L-arginine exerts a dual role in nociceptive processing in the brain: involvement of the kyotorphin-Met-enkephalin pathway and NO-cyclic GMP pathway.

1. Intracerebroventricular (i.c.v.) administration of L-arginine (L-Arg), at 10-100 micrograms per mouse, produced antinociception in mice, as assessed by the tail flick test; this antinociception was reversed by pretreatment (s.c.) with naltrindole (NTI), a delta-selective opioid antagonist, and by co-administered L-leucyl-L-arginine (Leu-Arg), a kyotorphin (endogenous Met-enkephalin releaser) receptor antagonist. 2. L-NG-nitroarginine methyl ester (L-NAME), a NO synthase inhibitor, but not D-NG-nitroarginine methyl ester, given i.c.v. at 3-10 micrograms per mouse, exhibited antinociceptive activity that was resistant to naloxone (s.c.), NTI (s.c.) and Leu-Arg (i.c.v.). 3. The L-NAME (i.c.v.)-induced antinociception was not reversed by L-Arg (i.c.v.), which was antinociceptive by itself, but was abolished by combined injection of L-Arg plus Leu-Arg (i.c.v.) or by L-Arg (i.c.v.) after NTI (s.c.). 4. Methylene blue (MB), a soluble guanylate cyclase inhibitor, at 0.1-1 microgram per mouse, produced antinociception by i.c.v. administration. The antinociception induced by MB (i.c.v.) or L-NAME (i.c.v.) was reversed by co-administered dibutyryl cyclic GMP. 5. These findings suggest that L-Arg plays a dual role in nociceptive processing in the brain, being antinociceptive via the kyotorphin-Met-enkephalin pathway and nociceptive via the NO-cyclic GMP pathway.