P2X 7 receptor in the trigeminal sensory nuclear complex contributes to tactile allodynia/hyperalgesia following trigeminal nerve injury

Background The present study directly addresses the roles of the P2X 7 receptor ( P2X 7 R ), an ionotropic adenosine triphosphate (ATP) receptor, and cytokines in the induction of orofacial pain following chronic constriction injury ( CCI ) of the infraorbital nerve ( IoN ). Methods Rats were anesthetized, and ligatures of 4‐0 chromic gut were tied around the IoN . A 438079, a P2X 7 R antagonist or SB 203580, a phosphorylated (p)‐p38 mitogen‐activated protein kinase ( MAPK ) inhibitor, was infused intrathecally into CCI ‐treated rats. In another group of rats, 3′‐O‐(4‐benzoylbenzoyl) adenosine 5′‐triphosphate (BzATP) , a P2X 7 R agonist, was infused intrathecally with A 438079, SB 203580 or etanercept, a tumor necrosis factor ( TNF )‐α receptor‐binding recombinant drug. Results CCI of the IoN induced tactile allodynia/hyperalgesia and up‐regulation of P2X 7 R , membrane‐bound TNF ‐α (mTNF‐α) and soluble TNF ‐α (s TNF ‐α) in the trigeminal sensory nuclear complex ( TNC ). Tactile allodynia/hyperalgesia or up‐regulation of mTNF‐α and s TNF ‐α in the TNC following CCI of the IoN was inhibited by A 438079. SB 203580 also attenuated tactile allodynia/hyperalgesia or up‐regulation of m TNF ‐α, but not the up‐regulation of s TNF ‐α in the TNC . Treatment of rats with BzATP induced tactile allodynia/hyperalgesia and up‐regulation of s TNF ‐α and p‐p38 in the TNC . Tactile allodynia/hyperalgesia or up‐regulation of s TNF ‐α following BzATP treatment was inhibited by SB203580 and etanercept. Conclusions Based on these findings, phosphorylation of p38 MAPK via P2X 7 R may induce tactile allodynia/hyperalgesia, which is most likely mediated by sTNF ‐α released by microglia.