l‐Arginine exerts a dual role in nociceptive processing in the brain: involvement of the kyotorphin‐Met‐enkephalin pathway and NO‐cyclic GMP pathway

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Abstract
1 Intracerebroventricular (i.c.v.) administration of l-arginine (l-Arg), at 10–100 μg 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 δ-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 μg 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 μg 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.