Antinociceptive effect of a kappa-opioid receptor agonist that minimally crosses the blood-brain barrier (ICI 204448) in a rat model of mononeuropathy.

The antinociceptive effect of intraplantar (i.pl.) ICI 204448 ((R,S)-N-[2-(N-methyl-3,4-dichloro-phenylacetamido)-2-(3-carbox yph enyl)- ethyl]pyrrolidine hydrochloride)) (20, 30, 40 and 50 micrograms), a kappa-opioid receptor agonist which has limited access to the central nervous system, was studied in a well-established rat model of peripheral mononeuropathy produced by moderate constriction of the sciatic nerve. Vocalization thresholds to paw pressure were used as a nociceptive test. On the injected nerve-injured paw, ICI 204448 at 20 and 30 micrograms had no significant effect, but higher doses (40 micrograms) produced a significant antinociceptive effect, which plateaued at 50 micrograms. By contrast, no antinociceptive effect was observed on the contralateral paw. The effect of ICI 204448 (40 micrograms) was significantly antagonised by the specific kappa-opioid receptor antagonist nor-binaltorphimine (20 and 30 micrograms), when co-injected in the nerve-injured paw.