title: Thrombin receptor: An endogenous inhibitor of inflammatory pain, activating opioid pathways.
abstract: Serine proteases such as thrombin, trypsin and mast cell tryptase can act on different cell types through protease-activated receptors (PARs). These receptors have been shown to be implicated in several phenomena such as inflammation, platelet activation, immune response and atherosclerosis. Several studies recently reported PARs expression on neurons and some of them demonstrated that these receptors could interfere with nociception. The contribution of PAR(1) to inflammatory pain and the mechanism involved in this phenomenon were investigated. Intraplantar injection of PAR(1) agonist increased withdrawal latency and reduced response frequency to von Frey filaments, thus inhibiting nociceptive response to both mechanical and thermal stimuli in mice. PAR(1) agonist also reduced carrageenan-induced inflammatory hyperalgesia. The anti-nociceptive effects of PAR(1) agonist were mediated by endogenous opioids, as this effect was inhibited by local injection of naloxone methiodide, and because intraplantar injection of PAR(1) agonist increased mRNA expression of the endogenous opioid precursor proenkephalin. However, PAR(1) agonist was not able to inhibit calcium signals in isolated sensory neurons exposed to pro-nociceptive agents. Finally, despite similar inflammatory parameters, PAR(1)-deficient mice showed a strong potentiation of inflammatory hyperalgesia induced by the intraplantar injection of either formalin or carrageenan, or in the chronic model of collagen-induced arthritis, compared to wild-type mice. This study highlights a previously unknown endogenous mechanism of analgesia, showing a central role for the thrombin receptor PAR(1) in the regulation of inflammatory pain and as an activator of opioid pathways.
authors.affiliation: INSERM, U563, Centre de Physiopathologie de Toulouse Purpan, F-31000 Toulouse, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Martin
authors.forename: Céline
authors.initials: C
authors.lastname: Augé
authors.forename: Jérôme
authors.initials: J
authors.lastname: Boué
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Buresi
authors.forename: Kevin
authors.initials: K
authors.lastname: Chapman
authors.forename: Samuel
authors.initials: S
authors.lastname: Asfaha
authors.forename: Patricia
authors.initials: P
authors.lastname: Andrade-Gordon
authors.forename: Martin
authors.initials: M
authors.lastname: Steinhoff
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cenac
authors.forename: Gilles
authors.initials: G
authors.lastname: Dietrich
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vergnolle
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D005528:Foot; D006930:Hyperalgesia / Q000139:chemically induced / Q000473:pathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D007267:Injections; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009619:Nociceptors / Q000187:drug effects; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D018847:Opioid Peptides / Q000502:physiology*; D010146:Pain / Q000139:chemically induced / Q000209:etiology / Q000503:physiopathology*; D010147:Pain Measurement / Q000187:drug effects; D044463:Receptor, PAR-1 / Q000819:agonists / Q000502:physiology; D011957:Receptors, Opioid / Q000187:drug effects; D018179:Receptors, Thrombin / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D011984:Sensory Receptor Cells / Q000187:drug effects; D015398:Signal Transduction / Q000502:physiology
chemical_list: D009842:Oligopeptides; D018847:Opioid Peptides; C462999:PAR-1-activating peptide; D044463:Receptor, PAR-1; D011957:Receptors, Opioid; D018179:Receptors, Thrombin; D002118:Calcium