Pain Control pp 239-260 | Cite as

The Role of Proteases in Pain

  • Jason J. McDougallEmail author
  • Milind M. Muley
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 227)


Proteinase-activated receptors (PARs) are a family of G protein-coupled receptor that are activated by extracellular cleavage of the receptor in the N-terminal domain. This slicing of the receptor exposes a tethered ligand which binds to a specific docking point on the receptor surface to initiate intracellular signalling. PARs are expressed by numerous tissues in the body, and they are involved in various physiological and pathological processes such as food digestion, tissue remodelling and blood coagulation. This chapter will summarise how serine proteinases activate PARs leading to the development of pain in several chronic pain conditions. The potential of PARs as a drug target for pain relief is also discussed.


Proteinase-activated receptor Pain Inflammation 


  1. Abraham AA, Jenkins AL, Stone SR, Mackie EJ (1998) Expression of the thrombin receptor in developing bone and associated tissues. J Bone Miner Res 13(5):818–827PubMedGoogle Scholar
  2. Abraham LA, MacKie EJ (1999) Modulation of osteoblast-like cell behavior by activation of protease-activated receptor-1. J Bone Miner Res 14:1320–1329PubMedGoogle Scholar
  3. Afkhami-Goli A, Noorbakhsh F, Keller AJ, Vergnolle N, Westaway D, Jhamandas JH, Andrade-Gordon P, Hollenberg MD, Arab H, Dyck RH, Power C (2007) Proteinase-activated receptor-2 exerts protective and pathogenic cell type-specific effects in Alzheimer’s disease. J Immunol 179:5493–5503PubMedGoogle Scholar
  4. Annahazi A, Dabek M, Gecse K, Salvador-Cartier C, Polizzi A, Rosztoczy A, Roka R, Theodorou V, Wittmann T, Bueno L, Eutamene H (2012) Proteinase-activated receptor-4 evoked colorectal analgesia in mice: an endogenously activated feed-back loop in visceral inflammatory pain. Neurogastroenterol Motil 24(1):76–85, e13PubMedGoogle Scholar
  5. Annahazi A, Gecse K, Dabek M, Ait-Belgnaoui A, Rosztoczy A, Roka R, Molnar T, Theodorou V, Wittmann T, Bueno L, Eutamene H (2009) Fecal proteases from diarrheic-IBS and ulcerative colitis patients exert opposite effect on visceral sensitivity in mice. Pain 144:209–217PubMedGoogle Scholar
  6. Antoniak S, Rojas M, Spring D, Bullard TA, Verrier ED, Blaxall BC, Mackman N, Pawlinski R (2010) Protease-activated receptor 2 deficiency reduces cardiac ischemia/reperfusion injury. Arterioscler Thromb Vasc Biol 30:2136–2142PubMedCentralPubMedGoogle Scholar
  7. Antoniak S, Sparkenbaugh EM, Tencati M, Rojas M, Mackman N, Pawlinski R (2013) Protease activated receptor-2 contributes to heart failure. PLoS One 8:e81733PubMedCentralPubMedGoogle Scholar
  8. Arizmendi NG, Abel M, Mihara K, Davidson C, Polley D, Nadeem A, El Mays T, Gilmore BF, Walker B, Gordon JR, Hollenberg MD, Vliagoftis H (2011) Mucosal allergic sensitization to cockroach allergens is dependent on proteinase activity and proteinase-activated receptor-2 activation. J Immunol 186:3164–3172PubMedGoogle Scholar
  9. Asfaha S, Brussee V, Chapman K, Zochodne DW, Vergnolle N (2002) Proteinase-activated receptor-1 agonists attenuate nociception in response to noxious stimuli. Br J Pharmacol 135:1101–1106PubMedCentralPubMedGoogle Scholar
