ABSTRACT
Long-term use of opiates induces tolerance to the analgesic effect. Despite significant investigations, the precise cellular mechanisms underlying opioid tolerance is not clear. Many studies have revealed the key role of nitric oxide in the morphin-induced tolerance. The aim of this study was to evaluate the effects of nicorandil [a nitric oxide donor and ATP sensitive potassium channel opener] and glibenclamide [an ATP sensitive potassium channel blocker] on morphine-induced tolerance. In this study male mice weighting [20-30g] were randomly placed into groups of 8, and received different therapeutic regimens for 5 days. Different groups received either morphine [50mg/kg, i.p]+normal saline [10ml/kg, i.p], or morphine [50mg/kg, i.p]+nicorandil [2.5, 5, 10mg/kg, i.p] or morphine [50mg/kg, i.p]+glibanclamide [5, 10, 15mg/kg, i.p] every day. Nociception was assessed using a hotplate apparatus on the 6th day. The nociceptive effect was recorded when the animal licked its hind paw or jumped due to the heat effect. Our results showed that tolerance to the analgesic effect of morphine significantly increased in the group which received morphine+nicorandil [5, 10mg/kg, i.p], [p<0.05], while in morphine+glibenclamide group, tolerance significantly reduced [p<0.05]. The results of this study indicated that intraperitoneal injection of nicorandil increased tolerance to the analgesic effects of morphine while glibenclamide decreased tolerance. The above effect seems to be related to the role of nitric oxide [NO] and ATPsensitive potassium channel in this phenomenon