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

Manabe

et al. 1994

Self Cite

145

Japan 1 We investigated the effects of intraplantar (i.pl.) administration of L-arginine and N0-nitro-L-arginine methyl ester (L-NAME) on formalin-induced behavioural nociception in the mouse. 2 L-but not D-arginine, at 0.1-1 -g per paw, coadministered with i.pl. formalin, enhanced the secondbut not the first-phase nociceptive responses, whereas it was without significant effects at 3 fg per paw, and conversely, produced antinociception at 10 tLg per paw, resulting in a bell-shaped dose-response curve.3 L-NAME at 0.1-1 fig per paw, when administered i.pl., exhibited antinociceptive activity in the second phase in a dose-dependent manner, although its D-enantiomer produced no effect. 4 An antinociceptive dose (1 pg per paw) of L-NAME (i.pl.) considerably reduced the increase in second-phase nociception elicited by low doses (1 fg per paw) of i.pl. L-arginine. The second-phase nociception decrease induced by a large dose (10 pg per paw) of i.pl. L-arginine was markedly reversed by i.pl. L-NAME at 0.1 pg per paw, raising it to a level above that of the control (formalin only). 5 These results suggest that peripheral NO plays a dual role in nociceptive modulation, depending on the tissue level, inducing either nociceptive or antinociceptive responses.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of topical administration of l‐arginine on formalin‐induced nociception in the mouse: a dual role of peripherally formed NO in pain modulation

Manabe

et al. 1994

Self Cite

145

“…it is antinocicepti its physiological concentration (100 JAM) in the brain (Ueda et upon the above evidence and recent reports regarding the spinal and peripheral mechanism of the L-Arg-NO-cyclic GMP pathway (Duarte et al, 1990;Meller et al, 1990;Ferreira et al, 1992;Haley et al, 1992;Ialenti et al, 1992;Kawabata et al, 1992a;Morris et al, 1992), we show a hypothetical scheme that explains the role of L-Arg in nociceptive events in the CNS and periphery, and that indicates the points of action of the inhibitors and blockers used ( Figure 5). …”

Section: Discussionmentioning

confidence: 99%

“…The peripheral mechanism is 'Author for correspondence. complex, both inhibitory and promotive roles having been reported for this pathway in nociceptive events (Meller et al, 1990;Duarte et al, 1990;Ferreira et al, 1992;Haley et al, 1992;Kawabata et al, 1992a). Evidence for the spinal nociceptive action of this pathway has come from findings that spinal injections of a NO synthase (NOS) inhibitor, L-NG-nitroarginine methyl ester (L-NAME), reduced neural activity in the dorsal horn in response to formalin injected into the peripheral receptive field (Haley et al, 1992), and from findings that intrathecal L-arginine and N-methyl-Daspartate (NMDA) produced a rapid and transient facilitation of the nociceptive tail-flick reflex, the latter effect being reversed by L-NAME and by methylene blue, a guanylate cyclase (a known NO target) inhibitor (Meller et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

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

Umeda

Takagi

1993

Self Cite

117

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.

“…For instance, Larginine, the antinociceptive effect of which is not so potent in animal experiments, produces dramatic analgesia in patients with chronic pain (Takagi et al, 1990;Harima et al, 1991;Kawabata et al, 1992). In our preliminary clinical study in collaboration with Dr A Harima (Kyoto Nansei Hospital, Japan), L-DOPS actually elicited potent analgesia in patients with cluster headache and with various somatic pains, without producing any notable side effects (unpublished data).…”

Section: Lack Of Naloxone-reversibility Of L-dops-induced Antinocicepmentioning

confidence: 96%

The noradrenaline precursor l‐threo‐3,4‐dihydroxyphenylserine exhibits antinociceptive activity via central α‐adrenoceptors in the mouse

Kasamatsu

Umeda

et al. 1994

Self Cite

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.