The snake venom metalloproteinase BaP1 induces joint hypernociception through TNF-alpha and PGE2-dependent mechanisms.

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.

Endothelin ETB receptors inhibit articular nociception and priming induced by carrageenan in the rat knee-joint.

The participation of the endothelin system on nociception and priming induced by carrageenan in the knee-joint was investigated. Intra-articular (i.a.) carrageenan (300 microg) caused long-lasting nociceptive effects (i.e., increases in paw elevation time [PET]), which were potentiated by endothelin-1 (dual endothelin ETA/ETB receptor agonist) and inhibited by sarafotoxin S6c (endothelin ETB receptor agonist; both at 30 pmol, i.a., 24 h beforehand). Priming the naive joint with carrageenan augmented nociceptive responses to a second carrageenan challenge, 72 h later. Carrageenan-induced priming, but not nociception, was potentiated by local BQ-788 (10 nmol, i.a., 15 min before priming; endothelin ETB receptor antagonist; N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D-1-methoxycarbonyl-tryptophanil-D-norleucine), but BQ-123 (endothelin ETA receptor antagonist; cyclo [D-Asp-Pro-D-Val-Leu]) was ineffective. Sarafotoxin S6c markedly suppressed carrageenan-induced priming to nociception triggered by carrageenan, endothelin-1 or sarafotoxin S6c, and BQ-788 prevented this action. Thus, selective endothelin ETB receptor agonists inhibit carrageenan-induced nociception and priming in the naive joint. This priming effect of carrageenan to nociception evoked by subsequent inflammatory insults is limited by an endothelin ETB receptor-operated mechanism.