  10. Asfaha S, Cenac N, Houle S, Altier C, Papez MD, Nguyen C, Steinhoff M, Chapman K, Zamponi GW, Vergnolle N (2007) Protease-activated receptor-4: a novel mechanism of inflammatory pain modulation. Br J Pharmacol 150:176–185PubMedCentralPubMedGoogle Scholar
  11. Barnsley L, Lord SM, Wallis BJ, Bogduk N (1995) The prevalence of chronic cervical zygapophysial joint pain after whiplash. Spine (Phila Pa 1976) 20:20–25; discussion 26Google Scholar
  12. Barrett AJ (2001) Proteolytic enzymes: nomenclature and classification. In: Beynon R, Bond JS (eds) Proteolytic enzymes. A practical approach, 2nd edn. Oxford University Press, Oxford, pp 1–21Google Scholar
  13. Barrett AJ, Rawlings ND, Woessner JF Jr (eds) (2004) Handbook of proteolytic enzymes, 2nd edn. Academic, AmsterdamGoogle Scholar
  14. Barry GD, Le GT, Fairlie DP (2006) Agonists and antagonists of protease activated receptors (PARs). Curr Med Chem 13(3):243–265PubMedGoogle Scholar
  15. Barry GD, Suen JY, Le GT, Cotterell A, Reid RC, Fairlie DP (2010) Novel agonists and antagonists for human protease activated receptor 2. J Med Chem 53:7428–7440PubMedGoogle Scholar
  16. Beecher KL, Andersen TT, Fenton JW 2nd, Festoff BW (1994) Thrombin receptor peptides induce shape change in neonatal murine astrocytes in culture. J Neurosci Res 37:108–115PubMedGoogle Scholar
  17. Belham CM, Tate RJ, Scott PH, Pemberton AD, Miller HR, Wadsworth RM, Gould GW, Plevin R (1996) Trypsin stimulates proteinase-activated receptor-2-dependent and -independent activation of mitogen-activated protein kinases. Biochem J 320(Pt 3):939–946PubMedCentralPubMedGoogle Scholar
  18. Benka ML, Lee M, Wang GR, Buckman S, Burlacu A, Cole L, DePina A, Dias P, Granger A, Grant B et al (1995) The thrombin receptor in human platelets is coupled to a GTP binding protein of the G alpha q family. FEBS Lett 363:49–52PubMedGoogle Scholar
  19. Bluteau G, Pilet P, Bourges X, Bilban M, Spaethe R, Daculsi G, Guicheux J (2006) The modulation of gene expression in osteoblasts by thrombin coated on biphasic calcium phosphate ceramic. Biomaterials 27:2934–2943PubMedGoogle Scholar
  20. Bohm SK, Kong W, Bromme D, Smeekens SP, Anderson DC, Connolly A, Kahn M, Nelken NA, Coughlin SR, Payan DG, Bunnett NW (1996) Molecular cloning, expression and potential functions of the human proteinase-activated receptor-2. Biochem J 314(Pt 3):1009–1016PubMedCentralPubMedGoogle Scholar
  21. Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME (1999) Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286:1358–1362PubMedGoogle Scholar
  22. Busso N, Frasnelli M, Feifel R, Cenni B, Steinhoff M, Hamilton J, So A (2007) Evaluation of protease-activated receptor 2 in murine models of arthritis. Arthritis Rheum 56:101–107PubMedGoogle Scholar
  23. Ceppa EP, Lyo V, Grady EF, Knecht W, Grahn S, Peterson A, Bunnett NW, Kirkwood KS, Cattaruzza F (2011) Serine proteases mediate inflammatory pain in acute pancreatitis. Am J Physiol Gastrointest Liver Physiol 300:G1033–G1042PubMedCentralPubMedGoogle Scholar
  24. Chen HS, Kuo SC, Teng CM, Lee FY, Wang JP, Lee YC, Kuo CW, Huang CC, Wu CC, Huang LJ (2008) Synthesis and antiplatelet activity of ethyl 4-(1-benzyl-1H-indazol-3-yl)benzoate (YD-3) derivatives. Bioorg Med Chem 16:1262–1278PubMedGoogle Scholar
  25. Chen Y, Yang C, Wang ZJ (2011) Proteinase-activated receptor 2 sensitizes transient receptor potential vanilloid 1, transient receptor potential vanilloid 4, and transient receptor potential ankyrin 1 in paclitaxel-induced neuropathic pain. Neuroscience 193:440–451PubMedGoogle Scholar
