Sex Differences in Morphine-Induced Antinociception and Reward Using a Chronic Inflammatory Pain Model in Rats
There is a species difference between rodents and humans in the sexual dimorphism of morphine analgesia. Women self-administer less morphine than men suggesting morphine produces greater analgesia in that sex. In contrast, numerous rodent studies have shown morphine to be more potent in males compared to females. Several factors, such as the preclinical pain model used, opioid tolerance development, and the affective response to pain or analgesia may explain this species difference. For Experiment 1, male and female rats were compared on their sensitivity to morphine's antinociceptive, anti-hyperalgesic, anti-allodynic, and locomotor effects using a CFA-induced model of inflammatory pain. No sex differences were observed on any of the nociceptive measures. However, males demonstrated greater morphine tolerance development to the antinociceptive measure, while females showed greater morphine tolerance development on a measure of mechanical allodynia. In Experiment 2, gonadectomized rats, with or without sex-specific hormone replacement, were assessed using the same model of inflammatory pain. Testosterone did not modulate morphine sensitivity on any nociceptive assay, but did suppress morphine tolerance development on a measure of antinociception. Estradiol suppressed the sensitivity to morphine on the measure of thermal hyperalgesia, and disrupted the development of tolerance on the measures of allodynia and locomotor activity. Experiment 3 used a model of place conditioning to see if relief of inflammatory pain produces a preference for the morphine-paired cue, indicating an affective response to analgesia. There were no significant effects of either sex or morphine on this model of place conditioning. Conditioning appeared to be better when morphine was given in the morning versus the afternoon conditioning trial, suggesting that time-of-day influences place preference in rats. These results indicate that the observed species difference is likely not a result of the use of acute pain models in preclinical studies. Better characterization of morphine tolerance development is necessary in chronic pain conditions in order to definitively conclude whether this factor contributes to the species difference. The lack of a morphine effect in Experiment 3 is likely due to weak conditioning, therefore more research is warranted to determine if there is a species difference in the affective response to pain and/or analgesia.