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

• 批准号: 10453747
• 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
• 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/10453747
• 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; 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; base; behavioral study; central sensitization; chronic pain; dopaminergic neuron; experience; ganglion cell; hypothalamic-pituitary-adrenal axis; imaging study; improved; innovation; kappa opioid receptors; lactotroph; male; men; neuroadaptation; neurochemistry; novel; overexpression; pre-clinical; prevent; receptor expression; relating to nervous system; reproductive; restraint stress; selective expression; sexual dimorphism; triptans; 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; 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; base; behavioral study; central sensitization; chronic pain; dopaminergic neuron; experience; ganglion cell; hypothalamic-pituitary-adrenal axis; imaging study; improved; innovation; kappa opioid receptors; lactotroph; male; men; neuroadaptation; neurochemistry; novel; overexpression; pre-clinical; prevent; receptor expression; relating to nervous system; reproductive; restraint stress; selective expression; sexual dimorphism; triptans

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.

项目摘要： 在没有可识别损伤的情况下，许多患者患有慢性疼痛。这种痛苦被称为“功能” 包括肠易激综合征，颞下颌关节疾病，纤维肌痛，偏头痛等。为了 尚不清楚的原因，几乎所有功能性疼痛综合征（FPS）都是女性普遍存在的。 FPS患者 经历无痛的充线期，疼痛发作会打断。攻击的频率是预测的 重新化的风险。因此，疼痛发作会产生启动作用，确立了增加脆弱性的状态 未来的攻击，可能反映外围和中心敏感性。 FPS患者通常将压力识别为 疼痛的关键触发因素。因此，重复的压力可能会以性二态性方式促进脆弱性和疼痛。 我们已经基于反复应力的高温启动开发了FPS的无损伤啮齿动物模型。 高温启动产生的无痛状态增加了脆弱性，称为“潜伏 敏化”（LS）。诱导LS后，通常子阈值触发器可以产生疼痛攻击，建模 FPS的间隔和发作时期。我们将使用该模型来测试重复应力的新假设 激活下丘脑中的Kappa阿片受体（Kor）信号传导，导致催乳素（PRL）和 雌性伤心症患者中催乳素受体（PRLR）同工型表达的失调。 PRL信号 通过PRLR长和短的同二聚体（即PRLR-L和PRLR-S）亚型分别调节 转录和疼痛。重复应力下调PRLR-L通过 应力诱导的PRL/PRLR-S信号传导。因此，PRLR同工型的平衡可能会“调整”女性伤害感受器 促进通常亚阈值刺激的LS和疼痛。 我们将使用遗传和化学发生操作以及解剖学，神经化学， 男性和雌性小鼠的电生理，药理和行为研究，以评估 背根神经节（DRG）PRLR-L-L下调和与压力相关的下丘脑KOR激活为 女性LS的基本机制和与压力有关的疼痛。 AIM 1将建立重复的效果 下丘脑KOR信号传导和PRL释放的压力。 AIM 2将建立潜在的因果关系 在DRG PRLR同工型表达，神经兴奋性，LS和LS上的重复应力或下丘脑kor激活 与压力有关的疼痛。 AIM 3将确定KOR拮抗剂，DA激动剂或PRL抗体是否会防止LS和 女性选择性地选择性疼痛。 拟议的研究将表征以前未知的应激相关神经内分泌之间的联系 下丘脑KOR和PRL​​/PRLR信号传导可促进女性选择性功能性疼痛。重要的是，这些 研究将进一步了解以前未知的生物学机制，并可能阐明机制 用于治疗性干预措施，可以改善女性FPS的治疗。