Effects of A-317491, a novel and selective P2X3/P2X2/3 receptor antagonist, on neuropathic, inflammatory and chemogenic nociception following intrathecal and intraplantar administration.
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.
McGaraughty
Steve
S
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, R4PM, AP9-1, 100 Abbott Park Road, Abbott Park, IL 60064-6118, USA. Steve.P.McGaraughty@abbott.com
Wismer
Carol T
CT
Zhu
Chang Z
CZ
Mikusa
Joseph
J
Honore
Prisca
P
Chu
Katharine L
KL
Lee
Chih-Hung
CH
Faltynek
Connie R
CR
Jarvis
Michael F
MF
D000208:Acute Disease; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives*; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002351:Carrageenan; D002908:Chronic Disease; D006614:Hindlimb; D006358:Hot Temperature / Q000009:adverse effects; D007249:Inflammation / Q000188:drug therapy; D007278:Injections, Spinal; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009479:Neuropeptides / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy*; D010636:Phenols / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011083:Polycyclic Compounds / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3
C470346:A-317491; D018712:Analgesics, Non-Narcotic; D009479:Neuropeptides; C546403:P2rx2 protein, rat; C546410:P2rx3 protein, rat; D010636:Phenols; D011083:Polycyclic Compounds; D058919:Purinergic P2 Receptor Antagonists; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3; D000255:Adenosine Triphosphate; D002351:Carrageenan; C002630:alpha,beta-methyleneadenosine 5'-triphosphate