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16 Age has also been shown to interact with sex in the modulation of morphine analgesia.

In mice, sex differences in morphine tolerance on the tail-withdrawal test are observed, but the direction of this difference is contrary to that seen with rats.

Repeated subcutaneous morphine injections daily for 3 or 7 days produced tolerance in both sexes, but there was a significantly greater rightward shift in the morphine dose-response curve and increased EDvalue for females.

3 Finally, sex differences fluctuate throughout the day in mice and are maximal during the dark period, during which opioid sensitivity is greater in males. Differences between sex have been observed in the magnitude and potency of morphine tolerance.

In one study, for example, there was a significant attenuation of morphine analgesia on the hot-plate and jump tests in male rats treated with morphine for 14 days.

23 Despite the greater loss of analgesia in males, recovery of morphine analgesic potency after discontinuation of chronic treatment was more rapid in this sex.

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