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. 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.). 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.). 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. 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.

administration of L-threo-3,4-dihydroxyphenylserine (droxidopa, L-threo-DOPS; L-DOPS), a noradrenaline precursor, at a dose-range of 100-800 mg kg-', produced naloxoneresistant antinociception in a dose-dependent manner in the mouse, as assessed by the tail flick test, kaolin-induced writhing test and formalin-induced nociception test. 2 Antinociception elicited by L-DOPS (400 mg kg-', s.c.) was not affected by s.c. injection of benserazide, a peripherally preferential L-aromatic amino acid decarboxylase inhibitor, but was suppressed by its intracerebroventricular (i.c.v.) injection. 3 I.c.v. or intrathecal (i.t.) administration of the non-selective a-blocker, phentolamine, significantly reduced L-DOPS-induced antinociception. 4 I.c.v. administration of the a1-blocker, prazosin, but not the a2-blocker, yohimbine, abolished the antinociceptive effects of L-DOPS. In contrast, both blockers, when administered i.t., exhibited significant inhibitory effects. 5 These results suggest that systemic L-DOPS produces opioid-independent antinociception, mediated by supraspinal a1-adrenoceptors and by spinal a1-and a2-adrenoceptors and may predict additional therapeutic applications of L-DOPS as an analgesic.

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