascular function. Acta Physiol (Oxf). 2011;203:99–116. doi:10.1111/j.1748-1716.2010.02217.CrossRefPubMedGoogle Scholar
  60. 60.
    Pozsgai G, Bodkin JV, Graepel R, Bevan S, Andersson DA, Brain SD. Evidence for the pathophysiological relevance of TRPA1 receptors in the cardiovascular system in vivo. Cardiovasc Res. 2010;87:760–8. doi:10.1093/cvr/cvq118.CrossRefPubMedGoogle Scholar
  61. 61.
    Fernandes ES, Fernandes MA, Keeble JE. The functions of TRPA1 and TRPV1: moving away from sensory nerves. Br J Pharmacol. 2012;166:510–21. doi:10.1111/j.1476-5381.2012.01851.x.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Kun J, Helyes Z, Perkecz A, Bán Á, Polgár B, Szolcsányi J, Pintér E. Effect of surgical and chemical sensory denervation on non-neural expression of the transient receptor potential vanilloid 1 (TRPV1) receptors in the rat. J Mol Neurosci. 2012;48:795–803.CrossRefPubMedGoogle Scholar
  63. 63.
    Kun J, Szitter I, Kemény A, Perkecz A, Kereskai L, Pohóczky K, Vincze A, Gódi S, Szabó I, Szolcsányi J, Pintér E, Helyes Z. Upregulation of the transient receptor potential ankyrin 1 ion channel in the inflamed human and mouse colon and its protective roles. PLoS ONE. 2014;9:e108164. doi:10.1371/journal.pone.0108164.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Bíró T, Maurer M, Modarres S, Lewin NE, Brodie C, Acs G, Acs P, Paus R, Blumberg PM. Characterization of functional vanilloid receptors expressed by mast cells. Blood. 1998;91:1332–40.PubMedGoogle Scholar
  65. 65.
    Vyklický L, Nováková-Tousová K, Benedikt J, Samad A, Touska F, Vlachová V. Calcium-dependent desensitization of vanilloid receptor TRPV1: a mechanism possibly involved in analgesia induced by topical application of capsaicin. Physiol Res. 2008;57(Suppl 3):S59–68.PubMedGoogle Scholar
  66. 66.
    Anand P, Bley K. Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. Br J Anaesth. 2011;107:490–502. doi:10.1093/bja/aer260.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Ferrell WR, Lockhart JC, Karimian SM. Tachykinin regulation of basal synovial blood flow. Br J Pharmacol. 1997;121:29–34.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Lam FY, Wong MC. Characterization of tachykinin receptors mediating plasma extravasation and vasodilatation in normal and acutely inflamed knee joints of the rat. Br J Pharmacol. 1996;118:2107–14.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Walsh DA, Mapp PI, Kelly S. Calcitonin gene-related peptide in the joint: contributions to pain and inflammation. Br J Clin Pharmacol. 2015;. doi:10.1111/bcp.12669.PubMedGoogle Scholar
  70. 70.
    Wang H, Zhang X, He JY, Zheng XF, Li D, Li Z, Zhu JF, Shen C, Cai GQ, Chen XD. Increasing expression of substance P and calcitonin gene-related peptide in synovial tissue and fluid contribute to the progress of arthritis in developmental dysplasia of the hip. Arthritis Res Ther. 2015;17:4. doi:10.1186/s13075-014-0513-1.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Dong T, Chang H, Zhang F, Chen W, Zhu Y, Wu T, Zhang Y. Calcitonin gene-related peptide can be selected as a predictive biomarker on progression and prognosis of knee osteoarthritis. Int Orthop. 2015;39:1237–43. doi:10.1007/s00264-015-2744-4.CrossRefPubMedGoogle Scholar
  72. 72.
    Grässel SG. The role of peripheral nerve fibers and their neurotransmitters in cartilage and bone physiology and pathophysiology. Arthritis Res Ther. 2014;16:485.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Ahmed M, Bjurholm A, Srinivasan GR, Lundeberg T, Theodorsson E, Schultzberg M, Kreicbergs A. Capsaicin effects on substance P and CGRP in rat adjuvant arthritis. Regul Pept. 1995;55:85–102.CrossRefPubMedGoogle Scholar
  74. 74.
    Ahmed M, Srinivasan GR, Theodorsson E, Schultzberg M, Kreicbergs A. Effects of surgical denervation on substance P and calcitonin gene-related peptide in adjuvant arthritis. Peptides. 1995;16:569–79.CrossRefPubMedGoogle Scholar
  75. 75.
    Chen Y, Willcockson HH, Valtschanoff JG. Increased expression of CGRP in sensory afferents of arthritic mice–effect of genetic deletion of the vanilloid receptor TRPV1. Neuropeptides. 2008;42:551–6. doi:10.1016/j.npep.2008.08.001.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Willcockson HH, Chen Y, Han JE, Valtschanoff JG. Effect of genetic deletion of the vanilloid receptor TRPV1 on the expression of substance P in sensory neurons of mice with adjuvant-induced arthritis. Neuropeptides. 2010;44:293–7. doi:10.1016/j.npep.2010.02.003.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing 2016

Authors and Affiliations

  • Éva Borbély
    • 1
    • 2
  • Katalin Sándor
    • 1
  • Adrienn Markovics
    • 1
    • 2
  • Ágnes Kemény
    • 1
    • 2
  • Erika Pintér
    • 1
    • 2
  • János Szolcsányi
    • 1
    • 2
  • John P. Quinn
    • 4
  • Jason J. McDougall
    • 5
  • Zsuzsanna Helyes
    • 1
    • 2
    • 3
  1. 1.Department of Pharmacology and Pharmacotherapy, Medical SchoolUniversity of PécsPecsHungary
  2. 2.János Szentágothai Research Centre, Molecular Pharmacology Research GroupCentre for Neuroscience, University of PécsPecsHungary
  3. 3.MTA-PTE NAP B Chronic Pain Research GroupPecsHungary
  4. 4.School of Biomedical SciencesLiverpool UniversityLiverpoolUK
  5. 5.Department of PharmacologyDalhousie UniversityHalifaxCanada

Personalised recommendations