Nicorandil inibe a alodínia mecânica em modelos de dor neuropática por meio da ativação de mecanismos opioidérgicos e serotoninérgicos

Abstract

Neuropathic pain is a chronic disorder usually associated with central or peripheral nervous system lesions or diseases. A myriad of neurochemical mechanisms may contribute to establishment of neuropathic pain, thus contributing to the refractoriness to the traditional analgesic therapies. As low as 25% of the patients exhibiting neuropathic pain get a relief greater than 50% after using the available analgesic medicines. Nicorandil, a drug that releases NO and opens ATP-sensitive potassium channels, has been approved in some countries to treat patients with angina pectoris. The activity of nicorandil in models of nociceptive and inflammatory pain has been recently demonstrated, thus justifying additional investigations in models of neuropathic pain. In the present study, the effect induced by nicorandil (50, 100 or 150 mg/kg, p.o.) were investigated in the models of neuropathic pain induced by paclitaxel (2 mg/kg, 2 mL/kg, i.p.) or chronic constriction injury of the sciatic nerve in mice. Nicorandil inhibited the mechanical allodynia induced by paclitaxel when administered once or twice in the seventh or fourteenth day after injection of paclitaxel. The activity was greater when the drug was administered twice in a 2 h interval. Equimolar doses of nicotinic acid or nicotinamide did not induce antinociceptive activity. The antinociceptive activity of nicorandil (100 and 150 mg/kg, 2x) was not changed after two additional administrations in the fifteenth and sixteenth days. Nicorandil also exhibited activity in the model of neuropathic pain induce by chronic constriction injury of the sciatic nerve. The antinociceptive activity of nicorandil was not associated with motor activity impairment. To investigate mechanisms involved in the antinociceptive activity of nicorandil, the animals were previously treated with naltrexone (5 or 10 mg/Kg, i.p., -15 min), glibenclamide (20 or 40 mg/kg, p.o., -30 min) or ciproheptadine (5 or 10 mg/kg, i.p. -15 min). The results indicate that activation of opioidergic and serotonergic receptors, but not ATPsensitive potassium channels, mediate the antinociceptive activity of nicorandil. Concluding, the results demonstrate that nicorandil exhibit activity in the models of neuropathic pain induced by paclitaxel and chronic constriction injury. It seems that conversion to nicotinamide or nicotinic acid is not essential to the activity of nicorandil. This activity may be mediated by activation of opioidergic and serotonergic receptors, but not ATP-sensitive potassium channels. The results indicate that nicorandil may represent a pharmacotherapeutic strategy in the treatment of patients with neuropathic pain and justify additional preclinical and clinical assays aiming to evaluate its potential use as an analgesic drug.