Atividade antinociceptiva do nicorandil e seus possíveis mecanismos de ação

Abstract

Recently, the antinociceptive and anti-inflammatory activities of nicotinamide and other derivatives of the vitamin B complex have been demonstrated in experimental models of pain and inflammation. Structurally, nicorandil (2-nicotinamidoetil nitrate) is a compound characterized by nicotinamide coupled to a nitric oxide (NO) donor. Nicorandil, which is clinically used to treat patients with angina pectoris, releases NO and opens ATP-dependent K+ channels. The interest in investigating the effects induced by nicorandil in experimental models of pain and inflammation results from the observation that nicotinamide, as well as compounds that release NO, exhibit antinociceptive and anti-inflammatory activities. Thus, the effects induced by nicorandil (50, 100 and 150 mg/Kg, p.o., -1 h) or by equimolar doses of N-(2-hydroxyethyl) nicotinamide (NHN), its principal oxidized metabolite, or nicotinamide, were evaluated in the model of nociception induced by formaldehyde (0.92%, 20 µl, s.c.) in male Swiss mice (25-30 g). Only the first one induced antinociceptive effect, reducing the second phase of nociceptive response Such effect was not observed after the local administration of nicorandil (125, 250 or 500 µg/paw, i.pl., -20 min). The antinociceptive effect of nicorandil was not associated with motor activity impairment evaluated in the rota-rod apparatus (14 rpm, 2 min). The prior administration to nicorandil of glibenclamide (30 or 60 mg/Kg, p.o., -1 h), naltrexone (2 or 5 mg/Kg, ip, -30 min) or ODQ (0.5; 1 or 2 mg /Kg, i.p. -30 min) was performed to investigate possible mechanisms involved in the antinociceptive activity of the drug. The results indicate the participation of opioid receptors, but not of ATP-dependent K+ channels. To evaluate the duration of antinociceptive effect induced by nicorandil, the drug was administered p.o. 0.5, 1, 2, 3 or 4 h before formaldehyde. The antinociceptive activity of nicorandil was observed when the drug was administered between 0.5 and 2 h before the injection of formaldehyde. After p.o. administration of nicorandil (50 mg/kg), peak plasma concentrations of this drug (30,916 ng/mL) and its primary metabolite (NHN; 16,181 ng/mL) were observed 0.63 and 4 h, respectively, but plasma concentrations of nicotinamide oscillated between 1,400 and 3,300 ng/mL and did not differ from that found in the plasma of untreated animals. In conclusion, the results indicate that nicorandil exhibits antinociceptive activity in the model of nociception induced by formaldehyde in mice. This activity is not mediated by nicotinamide or by NHN. Opioid receptors mediate the antinociceptive activity of nicorandil, but the role of NO-cGMP pathway seems partially important and requires more studies. The results indicate that nicorandil, a drug in clinical use in some countries, may represent an important alternative in the pharmacotherapy of patients with various painful conditions and serve as a stimulus for performing pre-clinical and clinical studies to investigate its potential use as an analgesic.