We have recently reported a sex difference in morphine-induced analgesia in a visceral pain model. To test the hypothesis that estrogen plays a role in mediating this sex difference, the effect of morphine on the visceromotor response (vmr) to colorectal distention was compared between ovariectomized (OVx) and OVx with estrogen replacement (E2) rats. After demonstrating that estrogen attenuates the potency of systemically administered morphine, we tested peripheral, spinal, and supraspinal sites for estrogen modulation of micro-opioid receptor (MOR) activity. The peripheral MOR antagonist naloxone methiodide reversed the effect of systemic morphine. The peripheral MOR agonist loperamide also attenuated the vmr and in addition was more potent in OVx rats than E2 rats, demonstrating estrogen modulation of peripheral micro-opioid analgesia. Intrathecally injected morphine attenuated the vmr, with no difference in potency noted between the 2 groups. Morphine given by intracerebroventricular injection was more potent in OVx rats than in E2 rats, suggesting estrogen modulation of supraspinal micro-opioid receptors. Results from all administration routes revealed that the potency of morphine in OVx and E2 rats was similar to male and intact female rats, respectively, suggesting that estrogen is one of the key factors contributing to the sex difference in micro-opioid analgesia.
Perspective: Female rats are less sensitive to morphine analgesia of visceral pain than male rats. This study demonstrates that estrogen decreases the analgesic potency of peripheral and supraspinal but not spinal morphine in a model of visceral pain and may be a key factor contributing to the sex difference in micro-opioid analgesia.