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

Abstract

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.

The antinociceptive effects of magnesium sulfate and MK-801 in visceral inflammatory pain model: The role of NO/cGMP/K+ATP pathway

“…Furthermore, the antinociceptive action of MS was not associated with the increase of NO. These contradictions might be explained by considering that NO is a controversial molecule with dual effects, depending on its concentrations, NOS isoforms, redox balance, and the function of neuron subpopulations (Kawabata, 1994;Zhang et al, 2006). On one hand, increased NO production has been shown to produce antinociception (Bulutcu et al, 2002;Galdino et al, 2010;Garrido-Suárez et al, 2009;Granados-Soto et al, 1997;Sachs et al, 2004), on the other hand, NOS inhibitors elicit antinociception in some models of acute and persistent pain (De Alba et al, 2006;Milovanović et al, 2009;Yonehara et al, 1997).…”

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

“…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.…”

“…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] .…”

L-Arginine-No System Participates in the Analgesic Effect of Flunixin Meglumine in the Rat

“…(10-100 mg/kg) as a pretreatment decreased formalin-induced hyperalgesia in the mouse paw in a dosedependent manner. Also, when L-NAME was co-administered with formalin intraplantarly [26] or given intrathecally (i.t.) before induction of infl ammation [27], dose-dependent antinociceptive activity was observed.…”