Transient changes in the synthesis of nitric oxide result in long-term as well as short-term changes in acetic acid-induced writhing in mice

A single injection of nitric oxide (NO) synthase (NOS) inhibitors prevents the development of persistent hyperalgesia induced by various manipulations , suggesting that NO precipitates long-term changes in nociception. We exam ined the possibility that inhibition of NOS may also be sufficient to produ ce long-term decreases in nociceptive assays, such as writhing, that are kn own to be sensitive to the short-term effects of NOS inhibitors. We charact erized short- and long-term effects of NOS inhibitors, N-omega-nitro-L-argi nine (L-NAME) or 7-nitro indazole (7-NI) injected intrathecally (i.t.) in m ice on acetic acid-induced writhing. Doses of L-NAME that had no effect on hot plate or tail flick latencies inhibited writhing (0.01-30 nmol) as well as spinal nNOS activity (5 and 100 nmol) when injected i.t. 60-90 min befo re testing. Anti-nociception was not mimicked by D-NAME but was prevented b y co-administration with the NO precursor, L-arginine. Injection i.t. of 7- NI (30 min), a selective inhibitor of neuronal NOS (nNOS), inhibited NOS ac tivity in the spinal cord and produced anti-nociception, confirming that wr ithing is sensitive to inhibition of nNOS. Although the acute action of bot h NOS inhibitors dissipated completely by 3-6 h, a delayed and prolonged in hibition of writhing was again observed 24 h after L-NAME (5-100 nmol), a t ime when spinal NOS activity was no longer inhibited by L-NAME (5 and 100 n mol) or 7-NI (25 nmol). This novel effect appears to be initiated by the tr ansient inhibition of nNOS as delayed anti-nociception was mimicked by 7-NI at doses (10-100 nmol) that no longer inhibited spinal nNOS (25 nmol) at 2 4 h. Go-administration with L-arginine prevented the delayed (24 h) anti-no ciceptive effects of L-NAME (30 nmol). L-Arginine (30 and 100 nmol) was wit hout effect on nociception when administered alone 60 min or 24 h prior to testing. Together these data indicate that brief changes in the activity of nNOS induce both long- as well as short-term changes in nociception. (C) 2 000 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.