Sex Hormones and Visceral Hypersensitivity

描述(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，IBS是一种极其常见的疾病，影响着高达15%的美国人口，具有重大的社会经济影响，同时也是治疗它的医生面临的最令人烦恼的临床挑战之一。女性受到影响的频率大约是男性的两倍；然而，这种性二型性的生理基础仍然难以捉摸。慢性内脏高敏感性机制的一个核心概念是脊髓灰质神经元的超兴奋性的发展，这种兴奋性可以随着周围组织的刺激而演变。我们早些时候已经证明，急性内脏痛和炎症性内脏痛在中枢神经系统(CNS)是由突触后背柱(PSDC)神经元的轴突形成的相对特定的内脏痛通路，这些轴突从背柱(DC)上升到背柱核(DCN)。此外，我们还证明了持续性无炎症腹痛可以在动物身上模拟。结肠刺激(CI)在新生大鼠而不是成年大鼠，可导致长期的内脏高敏感性，在最初的损伤解决后持续存在，并且在没有可识别的病理学的情况下持续存在。这种过敏反应在雄性和雌性大鼠身上都有不同程度的观察。因此，在这项研究中，我们建议研究在慢性内脏高敏感中观察到的性二型性的激素基础及其潜在的生理机制。中心假设是性激素在内脏疼痛的性别差异中起着关键作用，可能是通过它们在中枢神经系统的疼痛通路上发挥作用。性激素调节1)内脏敏感性，2)中枢神经敏化，3)直接作用于PSDC神经元上的雌激素受体，或4)调节这些神经元上的谷氨酸受体。明确导致持续性内脏高敏感性的生理和细胞机制，包括性激素的作用，对于促进我们对内脏疼痛，特别是功能性腹痛的理解，以及促进胃肠道疾病疼痛的新方法，从而导致开发新的、对性别敏感的治疗工具来管理慢性内脏疼痛，具有核心意义。 公共卫生相关性：在这项研究中，我们建议研究在慢性内脏高敏感性中观察到的性二型性的激素基础及其潜在的生理机制。中心假设是性激素在内脏疼痛的性别差异中起着关键作用，可能是通过它们在中枢神经系统的疼痛通路上发挥作用。性激素调节1)内脏敏感性，2)中枢神经敏化，3)直接作用于突触后背柱(PSDC)神经元上的雌激素受体，或4)调节位于这些神经元上的谷氨酸受体。明确导致持续性内脏高敏感性的生理和细胞机制，包括性激素的作用，对于促进我们对内脏疼痛，特别是功能性腹痛的理解，以及促进胃肠道疾病疼痛的新方法，从而导致开发新的、对性别敏感的治疗工具来管理慢性内脏疼痛，具有核心意义。

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.