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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
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Porter, Linda L
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University of Maryland Baltimore
Schools of Dentistry
United States
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Ji, Yaping; Hu, Bo; Li, Jiyun et al. (2018) Opposing Roles of Estradiol and Testosterone on Stress-Induced Visceral Hypersensitivity in Rats. J Pain 19:764-776
Cao, Dong-Yuan; Bai, Guang; Ji, Yaping et al. (2016) EXPRESS: Histone hyperacetylation modulates spinal type II metabotropic glutamate receptor alleviating stress-induced visceral hypersensitivity in female rats. Mol Pain 12:
Ji, Y; Bai, G; Cao, D-Y et al. (2015) Estradiol modulates visceral hyperalgesia by increasing thoracolumbar spinal GluN2B subunit activity in female rats. Neurogastroenterol Motil 27:775-86
Cao, Dong-Yuan; Bai, Guang; Ji, Yaping et al. (2015) Epigenetic upregulation of metabotropic glutamate receptor 2 in the spinal cord attenuates oestrogen-induced visceral hypersensitivity. Gut 64:1913-20
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Traub, Richard J; Ji, Yaping (2013) Sex differences and hormonal modulation of deep tissue pain. Front Neuroendocrinol 34:350-66
Cao, Dong-Yuan; Ji, Yaping; Tang, Bin et al. (2012) Estrogen receptor ? activation is antinociceptive in a model of visceral pain in the rat. J Pain 13:685-94
Ji, Yaping; Tang, Bin; Cao, Dong-Yuan et al. (2012) Sex differences in spinal processing of transient and inflammatory colorectal stimuli in the rat. Pain 153:1965-73
Ji, Yaping; Tang, Bin; Traub, Richard J (2011) Spinal estrogen receptor alpha mediates estradiol-induced pronociception in a visceral pain model in the rat. Pain 152:1182-91
Murphy, Anne Z; Suckow, Shelby K; Johns, Malcolm et al. (2009) Sex differences in the activation of the spinoparabrachial circuit by visceral pain. Physiol Behav 97:205-12

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