  26. Chinni C, de Niese MR, Jenkins AL, Pike RN, Bottomley SP, Mackie EJ (2000) Protease-activated receptor-2 mediates proliferative responses in skeletal myoblasts. J Cell Sci 113(Pt 24):4427–4433PubMedGoogle Scholar
  27. Cocks TM, Fong B, Chow JM, Anderson GP, Frauman AG, Goldie RG, Henry PJ, Carr MJ, Hamilton JR, Moffatt JD (1999a) A protective role for protease-activated receptors in the airways. Nature 398:156–160PubMedGoogle Scholar
  28. Cocks TM, Sozzi V, Moffatt JD, Selemidis S (1999b) Protease-activated receptors mediate apamin-sensitive relaxation of mouse and guinea pig gastrointestinal smooth muscle. Gastroenterology 116:586–592PubMedGoogle Scholar
  29. Corvera CU, Dery O, McConalogue K, Bohm SK, Khitin LM, Caughey GH, Payan DG, Bunnett NW (1997) Mast cell tryptase regulates rat colonic myocytes through proteinase-activated receptor 2. J Clin Invest 100:1383–1393PubMedCentralPubMedGoogle Scholar
  30. Coughlin SR (2000) Thrombin signalling and protease-activated receptors. Nature 407:258–264PubMedGoogle Scholar
  31. Covic L, Misra M, Badar J, Singh C, Kuliopulos A (2002) Pepducin-based intervention of thrombin-receptor signaling and systemic platelet activation. Nat Med 8:1161–1165PubMedGoogle Scholar
  32. DeFea KA, Zalevsky J, Thoma MS, Dery O, Mullins RD, Bunnett NW (2000) beta-arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2. J Cell Biol 148:1267–1281PubMedCentralPubMedGoogle Scholar
  33. Denadai-Souza A, Cenac N, Casatti CA, Camara PR, Yshii LM, Costa SK, Vergnolle N, Muscara MN (2010) PAR(2) and temporomandibular joint inflammation in the rat. J Dent Res 89:1123–1128PubMedGoogle Scholar
  34. Dong L, Smith JR, Winkelstein BA (2013) Ketorolac reduces spinal astrocytic activation and PAR1 expression associated with attenuation of pain after facet joint injury. J Neurotrauma 30:818–825PubMedCentralPubMedGoogle Scholar
  35. Duncan MB, Kalluri R (2009) Parstatin, a novel protease-activated receptor 1-derived inhibitor of angiogenesis. Mol Interv 9:168–170PubMedCentralPubMedGoogle Scholar
  36. Eberhart CE, Dubois RN (1995) Eicosanoids and the gastrointestinal tract. Gastroenterology 109:285–301PubMedGoogle Scholar
  37. Gingrich MB, Junge CE, Lyuboslavsky P, Traynelis SF (2000) Potentiation of NMDA receptor function by the serine protease thrombin. J Neurosci 20:4582–4595PubMedGoogle Scholar
  38. Gustafson GT, Lerner U (1983) Thrombin, a stimulator of bone resorption. Biosci Rep 3:255–261PubMedGoogle Scholar
  39. Helyes Z, Sandor K, Borbely E, Tekus V, Pinter E, Elekes K, Toth DM, Szolcsanyi J, McDougall JJ (2010) Involvement of transient receptor potential vanilloid 1 receptors in protease-activated receptor-2-induced joint inflammation and nociception. Eur J Pain 14:351–358PubMedGoogle Scholar
  40. Hoffmann O, Klaushofer K, Koller K, Peterlik M, Mavreas T, Stern P (1986) Indomethacin inhibits thrombin-, but not thyroxin-stimulated resorption of fetal rat limb bones. Prostaglandins 31(4):601–608PubMedGoogle Scholar
  41. Hollenberg MD, Compton SJ (2002) International Union of Pharmacology. XXVIII. Proteinase-activated receptors. Pharmacol Rev 54:203–217PubMedGoogle Scholar
  42. Huang ZJ, Li HC, Cowan AA, Liu S, Zhang YK, Song XJ (2012) Chronic compression or acute dissociation of dorsal root ganglion induces cAMP-dependent neuronal hyperexcitability through activation of PAR2. Pain 153:1426–1437PubMedGoogle Scholar
