TY - JOUR
T1 - A-317491, a selective P2X 3/P2X 2/3 receptor antagonist, reverses inflammatory mechanical hyperalgesia through action at peripheral receptors in rats
AU - Wu, Gang
AU - Whiteside, Garth T.
AU - Lee, Gary
AU - Nolan, Scott
AU - Niosi, Mark
AU - Pearson, Michelle S.
AU - Ilyin, Victor I.
PY - 2004/11/3
Y1 - 2004/11/3
N2 - The effect of A-317491 (5-({(3-Phenoxybenzyl)[(1S)-1,2,3,4-tetrahydro-1- naphthalenyl]amino}carbonyl)-1,2,4-benzenetricarboxylic acid), a recently described selective P2X 3 and P2X 2/3 receptor antagonist, on inflammatory mechanical hyperalgesia was examined. In the rat Freund's complete adjuvant model of inflammatory pain, s.c. administration of A-317491 dose-dependently reversed mechanical hyperalgesia. Maximum percent reversal (72%) was seen 3 h after administration at 10 mg/kg. Substantial plasma concentrations were measured for A-317491 after s.c. dosing 3, 10 and 30 mg/kg. However, the brain-to-plasma concentration ratio, determined 1 h after a 10 mg/kg s.c. dose, indicated limited penetration of A-317491 into the central nervous system. As revealed by neural activity recorded from single C-fiber nociceptive afferent in a Freund's complete adjuvant-inflamed rat skin-nerve preparation, topical application of A-317491 completely blocked afferent activation and mechanical sensitization induced by α,β-methylene ATP, a P2X agonist. These results suggest that A-317491 is a peripherally acting P2X blocker. Its efficacy demonstrates the importance of peripheral P2X 3/P2X 2/3 receptors in mediating ATP-associated mechanical hyperalgesia following inflammation, confirming previous suggestions of a significant role for P2X 2/3.
AB - The effect of A-317491 (5-({(3-Phenoxybenzyl)[(1S)-1,2,3,4-tetrahydro-1- naphthalenyl]amino}carbonyl)-1,2,4-benzenetricarboxylic acid), a recently described selective P2X 3 and P2X 2/3 receptor antagonist, on inflammatory mechanical hyperalgesia was examined. In the rat Freund's complete adjuvant model of inflammatory pain, s.c. administration of A-317491 dose-dependently reversed mechanical hyperalgesia. Maximum percent reversal (72%) was seen 3 h after administration at 10 mg/kg. Substantial plasma concentrations were measured for A-317491 after s.c. dosing 3, 10 and 30 mg/kg. However, the brain-to-plasma concentration ratio, determined 1 h after a 10 mg/kg s.c. dose, indicated limited penetration of A-317491 into the central nervous system. As revealed by neural activity recorded from single C-fiber nociceptive afferent in a Freund's complete adjuvant-inflamed rat skin-nerve preparation, topical application of A-317491 completely blocked afferent activation and mechanical sensitization induced by α,β-methylene ATP, a P2X agonist. These results suggest that A-317491 is a peripherally acting P2X blocker. Its efficacy demonstrates the importance of peripheral P2X 3/P2X 2/3 receptors in mediating ATP-associated mechanical hyperalgesia following inflammation, confirming previous suggestions of a significant role for P2X 2/3.
KW - Hyperalgesia
KW - Inflammation
KW - Mechanosensitivity
KW - P2X receptors
KW - Pain
KW - Peripheral sensitization
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U2 - 10.1016/j.ejphar.2004.09.056
DO - 10.1016/j.ejphar.2004.09.056
M3 - Article
C2 - 15507220
AN - SCOPUS:6944246360
SN - 0014-2999
VL - 504
SP - 45
EP - 53
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-2
ER -