Peripheral mechanisms underlying the essential role of P2X7 receptors in the development of inflammatory hyperalgesia

Activation of P2X7 receptors by endogenous ATP contributes to the development of inflammatory hyperalgesia. Given the clinical importance of mechanical hyperalgesia in inflammatory states, we hypothesized that the activation of the P2X7 receptor by endogenous ATP contributes to carrageenan-induced mechanical hyperalgesia, and that this contribution is mediated by an indirect sensitization of the primary afferent nociceptors. Co-administration of the selective P2X7 receptor antagonist, A-438079, or the P2X7 receptor antagonist, oATP, with carrageenan blocked the mechanical hyperalgesia induced by carrageenan and significantly reduced the increased concentration of TNF-α, IL-6 and CINC-1, but not of IL-1β induced by carrageenan in the subcutaneous tissue of the rat's hind paw. We concluded that the activation of P2X7 receptors by endogenous ATP is essential to the development of the mechanical hyperalgesia induced by carrageenan in the subcutaneous tissue. It is suggested that this essential role of P2X7 receptors in the development of carrageenan-induced mechanical hyperalgesia is mediated by an indirect sensitization of the primary afferent nociceptors dependent on the previous release of TNF-α, IL-6 and CINC-1, but not of IL-1β.