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

Abstract

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.

Effects of multiple intrathecal administration of L-arginine with different doses on formalin-induced nociceptive behavioral responses in rats

“…Besides, locally in the foot, Arg can increase the phase II response at low doses while higher doses can reduce the response. Discrepancies between these findings and our report may be due to the chronic application of NO precursor L-Arg at different doses here, or to some unkown factors, since NO has very complex effects, depending on its concentration, experimental methods, the system, and the cellular environment [4,6,15] .…”

“…Others report that NO produces dual effects on nociception, depending on the dose and the pain model [6] . Although many studies have demonstrated that NO precursor L-Arg exerts dual effects on nociception [4,5] , the Ge et al [14] have reported that inhibition of spinal NO production contributes to the antinociceptive effect of emulsified isoflurane on formalin-induced pain. Kolesnikov et al [1] also report that supraspinal administration of the NOS inhibitor NOArg or oligodeoxynucleotide targeting the 4 nNOS isoforms can suppress the formalin response.…”

“…Low concentrations of NO that is produced via nNOS in the spinal cord exerts antinociceptive effects via kyotorphin-Met-enkephalin system [4] . Muscoli et al suggest that systemical administration of L-Arg in rats with carrageenin-induced hyperalgesia mainly produces an antinociceptive effect, mediated by central opiodergic mechanisms [16] .…”

“…injection of L-arginine (L-Arg) can elicit antinociception in mice [3] . Another study suggests that NO plays dual roles in nociception in the brain or in the periphery [4,5] . Angela has reported that NO donor has dual effects on nociception, depending on the application dose and the pain model utilized [6] .…”

Comparison of antinociception induced by supraspinally administered l‐arginine and kyotorphin

“…In addition, NO synthase inhibitors, administered i.c.v., exhibit antinociceptive activity in the mouse, suggesting a nociceptive role of NO in the brain (Moore et al, 1991;Babbedge et al, 1993;Kawabata et al, 1993). It is unlikely that brain NO is involved in the production of the antinociceptive effect of L-Arg.…”