A prolactin-mediated neuroendocrine link between stress-induced latent sensitization and female-selective pain

催乳素介导的神经内分泌应激诱发的潜在敏化与女性选择性疼痛之间的联系

基本信息

批准号：
10676960
负责人：
Edita Navratilova
金额：
$ 45.68万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676960
关键词：
Afferent Neurons Age Agonist Anatomy Animals Antibodies Biological Brain region CRISPR/Cas technology Chronic stress Clustered Regularly Interspaced Short Palindromic Repeats Coupled Down-Regulation Dynorphins Electrophysiology (science)Equilibrium Event Female Fibromyalgia Frequencies Future Genetic Genetic Transcription Human Hypothalamic structure Injury Irritable Bowel Syndrome Irritants Knowledge Link Mediating Migraine Modeling Mus Neurosecretory Systems Nociception Nociceptors Opioid Opioid Antagonist Opioid agonist Pain Pain Disorder Pain Free Pathologic Patients Peripheral Persistent pain Pharmaceutical Preparations Pharmacology Study Phase Physiological Physiology Pituitary Gland Prevalence Prevention Prolactin Prolactin Receptor Protein Isoforms Receptor Activation Receptor Signaling Risk Rodent Rodent Model Role Signal Transduction Spinal Ganglia Stimulus Stress Structure of nucleus infundibularis hypothalami Structure of trigeminal ganglion Synapses Syndrome TRPA channel Temporomandibular Joint Disorders Testing Therapeutic Intervention Woman acute stress allodynia behavioral study central sensitization chronic pain dopaminergic neuron experience ganglion cell genetic manipulation hypothalamic-pituitary-adrenal axis imaging study improved innovation kappa opioid receptors lactotroph male men neural neuroadaptation neurochemistry novel overexpression pharmacologic pre-clinical prevent receptor expression reproductive restraint stress risk prediction selective expression sexual dimorphism triptans

项目摘要

Project Summary: Many patients suffer from chronic pain in the absence of identifiable injury. Such pains are termed “functional” and include irritable bowel syndrome, temporomandibular joint disorder, fibromyalgia, migraine and others. For reasons that are not understood, almost all functional pain syndromes (FPS) are female prevalent. FPS patients experience pain-free interictal periods punctuated by attacks of pain. The frequency of attacks is predictive of risk of chronification. Pain episodes thus produce a priming effect, establishing a state of increased vulnerability to future attacks, likely reflecting peripheral and central sensitization. FPS patients commonly identify stress as a key trigger of pain. Repeated stress may thus promote vulnerability and pain in a sexually dimorphic fashion. We have developed an injury-free rodent model of FPS based on hyperalgesic priming with repeated stress. Hyperalgesic priming produces a pain-free state of increased vulnerability that has been termed “latent sensitization” (LS). Following induction of LS, normally subthreshold triggers can produce pain attacks, modeling the interictal and ictal periods of FPS. We will use this model to test the novel hypothesis that repeated stress activates kappa opioid receptor (KOR) signaling in the hypothalamus resulting in release of prolactin (PRL) and dysregulation of prolactin receptor (PRLR) isoform expression selectively in female nociceptors. PRL signals through homodimers of PRLR long and short (i.e., PRLR-L and PRLR-S) isoforms that respectively regulate transcription and pain. Repeated stress down-regulates PRLR-L promoting female-selective pain through stress-induced PRL/PRLR-S signaling. The balance of PRLR isoforms may therefore “tune” female nociceptors to promote LS and pain from normally subthreshold stimuli. We will use genetic and chemogenetic manipulations along with anatomical, neurochemical, electrophysiological, pharmacological and behavioral studies in male and female mice to evaluate the role of dorsal root ganglion (DRG) PRLR-L down-regulation and stress-related hypothalamic KOR activation as essential mechanisms of LS and stress-related pain in females. Aim 1 will establish the effects of repeated stress on hypothalamic KOR signaling and PRL release. Aim 2 will establish a potential causal relationship of repeated stress or hypothalamic KOR activation on DRG PRLR isoform expression, neural excitability, LS and stress-related pain. Aim 3 will determine if KOR antagonists, DA agonists or a PRL antibody will prevent LS and FPS-like pain selectively in females. The proposed studies will characterize a previously unknown stress-related neuroendocrine link between hypothalamic KOR and PRL/PRLR signaling to promote female selective functional pain. Importantly, these studies will advance knowledge about previously unknown biological mechanisms and may unravel mechanisms for therapeutic interventions allowing improved therapy of FPS in women.

项目概要：许多患者在没有明显损伤的情况下患有慢性疼痛，这种疼痛被称为“功能性”疼痛。包括肠易激综合症、颞下颌关节紊乱、纤维肌痛、偏头痛等。原因尚不明确，几乎所有功能性疼痛综合征 (FPS) 均以女性为主。经历无痛发作间期，期间伴有疼痛发作。发作频率可预测。因此，疼痛发作的风险会产生启动效应，从而建立一种更加脆弱的状态。对未来的攻击，可能反映了 FPS 患者通常将压力视为外周和中枢敏感性。因此，反复的压力可能会以性别二态的方式促进脆弱性和疼痛。我们开发了一种基于反复应激的痛觉过敏启动的无损伤 FPS 啮齿动物模型。痛觉过敏引发会产生一种无痛状态，增加脆弱性，这被称为“潜在的” 敏化”(LS) 诱导 LS 后，阈下触发通常会产生疼痛发作、建模。我们将使用该模型来检验 FPS 的发作间期和发作期。激活下丘脑中的 kappa 阿片受体 (KOR) 信号传导，导致催乳素 (PRL) 释放，女性伤害感受器中催乳素受体 (PRLR) 异构体选择性表达失调。通过 PRLR 长和短异构体（即 PRLR-L 和 PRLR-S）的同二聚体分别调节重复的压力会下调 PRLR-L，从而促进女性选择性疼痛。因此，应激诱导的 PRL/PRLR-S 信号传导可能会“调节”女性伤害感受器。促进正常阈下刺激的 LS 和疼痛。我们将使用遗传和化学遗传学操作以及解剖学、神经化学、对雄性和雌性小鼠进行电生理、药理学和行为研究，以评估背根神经节 (DRG) PRLR-L 下调和应激相关的下丘脑 KOR 激活 LS 和女性压力相关疼痛的基本机制目标 1 将确定重复的影响。下丘脑 KOR 信号传导和 PRL 释放的压力将建立潜在的因果关系。重复应激或下丘脑 KOR 激活对 DRG PRLR 同工型表达、神经兴奋性、LS 和目标 3 将确定 KOR 拮抗剂、DA 激动剂或 PRL 抗体是否可以预防 LS 和女性选择性地出现类似 FPS 的疼痛。拟议的研究将描述以前未知的与压力相关的神经内分泌联系下丘脑 KOR 和 PRL/PRLR 信号传导促进女性选择性功能性疼痛。研究将增进对以前未知的生物机制的了解，并可能解开机制用于改善女性 FPS 治疗的治疗干预措施。