  43. Jalink K, Moolenaar WH (1992) Thrombin receptor activation causes rapid neural cell rounding and neurite retraction independent of classic second messengers. J Cell Biol 118:411–419PubMedGoogle Scholar
  44. Jenkins AL, Bootman MD, Taylor CW, Mackie EJ, Stone SR (1993) Characterization of the receptor responsible for thrombin-induced intracellular calcium responses in osteoblast-like cells. J Biol Chem 268:21432–21437PubMedGoogle Scholar
  45. Jin G, Hayashi T, Kawagoe J, Takizawa T, Nagata T, Nagano I, Syoji M, Abe K (2005) Deficiency of PAR-2 gene increases acute focal ischemic brain injury. J Cereb Blood Flow Metab 25:302–313PubMedGoogle Scholar
  46. Jin C et al (2009) Protease-activated receptors in neuropathic pain: an important mediator between neuron and glia. J Med Coll PLA 24:244–249Google Scholar
  47. Kawabata A, Kuroda R, Nagata N, Kawao N, Masuko T, Nishikawa H, Kawai K (2001) In vivo evidence that protease-activated receptors 1 and 2 modulate gastrointestinal transit in the mouse. Br J Pharmacol 133:1213–1218PubMedCentralPubMedGoogle Scholar
  48. Kawabata A, Kawao N, Kuroda R, Tanaka A, Shimada C (2002) The PAR-1-activating peptide attenuates carrageenan-induced hyperalgesia in rats. Peptides 23:1181–1183PubMedGoogle Scholar
  49. Kawabata A, Kuroda R, Kuroki N, Nishikawa H, Kawai K (2000) Dual modulation by thrombin of the motility of rat oesophageal muscularis mucosae via two distinct protease-activated receptors (PARs): a novel role for PAR-4 as opposed to PAR-1. Br J Pharmacol 131:578–584PubMedCentralPubMedGoogle Scholar
  50. Kawabata A, Matsunami M, Tsutsumi M, Ishiki T, Fukushima O, Sekiguchi F, Kawao N, Minami T, Kanke T, Saito N (2006) Suppression of pancreatitis-related allodynia/hyperalgesia by proteinase-activated receptor-2 in mice. Br J Pharmacol 148:54–60PubMedCentralPubMedGoogle Scholar
  51. Kawao N, Ikeda H, Kitano T, Kuroda R, Sekiguchi F, Kataoka K, Kamanaka Y, Kawabata A (2004) Modulation of capsaicin-evoked visceral pain and referred hyperalgesia by protease-activated receptors 1 and 2. J Pharmacol Sci 94:277–285PubMedGoogle Scholar
  52. Kelso EB, Lockhart JC, Hembrough T, Dunning L, Plevin R, Hollenberg MD, Sommerhoff CP, McLean JS, Ferrell WR (2006) Therapeutic promise of proteinase-activated receptor-2 antagonism in joint inflammation. J Pharmacol Exp Ther 316:1017–1024PubMedGoogle Scholar
  53. Kirilak Y, Pavlos NJ, Willers CR, Han R, Feng H, Xu J, Asokananthan N, Stewart GA, Henry P, Wood D, Zheng MH (2006) Fibrin sealant promotes migration and proliferation of human articular chondrocytes: possible involvement of thrombin and protease-activated receptors. Int J Mol Med 17:551–558PubMedGoogle Scholar
  54. Kong W, McConalogue K, Khitin LM, Hollenberg MD, Payan DG, Bohm SK, Bunnett NW (1997) Luminal trypsin may regulate enterocytes through proteinase-activated receptor 2. Proc Natl Acad Sci U S A 94:8884–8889PubMedCentralPubMedGoogle Scholar
  55. Lee B, Descalzi G, Baek J, Kim JI, Lee HR, Lee K, Kaang BK, Zhuo M (2011) Genetic enhancement of behavioral itch responses in mice lacking phosphoinositide 3-kinase-gamma (PI3Kgamma). Mol Pain 7:96PubMedCentralPubMedGoogle Scholar
  56. Lee FY, Lien JC, Huang LJ, Huang TM, Tsai SC, Teng CM, Wu CC, Cheng FC, Kuo SC (2001) Synthesis of 1-benzyl-3-(5′-hydroxymethyl-2′-furyl)indazole analogues as novel antiplatelet agents. J Med Chem 44:3746–3749PubMedGoogle Scholar
