1. Possible interactions between non-steroidal anti-inflammatory drugs (
NSAIDs) and endogenous
opioids were examined in electrophysiological experiments in
alpha-chloralose anaesthetized spinalized rats without or with
carrageenan-induced acute
inflammation of one hindpaw. Spinal reflex responses, monitored as single motor unit discharges, were elicited by noxious pinch and electrical stimuli. 2. The mu-
opioid agonist,
fentanyl, was an effective depressant of reflexes under all conditions (ED50 6-14 micrograms kg-1, i.v.). In rats without peripheral
inflammation the
NSAID,
flunixin, a
niflumic acid derivative, had only a small effect that was not dose-dependent. However, in animals with unilateral
inflammation,
flunixin reduced spinal reflexes evoked both by noxious pinch stimuli (that activate peripheral nociceptors; ID50 4 mg kg-1, i.v.) and by electrical stimuli (that bypass nociceptor endings; ID50 6.5- 11 mg kg-1, i.v.), indicating that it has a central site of action at doses comparable to those used clinically. 3. The
opioid antagonist,
naloxone (1 mg kg-1, i.v.), reversed all actions of
fentanyl. It did not reverse the small effects that
flunixin had in rats without
inflammation, showing that the
NSAID is not a direct
opioid agonist. In rats with
carrageenan-induced
inflammation of the hindpaw, however,
naloxone fully reversed or prevented the antinociception by
flunixin, but not that by the alpha 2-adrenoceptor agonist,
medetomidine. 4. We conclude that under conditions of peripheral
inflammation and the resultant central changes, the
NSAID,
flunixin, has antinociceptive actions that are mediated by endogenous
opioids acting within the spinal cord.