The dual effect of a nitric oxide donor in nociception

Abstract

Low intrathecal (i.t.) doses of the nitric oxide (NO)-donor 3-morpholinosydnonimine (SIN-1) (0.1–2.0 μg/10 μl) reduced, while higher doses had no effect (5 or 100 μg/10 μl.) or increased (10 and 20 μg/10 μl) the mechanical allodynia induced by chronic ligature of the sciatic nerve in rats. SIN-1 (0.1–100 μg/10 μl; i.t.) produced only antinociceptive effect in the rat tail flick test. The inhibitor of guanylate cyclase, 1 H-[1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one (ODQ) (4 μg/10 μl; 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 μg/10 μl; 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 μg/10 μl; 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 μg/10 μl; 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.