Distinct neurochemical mechanisms are activated following administration of different P2X receptor agonists into the hindpaw of a rat.

Nocifensive behaviors induced by the intradermal injection of three different P2X receptor agonists, ATP, BzATP or alpha,beta-meATP, into a hindpaw were measured in rats that were injected intrathecally with either an NMDA (MK-801) or an NK-1 (L-703,606) receptor antagonist or were pretreated systemically with the VR1 agonist resiniferatoxin (RTX). The same procedures were performed in animals injected intradermally with either capsaicin or formalin. Spinal infusion of MK-801 (10-50 nmol/10 micro l) similarly reduced the number of nociceptive events triggered by each of the P2X agonists and was also effective against capsaicin and formalin induced behaviors. Intrathecal administration of L-703,606 (50-100 nmol/10 micro l) had its greatest antinociceptive effect against capsaicin-induced behaviors followed by ATP and BzATP. L-703,606 was completely ineffective against behaviors induced by formalin or the other P2X agonist, alpha,beta-meATP. Pretreatment with RTX 2 days prior to testing significantly decreased the number of nociceptive events caused by each of the P2X agonists as well as capsaicin and formalin (capsaicin>BzATP>ATP>formalin>alpha,beta-meATP). The remaining nociceptive events in RTX animals injected with alpha,beta-meATP were significantly higher than in animals injected with either ATP or BzATP. Intradermal administration of different P2X receptor agonists induced similar levels of nocifensive behaviors and activity at spinal NMDA receptors. Capsaicin-sensitive fibers were likely activated following injection of BzATP and ATP, but not alpha,beta-meATP, and appeared to trigger the spinal release of substance P. The differences in mechanisms employed by the different P2X agonists may be a function of respective selectivity for P2X receptor subtypes.