Involvement of Peripheral Purinoceptors in Sympathetic Modulation of Capsaicin-Induced Sensitization of Primary Afferent Fibers

Abstract

Purinoceptors are distributed in primary afferent terminals, where transmission of nociceptive information is modulated by these receptors. In the present study, we evaluated whether the activation or blockade of purinoceptors of subtypes P2X and P2Y in the periphery affected the sensitization of primary afferents induced by intradermal injection of capsaicin (CAP) and examined their role in sympathetic modulation of sensitization of primary nociceptive afferents. Afferent activity was recorded from single Adelta- and C-primary afferent fibers in the tibial nerve in anesthetized rats. Peripheral pretreatment with alpha,beta-methylene adenosine 5'-triphosphate (alpha,beta-meATP), a P2X-selective receptor agonist, could potentiate the CAP-induced enhancement of responses of Adelta- and C-primary afferent nociceptive fibers to mechanical stimuli in sympathetically intact rats. After sympathetic denervation, the enhanced responses of both Adelta- and C-fibers after CAP injection were dramatically reduced. However, this reduction could be restored when P2X receptors were activated by alpha,beta-meATP. A blockade of P2X receptors by pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid could significantly reduce the CAP-induced sensitization of Adelta- and C-fibers. Pretreatment with uridine 5'-triphosphate, a P2Y-selective receptor agonist, did not significantly affect or restore the CAP-induced sensitization of Adelta- and C-fibers under sympathetically intact or sympathectomized conditions. Our study supports the view that ATP plays a role in modulation of primary afferent nociceptor sensitivity mainly by P2X receptors. Combined with our previous study, our data also provide further evidence that the sensitization of primary afferent nociceptors is subject to sympathetic modulation by activation of P2X as well as alpha(1)-adrenergic receptors.