P2X₇-related modulation of pathological nociception in rats

Growing evidence supports a role for the immune system in the induction and maintenance of chronic pain. ATP is a key neurotransmitter in this process. Recent studies demonstrate that the glial ATP receptor, P2X₇, contributes to the modulation of pathological pain. To further delineate the endogenous mechanisms that are involved in P2X₇-related antinociception, we utilized a selective P2X₇ receptor antagonist, A-438079, in a series of in vivo and in vitro experiments. Injection of A-438079 (10-300 μmol/kg, i.p.) was anti-allodynic in three different rat models of neuropathic pain and it attenuated formalin-induced nocifensive behaviors. Using in vivo electrophysiology, A-438079 (80 μmol/kg, i.v.) reduced noxious and innocuous evoked activity of different classes of spinal neurons (low threshold, nociceptive specific, wide dynamic range) in neuropathic rats. The effects of A-438079 on evoked firing were diminished or absent in sham rats. Spontaneous activity of all classes of spinal neurons was also significantly reduced by A-438079 in neuropathic but not sham rats. In vitro, A-438079 (1 μM) blocked agonist-induced (2,3-O-(4-benzoylbenzoyl)-ATP, 30 μM) current in non-neuronal cells taken from the vicinity of the dorsal root ganglia. Furthermore, A-438079 dose-dependently (0.3-3 μM) decreased the quantity of the cytokine, interleukin-1β, released from peripheral macrophages. Thus, ATP, acting through the P2X₇ receptor, exerts a wide-ranging influence on spinal neuronal activity following a chronic injury. Antagonism of the P2X₇ receptor can in turn modulate central sensitization and produce antinociception in animal models of pathological pain. These effects are likely mediated through immuno-neural interactions that affect the release of endogenous cytokines.