The snake venom metalloproteinase BaP1 induces joint hypernociception through TNF‐α and PGE₂‐dependent mechanisms

Abstract

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-a levels were assessed in joint exudates following BaP1 injection. Key results: BaP1 (5 mg 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-a levels in the joint exudates. Pretreatment with either indomethacin (4 mg.kg À1 i.p.) or with an anti-TNF-a 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-a. BaP1-induced increase in PGE 2 is associated to increased COX-2 expression in macrophages. Blocking PGE 2 or TNF-a 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.

Multifunctional Toxins in Snake Venoms and Therapeutic Implications: From Pain to Hemorrhage and Necrosis

“…Acute pain through ASIC1 activation (Bohlen et al, 2011) Inflammatory pain, thermal hypersalgesia and mechanical allodynia (Zhang et al, 2017) Excitation of sensory neurons (Bohlen et al, 2011;Zhang et al, 2017) Neurogenic inflammation (Camara et al, 2003;Camargo et al, 2008) Non-neurogenic inflammation Endematogenic and pro-inflammatory (Camara et al, 2003;Casais-E-Silva et al, 2016;Costa et al, 2017) Inhibits platelet aggregation (Teixeira et al, 2011) Phospholipase activity (Gutierrez and Ownby, 2003) Myotoxic (Harris and Maltin, 1982) Pre-synaptic toxin, block of neuromuscular transmission leading to muscle paralysis (Sribar et al, 2014;Gutierrez et al, 2017) SVMP Inflammatory hyperalgesia (Fernandes et al, 2007;Bernardes et al, 2015;De Toni et al, 2015;Ferraz et al, 2015) Endematogenic activity independent of pro-inflammatory mediators (Laing et al, 2003) Cleavage of basement membrane of capillary vessels and endothelial cells adhesion proteins (Gutierrez et al, 2005;Escalante et al, 2011) Procoagulant through activation of prothrombin and Factor X (Takeda et al, 2012;Ainsworth et al, 2018) Inhibition of platelet aggregation (Kamiguti, 2005) Dermonecrotic activity dependent on TNF signaling (Laing et al, 2003) Potential paralysis through inhibition of α-7 neuronal AChR by the cysteine-rich and disintregin-like domains complex (Brust et al, 2013) SVSP Mild mechanical hyperalgesia (Menaldo et al, 2013) Leucocyte migration (Menaldo et al, 2013) Mild edema (Zychar et al, 2010) Procoagulant through activation of prothrombin and factors VII and X (Kini, 2005) Anti-coagulant through activation of Prot...…”

Inflammatory mediators involved in the paw edema and hyperalgesia induced by Batroxase, a metalloproteinase isolated from Bothrops atrox snake venom

“…Batroxase also induced hyperalgesic response peaking 1 h after injection. BaP1, a metalloproteinase from B. asper venom, also induced hyperalgesia, but in contrast to Batroxase, it showed a maximum response 2 h after injection [26]. According to Zychar et al [79], metalloproteinases present in the venom of B. jararaca are the main responsible for the hyperalgesia induced by this venom.…”

A Comprehensive View of the Structural and Functional Alterations of Extracellular Matrix by Snake Venom Metalloproteinases (SVMPs): Novel Perspectives on the Pathophysiology of Envenoming

“…Several aspects of the local pathological effects induced by SVMPs have been studied, such as the microvascular damage leading to hemorrhage [15,16], skeletal muscle necrosis and poor muscle regeneration [13,14,17], blistering, and dermonecrosis [18,19], as well as the identification of inflammatory mediators responsible for pain, edema, and leukocyte infiltration [20,21,22]. To a great extent, these alterations are considered to be associated in some manner with the action of SVMPs on the extracellular matrix (ECM).…”