The snake venom metalloproteinase BaP1 induces joint hypernociception through TNF-alpha and PGE2-dependent mechanisms.
OBJECTIVE
Matrix metalloproteinases (MMPs) have been implicated in joint tissue destruction in arthritis. However, MMPs have not been assigned a role in joint pain. We investigated the ability of BaP1, a metalloproteinase from Bothrops asper snake venom, with structural homology to MMPs, to induce joint hypernociception.


METHODS
Animals received intra-articular (i.art.) BaP1. Hypernociception was assessed using the rat-knee joint articular incapacitation test. Cell influx, prostaglandin E(2) (PGE(2)), and TNF-alpha levels were assessed in joint exudates following BaP1 injection.


RESULTS
BaP1 (5 microg per joint) provoked hypernociception between 1 and 6 h after i.art. injection. Cell influx, mostly neutrophils, was maximal 3 h after BaP1 i.art. injection. BaP1 also led to increase in PGE(2) and TNF-alpha levels in the joint exudates. Pretreatment with either indomethacin (4 mg.kg(-1) i.p.) or with an anti-TNF-alpha antiserum (i.art.) significantly inhibited both BaP1-induced joint hypernociception and cell influx. In isolated rat peritoneal macrophages, BaP1 increased cyclooxygenase (COX)-2 expression, while not altering that of COX-1.


CONCLUSIONS
This is the first demonstration that a metalloproteinase promotes joint hypernociception. This effect involves local release of PGE(2) and TNF-alpha. BaP1-induced increase in PGE(2) is associated to increased COX-2 expression in macrophages. Blocking PGE(2) or TNF-alpha inhibits BaP1-induced hypernociception. In addition to unravelling a hitherto unknown mechanism whereby TNF blockade provides analgesia in arthritis, the data show, for the first time that MMPs are involved in inflammatory joint hypernociception and induce COX-2 expression.
Fernandes
C M
CM
Laboratório de Farmacologia-Instituto Butantan, São Paulo, Brazil.
Pereira Teixeira
C de Fátima
Cde F
Leite
A C R M
AC
Gutiérrez
J M
JM
Rocha
F A C
FA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000503:physiopathology*; D017837:Bothrops; D003435:Crotalid Venoms / Q000633:toxicity*; D051545:Cyclooxygenase 1 / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005122:Exudates and Transudates / Q000378:metabolism; D007106:Immune Sera; D007213:Indomethacin / Q000627:therapeutic use; D007270:Injections, Intra-Articular; D017746:Joint Capsule / Q000187:drug effects / Q000503:physiopathology; D007719:Knee Joint / Q000187:drug effects / Q000503:physiopathology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008666:Metalloendopeptidases / Q000633:toxicity*; D009504:Neutrophils; D010146:Pain / Q000139:chemically induced*; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D003435:Crotalid Venoms; D007106:Immune Sera; D014409:Tumor Necrosis Factor-alpha; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C104933:BaP1 metalloproteinase; D008666:Metalloendopeptidases; D015232:Dinoprostone; D007213:Indomethacin