Nicorandil inhibits mechanical allodynia induced by paclitaxel by activating opioidergic and serotonergic mechanisms

Abstract

Recently, we demonstrated that nicorandil exhibits activities in models of inflammatory and nociceptive pain. In the present study, we extended this investigation by evaluating the effects of nicorandil in models of neuropathic pain induced by paclitaxel or nerve injury in mice. Four intraperitoneal (i.p.) injections of paclitaxel (2 mg/kg.day, cumulative dose 8 mg/kg) or chronic constriction injury (CCI) of the sciatic nerve induced a long lasting mechanical allodynia. Per os (p.o.) administration of two doses of nicorandil (50, 100 and 150 mg/kg) on the 14th day after the first paclitaxel injection attenuated the mechanical allodynia. Equimolar doses of nicotinamide (86.7 mg/kg, p.o.) or nicotinic acid (87.7 mg/kg, p.o.) were devoid of effect. Mechanical allodynia induced by CCI was also attenuated by p.o. administration of two doses of nicorandil (150 mg/kg) on the 14th day after nerve injury. Nicorandil (50, 100 and 150 mg/kg, p.o.) did not affect motor activity. The antinociceptive activity of nicorandil in the model of mechanical allodynia induced by paclitaxel was partially attenuated by naltrexone (5 and 10 mg/kg, i.p.) or cyproheptadine (5 and 10 mg/kg, i.p.), but not by glibenclamide (20 and 40 mg/kg, p.o.). Concluding, nicorandil exhibits activity in experimental models of neuropathic pain when mechanical allodynia is fully established. Activation of opioidergic and serotonergic pathways mediates the antinociceptive activity of nicorandil. It is unlikely that this activity requires biotransformation to nicotinamide or nicotinic acid. Nicorandil should be further evaluated aiming to identify a new alternative in the pharmacological management of neuropathic pain.

Keywords: Chronic constriction injury; Neuropathic pain; Nicorandil; Paclitaxel; Pain.