Hypnotic and Analgesic Effects of the alpha2-Adrenergic Agonist Dexmedetomidine in Morphine-Tolerant Rats

Combinations of alpha 2 agonists and opiates are used in the clinical management of pain to harness their potential synergistic interaction for analgesia while limiting their side-effects. To better predict the clinical consequences of this combination, we studied the behavioral effects of dexmedetomidine, a highly selective alpha 2 agonist with analgesic and hypnotic properties, during the development of, and recovery from, morphine tolerance. Rats were implanted with morphine pellets (or placebo), daily for 5 days. The analgesic response to morphine, dexmedetomidine, or the combination of the two drugs was assessed with the tail-flick latency response. The hypnotic response to dexmedetomidine, and to the combination of dexmedetomidine and morphine, was measured by the duration of the loss of righting reflex (sleep-time). One day after the last morphine pellet implantation, alpha 2 adrenoceptor binding was assessed in vitro in the locus coeruleus (LC) and the spinal cord (SC). Data were analyzed by analysis of variance (ANOVA), t-test, or Mann-Whitney test. The morphine tolerance was present after 1 day of morphine administration. At Days 1 and 3 of morphine administration, the hypnotic and analgesic responses to dexmedetomidine were significantly increased. After 5 days of morphine treatment, the analgesic response to dexmedetomidine was unaltered, while the hypnotic response to dexmedetomidine was now significantly decreased. The kd for the alpha 2 adrenoceptors was unaffected while the Bmax was significantly decreased only in the SC. Acutely administered morphine significantly enhanced the hypnotic and analgesic effects of dexmedetomidine in naive rats but not in morphine-tolerant rats. During morphine withdrawal, the hypnotic response to dexmedetomidine normalized; however, the analgesic response to dexmedetomidine was significantly decreased 5 days after withdrawal before returning to normal at Day 10 after withdrawal. We conclude that in the development of, and recovery from, the morphine-tolerant state, the hypnotic and analgesic responses to alpha 2 agonists are asynchronous.