Purinoceptors are distributed in primary afferent terminals, where transmission of nociceptive information is modulated by these receptors. In the present study, we have evaluated if 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 A- and C-primary afferent fibers in the tibial nerve in anesthetized rats. Peripheral pretreatment with ,-meATP, a P2X-selective receptor agonist, could potentiate the CAP-induced enhancement of responses of A- and C-primary afferent nociceptive fibers to mechanical stimuli in sympathetically intact rats. After sympathetic denervation, the enhanced responses of both A- and C-fibers following CAP injection were dramatically reduced. However, this reduction could be restored when P2X receptors were activated by ,-meATP. A blockade of P2X receptors by PPADS could reduce significantly the CAP-induced sensitization of A- and C-fibers. Pretreatment with UTP, a P2Y-selective receptor agonist, did not significantly affect or restore the CAP-induced sensitization of A- 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 via 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 ₁-adrenergic receptors.