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

Abstract

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 examined the possibility that inhibition of NOS may also be sufficient to produce long-term decreases in nociceptive assays, such as writhing, that are known to be sensitive to the short-term effects of NOS inhibitors. We characterized short- and long-term effects of NOS inhibitors, N ω-nitro- l-arginine ( l-NAME) or 7-nitro indazole (7-NI) injected intrathecally (i.t.) in mice 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 before testing. Anti-nociception was not mimicked by d-NAME but was prevented by 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 activity in the spinal cord and produced anti-nociception, confirming that writhing is sensitive to inhibition of nNOS. Although the acute action of both NOS inhibitors dissipated completely by 3–6 h, a delayed and prolonged inhibition of writhing was again observed 24 h after l-NAME (5–100 nmol), a time when spinal NOS activity was no longer inhibited by l-NAME (5 and 100 nmol) or 7-NI (25 nmol). This novel effect appears to be initiated by the transient 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 24 h. Co-administration with l-arginine prevented the delayed (24 h) anti-nociceptive effects of l-NAME (30 nmol). l-Arginine (30 and 100 nmol) was without 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.