• Joseph R Holtman and Elzbieta P Wala.
• Department of Anesthesiology, College of Medicine, University of Kentucky, Lexington, KY 40536-0293, USA. jrjr@uky.edu
• Pain. 2005 Mar 1;114(1-2):62-70.

AbstractThe 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 (0.002-0.2mg/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.

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