P2X3 receptors, either as a homomeric P2X3 or a combination of P2X2-P2X3 receptors, are primarily expressed on nociceptive sensory neurons143 and mediate the ATP nociceptive signaling.144 In the spinal cord, released ATP from injured cells facilitates glutamate release from primary afferent neurons by its action at the presynaptic P2X3 receptors.144,145 P2X3 knockout animals have shown to exhibit a reduction of activity of afferent nerves and nociceptive signaling,146 and P2X3 receptor expression downregulation by antagonist A-317491 has resulted in reduced mechanical hyperalgesia and neuropathic pain,147,148 supporting the effect of ATP on peripheral nerve afferents.146
