Inflammatory muscle pain is dependent on the activation of kinin B₁ and B₂ receptors and intracellular kinase pathways

Abstract

BACKGROUND AND PURPOSEB1 and B2 kinin receptors are involved in pain transmission but they may have different roles in the muscle pain induced by intense exercise or inflammation. We investigated the contribution of each of these receptors, and the intracellular pathways involved, in the initial development and maintenance of the muscle pain associated with inflammation-induced tissue damage. EXPERIMENTAL APPROACHMechanical hyperalgesia was measured using the Randall-Selitto apparatus after injecting 5% formalin solution into the gastrocnemius muscle in mice treated with selective antagonists for B1 or B2 receptors. The expression of kinin receptors and cytokines and the activation of intracellular kinases were monitored by real-time PCR and immunohistochemistry. KEY RESULTSThe i.m. injection of formalin induced an overexpression of B1 and B2 receptors. This overexpression was associated with the mechanical hyperalgesia induced by formalin because treatment with B1 receptor antagonists (des-Arg 9 [Leu 8 ]-BK, DALBK, and SSR240612) or B2 receptor antagonists (HOE 140 and FR173657) prevented the hyperalgesia. Formalin increased myeloperoxidase activity, and up-regulated TNF-a, IL-1b and IL-6 in gastrocnemius. Myeloperoxidase activity and TNF-a mRNA expression were inhibited by either DALBK or HOE 140, whereas IL-6 was inhibited only by HOE 140. The hyperalgesia induced by i.m. formalin was dependent on the activation of intracellular MAPKs p38, JNK and PKC. CONCLUSIONS AND IMPLICATIONSInflammatory muscle pain involves a cascade of events that is dependent on the activation of PKC, p38 and JNK, and the synthesis of IL-1b, TNF-a and IL-6 associated with the up-regulation of both B1 and B2 kinin receptors.Abbreviations DALBK,

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