Sex Hormones and Visceral Hypersensitivity

描述（申请人提供）：疼痛和内脏高敏感性是肠易激综合征（IBS）的主要特征，IBS是一种极其常见的疾病，影响高达15%的美国人口，具有重大的社会经济影响，同时对治疗它的医生提出了最令人烦恼的临床挑战之一。女性受影响的频率约为男性的两倍;然而，这种两性异形的生理基础仍然是难以捉摸的。慢性内脏高敏感性机制的中心概念是脊髓灰质中神经元的过度兴奋性的发展，其可以响应于外周组织刺激而演变。我们已经表明，急性和炎性内脏痛是在中枢神经系统（CNS）的一个相对特定的内脏痛通路形成的突触后背柱（PSDC）神经元的轴突，在背柱（DC）的背柱核（DCN）上升。此外，我们已经证明，持续性腹痛无炎症可以在动物中建模。新生大鼠（而非成年大鼠）的结肠刺激（CI）可引起持续时间较长的内脏高敏感性，在初始损伤消退后且无可识别病理学时仍持续存在。在雄性和雌性大鼠中观察到不同程度的超敏反应。因此，在这项研究中，我们建议研究慢性内脏高敏感性中观察到的性二态性的激素基础以及其潜在的生理机制。中心假设是，性激素可能通过其对中枢神经系统疼痛通路的作用，在内脏疼痛的性别特异性差异中起着至关重要的作用。性激素调节i）内脏敏感性，和ii）中枢神经敏化，iii）通过直接作用于位于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。定义的生理和细胞机制，有助于持续内脏高敏感性，包括性激素的作用，是至关重要的，以促进我们的理解内脏疼痛一般，特别是功能性腹痛，并促进一种新的方法来治疗胃肠道疾病的疼痛，导致新的，性别敏感的，治疗工具的发展，用于慢性内脏疼痛的管理。 公共卫生相关性：在这项研究中，我们建议研究慢性内脏高敏感性中观察到的两性异形的激素基础以及其潜在的生理机制。中心假设是，性激素可能通过其对中枢神经系统疼痛通路的作用，在内脏疼痛的性别特异性差异中起着至关重要的作用。性激素调节i）内脏敏感性，和ii）中枢神经敏化，iii）通过直接作用于位于突触后背柱（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。定义的生理和细胞机制，有助于持续内脏高敏感性，包括性激素的作用，是至关重要的，以促进我们的理解内脏疼痛的一般，特别是功能性腹痛，并促进一种新的方法来治疗胃肠道疾病的疼痛，导致新的，性别敏感的，治疗工具的发展，用于慢性内脏疼痛的管理。

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.