Estrogen Reduces Efficacy of μ- but Not κ-Opioid Agonist Inhibition in Response to Uterine Cervical Distension

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Abstract
Background: Although the uterine cervix is a common source of acute and chronic visceral pain in women, there is practically no neurobiological investigation of nociception from this visceral organ. With use of a novel model of uterine cervical distension nociception in rats, the estrogen dependency of opioid agonist-induced inhibition was investigated. Methods: Sprague Dawley rats were anesthetized with halothane and bilateral ovariectomy was performed, after which placebo or estrogen treatment was administered for 1 week. Animals were reanesthetized and fine metal rods were inserted into the uterine cervix for manual distension. Reflex contraction of the rectus abdominis in response to distension was recorded before and after cumulative dosing with the mu-opioid agonist morphine and the kappa-opioid agonist (-)U50488. Results: Uterine cervical distension increased reflex abdominal muscle contraction with a threshold of 75 g, regardless of estrogen treatment. Morphine and (-)U50488 reduced the reflex response to cervical distension in a dose-dependent manner. Estrogen reduced the inhibitory effect of morphine but not that of (-)U50488. Conclusions: It has been suggested that mu-opioid agonists are less potent in females than males, whereas kappa-opioid agonists are more potent in females than males. These data suggest that estrogen may influence the action of opioids, at least against visceral pain, which may explain this sex difference. In addition, these data suggest that kappa-opioid agonists may be effective in the treatment of pain originating from the uterine cervix, regardless of estrogen status.

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