The long-term goal of this research proposal is to provide the fundamental basis for new treatment approaches to gynecologic and obstetric pain. Most research in visceral pain has focused on the gastrointestinal tract, and little is known about pain originating from the lower uterine segment and cervix, the sites of obstetric and many types of gynecologic pain. In preliminary work, we have defined a model of uterine cervical distension (UCD) in order to study primary afferent and integrated responses. UCD in the lightly anesthetized rat results in overlapping stimulus response for activity of afferents in the hypogastric nerve and reflex contraction of the abdominal wall musculature, hemodynamic responses, and cFos expression in the low thoracic spinal cord. Preliminary pharmacological studies suggest that mu-opioid receptor (MOR) agonists inhibit responses to UCD by a central mechanism, whereas kappa-opioid receptor (KOR) agonists act in the periphery. Although peripherally restricted KOR agonists could represent a novel approach to treating pain from the uterine cervix, other visceral studies questioned whether these agents act via traditional opioid receptors or via Na channel blockade. Finally, sensitization of somatic afferents has been extensively examined, and there is an estrogen-dependent, sex difference in second messenger systems responsible for sensitization. Prostaglandins, especially PGE2, are released into the uterine cervix during menses and at the onset of labor, yet whether and how they sensitize afferents have not been examined. Thus, the specific aims of the current proposal are to: 1) Characterize uterine cervical afferent responses, with a focus on their polymodal nature, coding properties, and alteration by estrogen; 2) Examine direct stimulation and sensitization of uterine cervical afferent responses by PGE2 and determine the second messenger mechanisms it activates; 3) Determine receptor mechanisms by which KOR agonists inhibit responses to uterine cervical afferent stimulation. Together, this proposal will test the mechanisms of stimulation and sensitization of afferents that are responsible for obstetric and many types of gynecologic pain and lay the foundation for the study of the unique nature of these afferents.
