Antinociceptive Properties of a Selective Non-Nucleotide P2X3 /P2X2/3 Receptor Antagonist

Abstract

Acute systemic administration of a novel and highly selective non-nucleotide P2X(3)/P2X(2/3) receptor antagonist, A-317491, has been shown to reduce chronic hyperalgesia and allodynia in several animal models of pathological pain in the absence of cardiovascular and CNS side effects. Furthermore, these studies have also outlined the antinociceptive profile for a P2X(3)/P2X(2/3) receptor antagonist, as A-317491 was effective in models of chronic inflammatory and neuropathic pain, but not in models of acute, acute inflammatory or visceral pain. The development of A-317491 has also added to the current understanding of P2X(3)/P2X(2/3) receptor pharmacology and its contributions to nociceptive transmission and modulation. To this end, recent studies have demonstrated that both spinal and peripheral P2X(3)/P2X(2/3) receptors have significant but differential contributions to nociception in animal models of nerve or tissue injury, and that antagonism of spinal P2X(3)/P2X(2/3) receptors results in an indirect activation of the opioid system to alleviate inflammatory thermal hyperalgesia and chemogenic nociception. Thus, preclinical data have shown considerable promise for the utility of a P2X(3)/P2X(2/3) receptor antagonist to alleviate various forms of chronic pain. Furthermore, the discovery of this selective and metabolic stable antagonist for P2X(3)/P2X(2/3) receptors has also been useful in defining the contributions of these receptors to states of pathological pain.