The hypothesis tested was that inhibition of the L-arginine-nitric oxi
de (NO) pathway may represent a potential central mechanism of action
for acetaminophen (paracetamol). Spinal administration of N-methyl-D-a
spartate (NMDA, 0.5 nmol), pha-amino-3-hydroxy-5-methyl-4-isoxazolepro
pionate (AMPA, 0:1 nmol) or substance P (SP, 0.5 nmol) to the rat prov
oked a specific behaviour characterized by biting, scratching and lick
ing (BSL). This behaviour was antagonized by pretreatment with acetami
nophen 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 acetaminoph
en is related to inhibition of NO generation. Potential mechanisms for
this may involve NMDA and SP. Our data suggest that a significant por
tion of the analgesic effect of acetaminophen, when used clinically, m
ay be related to an interaction with the central nervous system L-argi
nine-NO pathway.