  57. Liu H, Miller DV, Lourenssen S, Wells RW, Blennerhassett MG, Paterson WG (2010) Proteinase-activated receptor-2 activation evokes oesophageal longitudinal smooth muscle contraction via a capsaicin-sensitive and neurokinin-2 receptor-dependent pathway. Neurogastroenterol Motil 22(2):210–216, e67PubMedGoogle Scholar
  58. Lohman RJ, Cotterell AJ, Barry GD, Liu L, Suen JY, Vesey DA, Fairlie DP (2012) An antagonist of human protease activated receptor-2 attenuates PAR2 signaling, macrophage activation, mast cell degranulation, and collagen-induced arthritis in rats. FASEB J 26:2877–2887PubMedGoogle Scholar
  59. Macfarlane SR, Seatter MJ, Kanke T, Hunter GD, Plevin R (2001) Proteinase-activated receptors. Pharmacol Rev 53:245–282PubMedGoogle Scholar
  60. Mackie EJ, Loh LH, Sivagurunathan S, Uaesoontrachoon K, Yoo HJ, Wong D, Georgy SR, Pagel CN (2008) Protease-activated receptors in the musculoskeletal system. Int J Biochem Cell Biol 40:1169–1184PubMedGoogle Scholar
  61. Martin L et al (2009) Thrombin receptor: an endogenous inhibitor of inflammatory pain, activating opioid pathways. Pain 146:121–129PubMedGoogle Scholar
  62. McDougall JJ, Linton P (2012) Neurophysiology of arthritis pain. Curr Pain Headache Rep 16:485–491PubMedGoogle Scholar
  63. McDougall JJ, Zhang C, Cellars L, Joubert E, Dixon CM, Vergnolle N (2009) Triggering of proteinase-activated receptor 4 leads to joint pain and inflammation in mice. Arthritis Rheum 60:728–737PubMedGoogle Scholar
  64. Murray DB, McLarty-Williams J, Nagalla KT, Janicki JS (2012) Tryptase activates isolated adult cardiac fibroblasts via protease activated receptor-2 (PAR-2). J Cell Commun Signal 6:45–51PubMedCentralPubMedGoogle Scholar
  65. Nakanishi-Matsui M, Zheng YW, Sulciner DJ, Weiss EJ, Ludeman MJ, Coughlin SR (2000) PAR3 is a cofactor for PAR4 activation by thrombin. Nature 404:609–613PubMedGoogle Scholar
  66. Narita M, Usui A, Niikura K, Nozaki H, Khotib J, Nagumo Y, Yajima Y, Suzuki T (2005) Protease-activated receptor-1 and platelet-derived growth factor in spinal cord neurons are implicated in neuropathic pain after nerve injury. J Neurosci 25:10000–10009PubMedGoogle Scholar
  67. Nelken NA, Soifer SJ, O’Keefe J, Vu TK, Charo IF, Coughlin SR (1992) Thrombin receptor expression in normal and atherosclerotic human arteries. J Clin Invest 90:1614–1621PubMedCentralPubMedGoogle Scholar
  68. Oliveira SM, Silva CR, Ferreira J (2013) Critical role of protease-activated receptor 2 activation by mast cell tryptase in the development of postoperative pain. Anesthesiology 118:679–690PubMedGoogle Scholar
  69. Ossovskaya VS, Bunnett NW (2004) Protease-activated receptors: contribution to physiology and disease. Physiol Rev 84:579–621PubMedGoogle Scholar
  70. Pagel CN, de Niese MR, Abraham LA, Chinni C, Song SJ, Pike RN, Mackie EJ (2003) Inhibition of osteoblast apoptosis by thrombin. Bone 33:733–743PubMedGoogle Scholar
  71. Pasero C (2004) Pathophysiology of neuropathic pain. Pain Manag Nurs 5:3–8PubMedGoogle Scholar
  72. Paterson WG, Miller DV, Dilworth N, Assini JB, Lourenssen S, Blennerhassett MG (2007) Intraluminal acid induces oesophageal shortening via capsaicin-sensitive neurokinin neurons. Gut 56:1347–1352PubMedCentralPubMedGoogle Scholar
