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.