Acetaminophen blocks spinal hyperalgesia induced by NMDA and substance P.
The hypothesis tested was that inhibition of the L-arginine-nitric oxide (NO) pathway may represent a potential central mechanism of action for acetaminophen (paracetamol). Spinal administration of N-methyl-D-aspartate (NMDA, 0.5 nmol), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA, 0.1 nmol) or substance P (SP, 0.5 nmol) to the rat provoked a specific behaviour characterized by biting, scratching and licking (BSL). This behaviour was antagonized by pretreatment with acetaminophen for NMDA and SP but not for AMPA. Further, the antinociceptive effect of acetaminophen was readily reversed by administration of the natural substrate for nitric oxide synthase (NOS), L-arginine, but not by D-arginine. This suggests that the analgesic effect of acetaminophen is related to inhibition of NO generation. Potential mechanisms for this may involve NMDA and SP. Our data suggest that a significant portion of the analgesic effect of acetaminophen, when used clinically, may be related to an interaction with the central nervous system L-arginine-NO pathway.
Björkman
R
R
Department of Pharmacology, University of Gothenburg and Sahlgren's Hospital, GothenburgSweden Department of Clinical Pharmacology, University of Gothenburg and Sahlgren's Hospital, GothenburgSweden.
Hallman
K M
KM
Hedner
J
J
Hedner
T
T
Henning
M
M
D000082:Acetaminophen / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000737:chemistry / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000139:chemically induced* / Q000503:physiopathology*; D007278:Injections, Spinal; D016202:N-Methylaspartate; D009619:Nociceptors / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013118:Spinal Cord Diseases / Q000139:chemically induced* / Q000503:physiopathology; D013373:Substance P; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
D013373:Substance P; D000082:Acetaminophen; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D001120:Arginine