The dual effect of a nitric oxide donor in nociception

Low intrathecal (i.t.) doses of the nitric oxide (NO)-donor 3-morpholinosydnonimine (SIN-1) (0.1-2.0 mug/10 mu1) reduced, while higher doses had no effect (5 or 100 mug/10 mu1.) or increased (10 and 20 mug/10 mu1) the mechanical allodynia induced by chronic ligature of the sciatic nerve in rats. SIN-1 (0.1-100 mug/10 mu1; i.t.) produced only antinociceptive effect in the rat tail flick test. The inhibitor of guanylate cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (4 mug/10 yl; i.t.), abolished the antinociceptive effects of SIN-1 in both tests and reduced the effect of high doses of SIN-1 in neuropathic rats. Hemoglobin (100 mug/10 mu1; i.t.), a NO scavenger, inhibited the effect of low dose of SIN-1 and reduced the effect of high dose of SIN-1 in neuropathic rats. 8-Bromo-cGMP (125-500 mug/10 mu1; i.t.), reduced the mechanical allodynia in neuropathic rats. The NO-synthase inhibitors, N-G-nitro-L-arginine (L-NOARG) and N-G-monomethyl-L-arginine (L-NMMA) (75-300 mug/10 mu1; i.t.) reduced the mechanical allodynia evoked by nerve injury and increased the tail-flick latency, respectively. These effects were reduced and inhibited, respectively, by previous i.t. ODQ. The effect of L-NOARG was enhanced in a non-significant manner by hemoglobin. These results indicate that SIN-1 and NO-synthase inhibitors reduce pain through a spinal mechanism that involves activation of guanylate cyclase. The effects of SIN-1 vary depending on the dose and pain model utilized, but its most sensitive effect seems to be antinociception. However, high doses of the NO-donor can intensify ongoing pain. (C) 2001 Elsevier Science B.V. All rights reserved.