Evaluation of the effects of metformin administration on morphine tolerance in mice.

Opioids are used in clinical practice to relieve moderate to severe pain. Prolonged use of opioids can lead to a situation of analgesic tolerance and dependence. Several mechanisms are involved in the tolerance to analgesic opioids, including desensitization or internalization of the opioid receptor, elevation of cAMP levels, microglial activation and neuroinflammation, elevation of spinal mTOR activity and change in the expression of some proteins involved in tolerance, such as nNOS. Activation of the AMPK pathway inhibits mTOR and p38 MAPK ameliorating neuroinflammation and tolerance induced by morphine. Metformin, a potent antidiabetic agent, can also activate AMPK. Morphine tolerance was induced in mice by intraperitoneal administration three times daily at 08:00, 11.00 and 16.00 h of 50, 50 and 75 mg/kg morphine, respectively during four days. On the fifth day mice received a single injection of morphine 50 mg/kg. To evaluate the effects of metformin in development of morphine-induced analgesic tolerance a group of mice received metformin (10 mg/kg) 45 min before each morphine administration. Tail flick and hot plate tests were performed to estimate analgesic latency on days 1, 3 and 5. At five days, the animals were sacrificed, the brain dissected and nitrite levels determined. Chronic metformin administration significantly increased the analgesic latency on days 3 and 5 compared to the morphine group in hot plate test and in tail flick test. Chronic and acute metformin administration significantly decreased nitric oxide level compare to morphine group. The present results revealed that metformin attenuated analgesic tolerance induced by repeated intraperitoneal injections of morphine in mice.