  73. Paukert M, Osteroth R, Geisler HS, Brandle U, Glowatzki E, Ruppersberg JP, Grunder S (2001) Inflammatory mediators potentiate ATP-gated channels through the P2X(3) subunit. J Biol Chem 276:21077–21082PubMedGoogle Scholar
  74. Ramachandran R (2012) Developing PAR1 antagonists: minding the endothelial gap. Discov Med 13(73):425–431PubMedGoogle Scholar
  75. Ramachandran R, Mihara K, Chung H, Renaux B, Lau CS, Muruve DA, DeFea KA, Bouvier M, Hollenberg MD (2011) Neutrophil elastase acts as a biased agonist for proteinase-activated receptor-2 (PAR2). J Biol Chem 286:24638–24648PubMedCentralPubMedGoogle Scholar
  76. Russell FA, McDougall JJ (2009) Proteinase activated receptor (PAR) involvement in mediating arthritis pain and inflammation. Inflamm Res 58:119–126PubMedGoogle Scholar
  77. Russell FA, Schuelert N, Veldhoen VE, Hollenberg MD, McDougall JJ (2012) Activation of PAR(2) receptors sensitizes primary afferents and causes leukocyte rolling and adherence in the rat knee joint. Br J Pharmacol 167:1665–1678PubMedCentralPubMedGoogle Scholar
  78. Russell FA, Veldhoen VE, Tchitchkan D, McDougall JJ (2010) Proteinase-activated receptor-4 (PAR4) activation leads to sensitization of rat joint primary afferents via a bradykinin B2 receptor-dependent mechanism. J Neurophysiol 103:155–163PubMedGoogle Scholar
  79. Sabri A, Muske G, Zhang H, Pak E, Darrow A, Andrade-Gordon P, Steinberg SF (2000) Signaling properties and functions of two distinct cardiomyocyte protease-activated receptors. Circ Res 86:1054–1061PubMedGoogle Scholar
  80. Saifeddine M, al-Ani B, Cheng CH, Wang L, Hollenberg MD (1996) Rat proteinase-activated receptor-2 (PAR-2): cDNA sequence and activity of receptor-derived peptides in gastric and vascular tissue. Br J Pharmacol 118:521–530PubMedCentralPubMedGoogle Scholar
  81. Seminario-Vidal L, Kreda S, Jones L, O’Neal W, Trejo J, Boucher RC, Lazarowski ER (2009) Thrombin promotes release of ATP from lung epithelial cells through coordinated activation of rho- and Ca2 + -dependent signaling pathways. J Biol Chem 284:20638–20648PubMedCentralPubMedGoogle Scholar
  82. Smith R, Ransjo M, Tatarczuch L, Song SJ, Pagel C, Morrison JR, Pike RN, Mackie EJ (2004) Activation of protease-activated receptor-2 leads to inhibition of osteoclast differentiation. J Bone Miner Res 19:507–516PubMedGoogle Scholar
  83. Soh UJ, Dores MR, Chen B, Trejo J (2010) Signal transduction by protease-activated receptors. Br J Pharmacol 160:191–203PubMedCentralPubMedGoogle Scholar
  84. Song SJ, Pagel CN, Campbell TM, Pike RN, Mackie EJ (2005) The role of protease-activated receptor-1 in bone healing. Am J Pathol 166:857–868PubMedCentralPubMedGoogle Scholar
  85. Song XJ, Hu SJ, Greenquist KW, Zhang JM, LaMotte RH (1999) Mechanical and thermal hyperalgesia and ectopic neuronal discharge after chronic compression of dorsal root ganglia. J Neurophysiol 82:3347–3358PubMedGoogle Scholar
  86. Steinberg SF (2005) The cardiovascular actions of protease-activated receptors. Mol Pharmacol 67:2–11PubMedGoogle Scholar
  87. 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 (2000) Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat Med 6:151–158PubMedGoogle Scholar
  88. Stoll G, Jander S, Schroeter M (1998) Inflammation and glial responses in ischemic brain lesions. Prog Neurobiol 56:149–171PubMedGoogle Scholar
