Pain arising from visceral organs is one of the most common forms of pain in the clinical setting, and one of the most frequent reasons why patients seek medical attention. In general, women are more sensitive to pain than men and functional bowel disorders, such as irritable bowel syndrome (IBS), are 2-3 times more prevalent in women. The severity of IBS symptoms in women fluctuates with the menstrual cycle and visceral sensitivity in rats fluctuates across the estrous cycle, suggesting gonadal hormones modulate nociceptive processing of visceral stimuli. However, the mechanisms underlying hormonal modulation of visceral pain are poorly understood. For example, estrogen has been reported to have pro- and anti-nociceptive effects, confounding a clear understanding of hormonal modulation of visceral pain. Two isoforms of the estrogen receptor, ER1 and ER2, mediate both transcriptional modulation and rapid effects of estrogen signaling in the nervous system, sometimes in opposing directions. In this application we will test the hypotheses that these 2 receptors modulate different aspects of visceral nociceptive processing at the level of the spinal cord and the interaction of these signaling systems can have an effect on visceral hypersensitivity associated with IBS. Utilizing a systems level approach we will address the following specific aims.
Specific Aim 1 will test the hypotheses that [1] estrogen receptors modulate colorectal sensory processing at the level of the spinal cord and that [2] the two isoforms of the estrogen receptor (ER1 and ER2) in the spinal cord differentially modulate the visceromotor response to colorectal distention (CRD). As a sub-Aim to [1], we will address the negative hypothesis that estradiol does not directly modulate the response of colonic afferents to CRD. A multidisciplinary electrophysiological, immunocytochemical and behavioral approach will be used to determine if ER1 or ER2 is expressed in colonic afferent DRG neurons and if agonists at these receptors modulate the physiology of colonic primary afferents.
Specific Aim 2 will test the hypothesis that ER1 and ER2 differentially modulate the activity of spinal dorsal horn neurons to colorectal distention. In electrophysiological experiments, the effects of selective ER agonists (ER1: PPT;ER2: DPN) on the response of each of three different phenotypes of CRD-responsive dorsal horn neurons will be determined.
Specific Aim 3 will test the hypothesis that ER1 and ER2 use different intracellular signaling mechanisms to modulate spinal processing of colorectal stimuli. A multidisciplinary approach will address colocalization of estrogen receptors in the same dorsal horn neurons, expression in glial cells, differential activation of MAPK pathways (ERK, p38 MAPK, JNK) in visceral nociceptive processing and the effect of activation of MAPK pathways on the response of the different phenotypes of visceroceptive dorsal horn neurons. The long-term goal of this project is to understand the role of estrogen receptors in modulating physiological and pathophysiological visceral sensory processing in the spinal cord in order to identify new therapeutic targets.

Public Health Relevance

Most chronic pain syndromes are more prevalent in one sex, the majority being in women. Symptoms in many of these conditions fluctuate with the menstrual cycle suggesting modulation by gonadal hormones. Using colorectal distention to model pain from the viscera, we will test the hypothesis that the two isoforms of the estrogen receptor, located in the spinal cord, differentially modulate visceral sensitivity. The long term goal of these studies is to identify novel therapeutic interventions for the treatment of visceral hypersensitivity associated with functional bowel disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-E (02))
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Porter, Linda L
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University of Maryland Baltimore
Other Basic Sciences
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
Traub, Richard J; Cao, Dong-Yuan; Karpowicz, Jane et al. (2014) A clinically relevant animal model of temporomandibular disorder and irritable bowel syndrome comorbidity. J Pain 15:956-66
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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