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: 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
• 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

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.

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