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

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 microgram 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 micrograms per paw, and conversely, produced antinociception at 10 micrograms per paw, resulting in a bell-shaped dose-response curve. 3. L-NAME at 0.1-1 microgram 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 microgram per paw) of L-NAME (i.pl.) considerably reduced the increase in second-phase nociception elicited by low doses (1 microgram per paw) of i.pl. L-arginine. The second-phase nociception decrease induced by a large dose (10 micrograms per paw) of i.pl. L-arginine was markedly reversed by i.pl. L-NAME at 0.1 micrograms 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.