Effects of A-317491, a novel and selective P2X3/P2X2/3 receptor antagonist, on neuropathic, inflammatory and chemogenic nociception following intrathecal and intraplantar administration

Br J Pharmacol. 2003 Dec;140(8):1381-8. doi: 10.1038/sj.bjp.0705574. Epub 2003 Nov 17.


We have recently reported that systemic delivery of A-317491, the first non-nucleotide antagonist that has high affinity and selectivity for blocking P2X3 homomeric and P2X2/3 heteromeric channels, is antinociceptive in rat models of chronic inflammatory and neuropathic pain. In an effort to further evaluate the role of P2X3/P2X2/3 receptors in nociceptive transmission, A-317491 was administered either intrathecally or into the hindpaw of a rat in several models of acute and chronic nociception. Intraplantar (ED50=300 nmol) and intrathecal (ED50=30 nmol) injections of A-317491 produced dose-related antinociception in the CFA model of chronic thermal hyperalgesia. Administration of A-317491 by either route was much less effective to reduce thermal hyperalgesia in the carrageenan model of acute inflammatory hyperalgesia. Intrathecal, but not intraplantar, delivery of A-317491 attenuated mechanical allodynia in both the chronic constriction injury and L5-L6 nerve ligation models of neuropathy (ED50=10 nmol for both models). Intrathecal injections of A-317491 did not impede locomotor performance. Both routes of injection were effective in reducing the number of nocifensive events triggered by the injection of formalin into a hindpaw. Nocifensive behaviors were significantly reduced in both the first and second phases of the formalin assay (intrathecal ED50=10 nmol, intraplantar ED50>300 nmol). Nocifensive behaviors induced by the P2X receptor agonist alpha,beta-meATP were also significantly reduced by intraplantar injection of A-317491. These data indicate that both spinal and peripheral P2X3/P2X2/3 receptors have significant contributions to nociception in several animal models of nerve or tissue injury. Intrathecal administration of A-317491 appears to be more effective than intraplantar administration to reduce tactile allodynia following peripheral nerve injury.

Publication types

  • Comparative Study

MeSH terms

  • Acute Disease
  • Adenosine Triphosphate / analogs & derivatives*
  • Analgesics, Non-Narcotic / administration & dosage
  • Analgesics, Non-Narcotic / pharmacology*
  • Analgesics, Non-Narcotic / therapeutic use
  • Animals
  • Carrageenan
  • Chronic Disease
  • Hindlimb
  • Hot Temperature / adverse effects
  • Inflammation / drug therapy
  • Injections, Spinal
  • Male
  • Motor Activity / drug effects
  • Neuropeptides / metabolism
  • Pain / drug therapy*
  • Pain / etiology
  • Pain Measurement
  • Peripheral Nervous System Diseases / drug therapy*
  • Phenols / administration & dosage
  • Phenols / pharmacology*
  • Phenols / therapeutic use
  • Polycyclic Compounds / administration & dosage
  • Polycyclic Compounds / pharmacology*
  • Polycyclic Compounds / therapeutic use
  • Purinergic P2 Receptor Antagonists*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Purinergic P2X2
  • Receptors, Purinergic P2X3


  • A-317491
  • Analgesics, Non-Narcotic
  • Neuropeptides
  • P2rx2 protein, rat
  • P2rx3 protein, rat
  • Phenols
  • Polycyclic Compounds
  • Purinergic P2 Receptor Antagonists
  • Receptors, Purinergic P2X2
  • Receptors, Purinergic P2X3
  • Adenosine Triphosphate
  • Carrageenan
  • alpha,beta-methyleneadenosine 5'-triphosphate