Characterization of morphine-induced hyperalgesia in male and female rats

The pain enhancing (hyperalgesic) effect of morphine was characterized in relation to pain stimulus (thermal, mechanical), dose, mode of administration (acute, chronic), sex and mechanism. We found that a low (subanalgesic) dose of morphine enhanced the sensitivity to thermal and mechanical noxious stimuli in a dose- and sex-related manner. Morphine hyperalgesia was inversely related to dose (0.002-0.2 mg/kg) and was more pronounced in female than male rats. The N-methyl-d-aspartate receptor antagonist, ketamine, antagonized morphine hyperalgesia. Tolerance developed to hyperalgesia following repeated (chronic) dosing with low dose morphine. Several additional findings were noted in rats tolerant to morphine-induced hyperalgesia. The efficacy of an analgesic dose of morphine was increased (female rats). Sex-related differences in morphine's analgesic action (male>female) were attenuated. Development of tolerance to the analgesic effect of morphine was delayed. The present findings may have an implication for the use of mu opioids in the clinical setting.