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 A beta-fibers are responsible for touch and innocuous sensation. It has been reported that the intrathecal (i.t.) administration of
prostaglandin F(2 alpha) (
PGF(2 alpha)) 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
PGF(2 alpha) receptor (FP) in the induction of
allodynia by use of mice lacking FP (FP(-/-)). Both
PGF(2 alpha) and the P2X receptor agonist alphabeta-methylene
ATP administered i.t. strongly induced
allodynia for 50 min by tactile stimuli to the flank of mice. The
allodynia induced by alphabeta-methylene
ATP, but not that by
PGF(2 alpha), 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 alphabeta-methylene
ATP as well as that by
PGF(2 alpha) was not observed in FP(-/-) mice. Immunostaining of
beta-galactosidase, a reporter knocked into the endogenous FP locus in FP(-/-) mice, showed that the
FP receptor was co-localized with P2X(2) and P2X(3) receptors in neurons of the spinal cord. alphabeta-Methylene
ATP evoked a transient or sustained [Ca(2+)](i) increase in most of the PGF(2 alpha)-responsive cells in the deeper layer of the spinal cord, and the alphabeta-methylene
ATP-evoked increase was blocked by the
FP receptor antagonist
AL-8810 in two-thirds of the cells. Neither
PGF(2 alpha) nor alphabeta-methylene
ATP induced the activation of spinal microglia. The present study demonstrates that the alphabeta-methylene
ATP-evoked
allodynia is mediated by the
FP receptor, possibly via the functional coupling between the activation of P2X(2/3) receptors on the central terminal of
capsaicin-insensitive fibers and FP receptors on spinal neurons.