Pharmacology of opioid inhibition to noxious uterine cervical distension

Abstract

Background: Reflex abdominal muscle contraction elicited by colorectal distension in male rats is inhibited by μ- and κ-opioid receptor agonists and sites of action and receptor subtypes have been probed. The authors examined the pharmacology of opioid agonist inhibition in visceral pain related to the uterine cervix, the source of labor pain. Methods: Ovariectomized female rats were anesthetized with halothane, and metal rods inserted in the uterine cervix through a small midline laparotomy. After a period of stabilization the cervix was distended by manual separation of the rods, using stimuli of 25-100 g, and reflex rectus abdominis electromyographic activity was recorded. After determining the stimulus response relationship, we tested inhibition of reflex activity by (-)U50,488 and morphine and their reversal with norbinaltorphimine, or with naltrexone and methyl-naltrexone, respectively. Results: Cervical distension produced a stimulus-dependent increase in electromyographic activity, with a threshold of 25 g. Morphine and (-)U50,488 produced dose-dependent inhibition of the reflex activity. Log linear regression analysis demonstrated an ID50 of 0.03 for morphine, and of 0.05 mg/kg for (-)U50,488. These effects were reversed by naltrexone, but not by methylnaltrexone or norbinaltorphimine. Conclusions: These data suggest that μ- and κ-opioid receptor agonists effectively inhibit responses to acute uterine cervical stimulation. Lack of reversal by norbinaltorphimine further supports evidence of a novel κ-opioid receptor by visceral afferents. Lack of morphine reversal by methylnaltrexone suggests central (spinal or supraspinal) sites of action for inhibition of this visceral noxious stimulus.