Morphine-Tolerant Mice Exhibit a Profound and Persistent Cardioprotective Phenotype

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Abstract
Background— Morphine and other opioids continue to be used as the major treatment for acute pain both before and after surgery. In this regard, much research has focused on the mechanisms of morphine tolerance and dependence in the central nervous system; however, few studies have examined the effect of morphine on peripheral organs, such as the heart, in morphine-tolerant animals. Here, we examine the effect of tolerance to the analgesic effect of morphine on ischemic tolerance in mice after prolonged morphine exposure and withdrawal. Methods and Results— Male C57/BL6 mice were implanted subcutaneously with either placebo or morphine pellets (25 or 75 mg). After prolonged exposure to and/or withdrawal from morphine or placebo, the hearts were excised and subjected to 25 minutes of ischemia and 45 minutes of reperfusion. Morphine-tolerant mice exhibited a markedly improved functional recovery compared with placebo and mice subjected to acute morphine. Lactate dehydrogenase release was also significantly reduced. The protection observed was equieffective 48 hours after withdrawal of pellet, whereas the onset of protection preceded analgesic tolerance. Conclusions— These data demonstrate that chronic exposure to morphine unexpectedly results in a profound and persistent cardioprotective phenotype.

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