Sex Hormones and Visceral Hypersensitivity

描述（由申请人提供）：疼痛和内脏过敏是肠易激综合征（IBS）的主要特征，这是一种极其常见的疾病，影响了高达15%的美国人口，对社会经济产生了重大影响，同时对治疗它的医生提出了最令人烦恼的临床挑战之一。女性受影响的频率大约是男性的两倍；然而，这种两性二态性的生理基础仍然难以捉摸。慢性内脏超敏反应机制的一个核心概念是脊髓灰质中神经元的高兴奋性的发展，这可能是对外周组织刺激的反应。我们之前已经表明，急性和炎症性内脏疼痛在中枢神经系统（CNS）中通过一个相对特定的内脏疼痛通路进行处理，该通路由突触后背柱（PSDC）神经元的轴突形成，该神经元在背柱（DC）上升到背柱核（DCN）。此外，我们已经证明，没有炎症的持续腹痛可以在动物身上建模。在新生大鼠而非成年大鼠中，结肠刺激（CI）可引起持久的内脏过敏，这种过敏在初始损伤消退后仍持续存在，且没有可识别的病理。在雄性和雌性大鼠中观察到不同程度的超敏反应。因此，在本研究中，我们建议研究慢性内脏变态反应中两性异形的激素基础及其潜在的生理机制。核心假设是性激素在内脏疼痛的性别差异中起着至关重要的作用，可能是通过它们对中枢神经系统疼痛通路的作用。性激素调节i)内脏敏感性，ii)中枢神经敏化，iii)通过直接作用于PSDC神经元上的雌激素受体或iv)通过调节位于这些神经元上的谷氨酸受体。定义导致持续内脏超敏反应的生理和细胞机制，包括性激素的作用，对于提高我们对内脏疼痛的理解，特别是对功能性腹痛的理解，以及促进胃肠道疾病疼痛的新方法，从而开发新的，性别敏感的治疗工具，用于慢性内脏疼痛的管理，具有至关重要的意义。

DESCRIPTION (provided by applicant): Pain and visceral hypersensitivity are the main characteristics of irritable bowel syndrome (IBS), an extremely common disorder affecting up to 15% of the US population with a major socioeconomic impact, while presenting one of the most vexing clinical challenges to physicians who treat it. Women are affected about twice as often as men; however the physiological basis of this sexual dimorphism remains elusive. A central concept to the mechanisms of chronic visceral hypersensitivity is the development of hyperexcitability of neurons in the spinal cord gray matter, which can evolve in response to peripheral tissue irritation. We have shown earlier that acute and inflammatory visceral pain is processed in the central nervous system (CNS) by a relatively specific visceral pain pathway formed by the axons of postsynaptic dorsal column (PSDC) neurons that ascend in the dorsal column (DC) to the dorsal column nuclei (DCN). In addition, we have shown that persistent abdominal pain without inflammation can be modeled in animals. Colon irritation (CI) in neonate but not adult rats, can cause a long lasting visceral hypersensitivity that persists after the initial injury has resolved and in the absence of identifiable pathology. This hypersensitivity is observed to variable extents in male and female rats. Therefore, in this study, we propose to study the hormonal basis of the sexual dimorphism observed in chronic visceral hypersensitivity as well as its underlying physiological mechanisms. The central hypothesis is that sex hormones play a crucial role in the sex-specific differences in visceral pain possibly via their action on pain pathways in the central nervous system. Sex hormones modulate i) visceral sensitivity, and ii) central neural sensitization, iii) via direct action on estrogen receptors located on PSDC neurons or iv) via regulation of glutamate receptors located on these neurons. Defining the physiological and cellular mechanisms that contribute to persistent visceral hypersensitivity, including the role of sex hormones, is of central importance to advancing our understanding of visceral pain in general, and functional abdominal pain in particular, and to foster a new approach to pain in gastrointestinal disorders that leads to the development of new, gender-sensitive, therapeutic tools for the management of chronic visceral pain. Public Health Relevance: In this study, we propose to study the hormonal basis of the sexual dimorphism observed in chronic visceral hypersensitivity as well as its underlying physiological mechanisms. The central hypothesis is that sex hormones play a crucial role in the sex-specific differences in visceral pain possibly via their action on pain pathways in the central nervous system. Sex hormones modulate i) visceral sensitivity, and ii) central neural sensitization, iii) via direct action on estrogen receptors located on postsynaptic dorsal column (PSDC) neurons or iv) via regulation of glutamate receptors located on these neurons. Defining the physiological and cellular mechanisms that contribute to persistent visceral hypersensitivity, including the role of sex hormones, is of central importance to advancing our understanding of visceral pain in general, and functional abdominal pain in particular, and to foster a new approach to pain in gastrointestinal disorders that leads to the development of new, gender-sensitive, therapeutic tools for the management of chronic visceral pain.