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 microg/10 microl) reduced, while higher doses had no effect (5 or 100 microg/10 microl) or increased (10 and 20 microg/10 microl) the mechanical allodynia induced by chronic ligature of the sciatic nerve in rats. SIN-1 (0.1-100 microg/10 microl; 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 microg/10 microl; 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 microg/10 microl; 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 microg/10 microl; i.t.), reduced the mechanical allodynia in neuropathic rats. The NO-synthase inhibitors, NG-nitro-L-arginine (L-NOARG) and NG-monomethyl-L-arginine (L-NMMA) (75-300 microg/10 microl; 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.
Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, USP, Av. Bandeirantes 3900, 149049-900, SP, Ribeirão Preto, Brazil.
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D000818:Animals; D002908:Chronic Disease; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006454:Hemoglobins / Q000494:pharmacology; D007278:Injections, Spinal; D008026:Ligation; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology*; D009408:Nerve Compression Syndromes / Q000188:drug therapy / Q000503:physiopathology; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D019335:Nitroarginine / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D010147:Pain Measurement; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012584:Sciatic Nerve / Q000503:physiopathology; D019323:omega-N-Methylarginine / Q000494:pharmacology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D006454:Hemoglobins; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D011810:Quinoxalines; D019335:Nitroarginine; D019323:omega-N-Methylarginine; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; C002385:linsidomine; D008981:Molsidomine; D006152:Cyclic GMP