  89. Suckow SK, Anderson EM, Caudle RM (2012) Lesioning of TRPV1 expressing primary afferent neurons prevents PAR-2 induced motility, but not mechanical hypersensitivity in the rat colon. Neurogastroenterol Motil 24:e125–e135PubMedCentralPubMedGoogle Scholar
  90. Suen JY, Barry GD, Lohman RJ, Halili MA, Cotterell AJ, Le GT, Fairlie DP (2012) Modulating human proteinase activated receptor 2 with a novel antagonist (GB88) and agonist (GB110). Br J Pharmacol 165:1413–1423PubMedCentralPubMedGoogle Scholar
  91. Suidan HS, Niclou SP, Monard D (1996) The thrombin receptor in the nervous system. Semin Thromb Hemost 22:125–133PubMedGoogle Scholar
  92. Takada M, Tanaka H, Yamada T, Ito O, Kogushi M, Yanagimachi M, Kawamura T, Musha T, Yoshida F, Ito M, Kobayashi H, Yoshitake S, Saito I (1998) Antibody to thrombin receptor inhibits neointimal smooth muscle cell accumulation without causing inhibition of platelet aggregation or altering hemostatic parameters after angioplasty in rat. Circ Res 82:980–987PubMedGoogle Scholar
  93. Turk B (2006) Targeting proteases: successes, failures and future prospects. Nat Rev Drug Discov 5:785–799PubMedGoogle Scholar
  94. Turnell AS, Brant DP, Brown GR, Finney M, Gallimore PH, Kirk CJ, Pagliuca TR, Campbell CJ, Michell RH, Grand RJ (1995) Regulation of neurite outgrowth from differentiated human neuroepithelial cells: a comparison of the activities of prothrombin and thrombin. Biochem J 308(Pt 3):965–973PubMedCentralPubMedGoogle Scholar
  95. Vecht CJ (1989) Nociceptive nerve pain and neuropathic pain. Pain 39(2):243–244PubMedGoogle Scholar
  96. Vergnolle N (2000) Review article: proteinase-activated receptors—novel signals for gastrointestinal pathophysiology. Aliment Pharmacol Ther 14:257–266PubMedGoogle Scholar
  97. Vergnolle N (2003) Proteinase-activated receptors and nociceptive pathways. Drug Dev Res 59:382–385Google Scholar
  98. Vergnolle N, Bunnett NW, Sharkey KA, Brussee V, Compton SJ, Grady EF, Cirino G, Gerard N, Basbaum AI, Andrade-Gordon P, Hollenberg MD, Wallace JL (2001) Proteinase-activated receptor-2 and hyperalgesia: a novel pain pathway. Nat Med 7:821–826PubMedGoogle Scholar
  99. Vu TK, Hung DT, Wheaton VI, Coughlin SR (1991) Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64(6):1057–1068PubMedGoogle Scholar
  100. Wang H, Reiser G (2003) Thrombin signalling in the brain: the role of protease-activated receptors. Biol Chem 384:193–202PubMedGoogle Scholar
  101. Wang S, Dai Y, Kobayashi K, Zhu W, Kogure Y, Yamanaka H, Wan Y, Zhang W, Noguchi K (2012) Potentiation of the P2X3 ATP receptor by PAR-2 in rat dorsal root ganglia neurons, through protein kinase-dependent mechanisms, contributes to inflammatory pain. Eur J Neurosci 36:2293–2301PubMedGoogle Scholar
  102. Xiang Y, Masuko-Hongo K, Sekine T, Nakamura H, Yudoh K, Nishioka K, Kato T (2006) Expression of proteinase-activated receptors (PAR)-2 in articular chondrocytes is modulated by IL-1beta, TNF-alpha and TGF-beta. Osteoarthritis Cartilage 14:1163–1173PubMedGoogle Scholar
  103. Zhu WJ, Yamanaka H, Obata K, Dai Y, Kobayashi K, Kozai T, Tokunaga A, Noguchi K (2005) Expression of mRNA for four subtypes of the proteinase-activated receptor in rat dorsal root ganglia. Brain Res 1041:205–211PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Departments of Pharmacology and Anaesthesia, Pain Management and Perioperative MedicineDalhousie UniversityHalifaxCanada

Personalised recommendations