Peripheral P2X receptors and nociception: interactions with biogenic amine systems

ATP is implicated in peripheral nociception following activation of P2X, and particularly P2X(3) receptors. The present study examined interactions between alphabeta-methylene-ATP (a P2X(3) receptor ligand) and 5-hydroxytryptamine (5-HT), noradrenaline (NA) and histamine, following local administration into the hindpaw, on spontaneous pain behaviors and thermal hyperalgesia in Sprague-Dawley rats. The interaction with NA was further explored using systemic 6-hydroxydopamine (6-OHDA) and locally administered indomethacin. alphabeta-methylene-ATP produced no spontaneous pain behaviors. Coadministration of 5-HT with alphabeta-methylene-ATP mildly augmented flinching behaviors, while histamine had no such effect. Coadministration of NA with alphabeta-methylene-ATP produced a pronounced expression of flinching and biting/licking behaviors. alphabeta-Methylene-ATP, given alone, produced thermal hyperalgesia, and this was markedly augmented by both 5-HT and NA, but not histamine. 6-OHDA (neurotoxin for sympathetic neurons) and indomethacin (cyclooxygenase inhibitor) reduced the augmenting effect of NA on alphabeta-methylene-ATP-induced thermal hyperalgesia, but had no effect on spontaneous pain behaviors produced by the alphabeta-methylene-ATP/NA combination. Effects of alphabeta-methylene-ATP, NA and their combination were also examined in Long Evans and Wistar rats. In both strains, alphabeta-methylene-ATP and NA both individually led to significant intrinsic flinching behaviors, and the effect of their combination was even more pronounced than in Sprague-Dawley rats. These results provide evidence for: (a) a strong enhancement by NA and 5-HT of nociception produced by peripheral P2X receptors in Sprague-Dawley rats, (b) an indirect action of NA, via sympathetic efferents and prostanoids, with thermal hyperalgesia, and (c) a greater expression of spontaneous pain behaviors with alphabeta-methylene-ATP and NA alone, and with their combination, in Wistar and Long Evans rats compared to Sprague-Dawley rats.