Irritable Bowel Syndrome (IBS) is characterized by abdominal pain in the absence of pathology. Epidemiological studies further show IBS is reported most often in menstruating women compared to post-menopausal women or men suggesting gonadal hormones could be a contributing factor. It was recently hypothesized that the pain of IBS could result from sensitization of visceral afferent fibers or hyperexcitability of dorsal horn neurons. Recent data suggests a role for spinal NMDA receptors in processing noxious and innocuous visceral stimuli and NMDA receptors in the brain are modulated by estrogen. The long-term goal of this application is to examine the effects of estrogen on spinal NMDA receptor-mediated processing of noxious and innocuous colorectal stimuli. We hypothesize that estrogen increases activity at spinal NMDA receptors in the absence and presence of colonic inflammation leading to colorectal allodynia and hyperalgesia. This modulation may result from alterations in NMDA receptor subunit composition or second messenger mediated phosphorylation. Using our model of colorectal distention (CRD), we will test these hypotheses by examining the effects of estrogen replacement in ovariectomized rats on visceral sensory processing in the spinal cord in the absence and presence of colonic inflammation, in the following specific aims: 1) Determine the effects of estrogen on responses to transient innocuous, noxious and inflammatory colorectal stimuli. Behavioral, immunocytochemical and electrophysiological studies will test the hypothesis that estrogen facilitates responses to CRD in the absence and presence of colonic inflammation. 2) Characterize the effects of estrogen on subpopulations of visceroceptive projection neurons using retrograde tract tracing and immunocytochemical localization of Fos expression. This will test the hypothesis that estrogen alters the percentage and segmental distribution of supraspinal projection neurons that respond to CRD in the absence and presence of colonic inflammation. 3) Determine if NMDA receptor-mediated modulation of viscerosensory processing is affected by ovariectomy and estrogen replacement. This will test the hypothesis that the modulation of responses to CRD by estrogen is due to altering activity at NMDA receptors. 4) Determine the mechanism(s) through which estrogen modulates CRD-evoked NMDA receptor activity in the absence and presence of colonic inflammation. This will test the hypothesis that estrogen alters NMDA receptor subunit composition and/or modulates second messenger-mediated phosphorylation of tile NMDA receptor.
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