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

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Abstract
1 We investigated the effects of intraplantar (i.pl.) administration of l-arginine and NG-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 μg per paw, coadministered with i.pl. formalin, enhanced the second-but not the first-phase nociceptive responses, whereas it was without significant effects at 3 μg per paw, and conversely, produced antinociception at 10 μg per paw, resulting in a bell-shaped dose-response curve. 3 l-NAME at 0.1 − 1 μg 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 μg per paw) of l-NAME (i.pl.) considerably reduced the increase in second-phase nociception elicited by low doses (1 μg per paw) of i.pl. l-arginine. The second-phase nociception decrease induced by a large dose (10 μg per paw) of i.pl. l-arginine was markedly reversed by i.pl. l-NAME at 0.1 μg 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.