The snake venom metalloproteinase BaP1 induces joint hypernociception through TNF-alpha and PGE2-dependent mechanisms.
| Autor: | Fernandes CM; Laboratório de Farmacologia-Instituto Butantan, São Paulo, Brazil., Pereira Teixeira Cde F, Leite AC, Gutiérrez JM, Rocha FA |
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| Jazyk: | angličtina |
| Zdroj: | British journal of pharmacology [Br J Pharmacol] 2007 Aug; Vol. 151 (8), pp. 1254-61. Date of Electronic Publication: 2007 Jun 25. |
| DOI: | 10.1038/sj.bjp.0707351 |
| Abstrakt: | Background and Purpose: 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. Experimental Approach: 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. Key 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 and Implications: 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. |
| Databáze: | MEDLINE |
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