Involvement of prostaglandin F2α receptor in ATP-induced mechanical allodynia

Nociceptive primary afferents have the capacity to induce a state of increased excitability in the dorsal horn neurons of the spinal cord. It is well accepted that capsaicin-sensitive C-fibers transduce noxious stimulation and acute pain and that capsaicin-insensitive Aβ-fibers are responsible for touch and innocuous sensation. It has been reported that the intrathecal (i.t.) administration of prostaglandin F2α (PGF2α) and ATP induces mechanical allodynia via the capsaicin-insensitive primary afferent pathway. In the present study, we investigated the interaction of purinoceptor P2X and the PGF2α receptor (FP) in the induction of allodynia by use of mice lacking FP (FP−/−). Both PGF2α and the P2X receptor agonist αβ-methylene ATP administered i.t. strongly induced allodynia for 50 min by tactile stimuli to the flank of mice. The allodynia induced by αβ-methylene ATP, but not that by PGF2α, was suppressed by simultaneous i.t. administration of P2X receptor antagonists pyridoxalphosphate-6-azophenyl-2,4-disulphonic acid and A-317491. In contrast, the allodynia induced by αβ-methylene ATP as well as that by PGF2α was not observed in FP−/− mice. Immunostaining of β-galactosidase, a reporter knocked into the endogenous FP locus in FP−/− mice, showed that the FP receptor was co-localized with P2X2 and P2X3 receptors in neurons of the spinal cord. αβ-Methylene ATP evoked a transient or sustained [Ca2+]i increase in most of the PGF2α-responsive cells in the deeper layer of the spinal cord, and the αβ-methylene ATP-evoked increase was blocked by the FP receptor antagonist AL-8810 in two-thirds of the cells. Neither PGF2α nor αβ-methylene ATP induced the activation of spinal microglia. The present study demonstrates that the αβ-methylene ATP-evoked allodynia is mediated by the FP receptor, possibly via the functional coupling between the activation of P2X2/3 receptors on the central terminal of capsaicin-insensitive fibers and FP receptors on spinal neurons.