Antinociceptive effect of L-arginine on the carrageenin-induced hyperalgesia of the rat: possible involvement of central opioidergic systems.

L-arginine is considered to be a precursor substance of kyotorphin (tyrosyl-arginine), a Met5]enkephalin releaser with antinociceptive action. We examined the antinociceptive effect of L-arginine in rats. L-Arginine (300-1000 mg/kg) administered subcutaneously (s.c.) elicited antinociception (assessed by the Randall-Selitto method) in rats with a carrageenin-treated hindpaw. Naloxone (2 mg/kg s.c.) but not N-methyl-levallorphan (20 mg/kg s.c.), a peripherally selective opioid antagonist, inhibited L-arginine-induced antinociception. Intracerebroventricular administration of L-arginine (0.2-1.0 mg/rat) produced a dose-related inhibition of the carrageenin-induced hyperalgesia. Intraplantar (i.pl.) injection of L-arginine (0.5-1.0 mg/paw) also induced antinociception, which was resistant to naloxone (2 mg/kg s.c.) but was antagonized by methylene blue (0.5 mg/paw i.pl.), a guanylate cyclase inhibitor. L-Arginine (1000 mg/kg s.c.) did not inhibit edema formation in the carrageenin-treated rat hindpaw. These results suggest that systemically administered L-arginine produces mainly an antinociceptive effect mediated by central opioidergic mechanisms in rats with carrageenin-induced hyperalgesia.