The role of delta opioid receptors in trigeminovascular pain

δ阿片受体在三叉血管疼痛中的作用

• 批准号: 9319659
• 负责人: Amynah Amir Ali Pradhan
• 金额: $ 35.36万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9319659
• 关键词: Absence of pain sensation; Acute; Adverse effects; Affect; Agonist; Analgesic Overuse Headaches; Anatomy; Animal Model; Animals; Anti-Anxiety Agents; Attenuated; Auras; Calcitonin Gene-Related Peptide; Centers for Disease Control and Prevention (U.S.); Cerebral cortex; Chronic; Clinical; Comorbidity; Complex; Coupled; Development; Disease; Dorsal; Drug Addiction; Electrophysiology (science); Emotional; Emotional disorder; Epidemic; Functional disorder; Ganglia; Goals; Gold; Hippocampus (Brain); Human; Hyperalgesia; Individual; Knock-out; Knockout Mice; Maintenance; Mediating; Migraine; Modeling; Mus; Neurons; Neuropeptides; Nitroglycerin; Nucleus Accumbens; Opiates; Opioid; Opioid Analgesics; Opioid Receptor; Pain; Peripheral; Pharmaceutical Preparations; Play; Population; Property; Prosencephalon; Refractory; Risk; Role; Sedation procedure; Signal Transduction; Spreading Cortical Depression; Structure of trigeminal ganglion; Symptoms; United States; Ventilatory Depression; Ventral Striatum; antidepressant effect; base; delta opioid receptor; disorder prevention; inflammatory neuropathic pain; insight; mouse model; negative affect; novel; novel therapeutics; pain inhibition; prescription drug abuse; prescription opioid; receptor; spinal nerve posterior root; voltage

Project Summary/Abstract Over 2 million people in the United States suffer from prescription drug abuse of opioid analgesics. One of the leading causes for the prescription of opioids is for the treatment of trigeminovascular pain (migraine); and the majority of these treatments target the µ opioid receptor. These µ agonists have poor efficacy for trigeminovascular pain, contribute to the progression of pain from an episodic to chronic state, and serve as an entry point to prescription drug abuse. Drugs that selectively activate the δ opioid receptor have distinct properties which make them promising alternatives to currently used µ-based therapies. We have recently developed a novel model of trigeminovascular pain, using the known human migraine trigger nitroglycerin (NTG). Chronic intermittent treatment with NTG results in acute and chronic hyperalgesia, which is inhibited by δ agonists. In addition, we have also shown that the δ agonist SNC80 can inhibit cortical spreading depression, a “gold standard” model of aura associated with trigeminovascular pain. The continued development of δ agonists for migraine depends upon a better understanding of where and how δ agonists inhibit trigeminovascular pain and related symptoms. δ opioid receptors are expressed in several central and peripheral regions that are important in pain processing, and emotional modulation. Which δORs are anatomically important for regulating trigeminovascular pathophysiology is currently unknown. A goal of this proposal will be to determine the role of central vs. peripheral δ opioid receptors in the development and treatment of trigeminovascular pain. For this purpose, we will use novel conditional knockout (cKO) mice with δ opioid receptors deleted in specific central and peripheral regions. We will examine the effects of these specific knockouts in the NTG model of trigeminovascular pain and negative affect, and on cortical spreading depression. We will also explore the mechanism by which δ agonists inhibit trigeminovascular pain. The neuropeptide, calcitonin gene related peptide (CGRP) plays a pivotal role in the induction and maintenance of trigeminovascular pain, primarily through the peripheral afferents projecting from the trigeminal ganglia. A further aim of this proposal will be to determine the expression of δORs on CGRP-expressing ganglia, as well as changes in CGRP release, when animals are naïve, in trigeminovascular pain, and chronically treated with δ agonists. Together, these studies will provide a deeper insight into how δORs affect trigeminovascular pain, thus enhancing the development of novel therapeutic compounds for this disorder.

项目总结/摘要 美国有超过200万人滥用阿片类镇痛药。之一 阿片类药物处方的主要原因是用于治疗三叉神经血管疼痛（偏头痛）; 大多数这些治疗靶向μ阿片受体。这些μ激动剂对以下疾病的疗效较差： 三叉神经血管疼痛，有助于疼痛从发作性进展到慢性状态，并作为一种治疗方法。 处方药滥用的切入点选择性激活δ阿片受体的药物具有明显的 这些特性使它们成为目前使用的基于µ的疗法的有前途的替代品。我们最近 开发了一种新的三叉神经血管疼痛模型，使用已知的人类偏头痛触发硝酸甘油（NTG）。 NTG的慢性间歇治疗导致急性和慢性痛觉过敏，δ 激动剂此外，我们还发现δ激动剂SNC 80可以抑制皮层扩散性抑制， 与三叉神经血管疼痛相关的先兆的“金标准”模型。δ受体激动剂的持续发展 依赖于更好地理解δ激动剂在何处以及如何抑制三叉神经血管疼痛 及相关症状。δ阿片受体在几个中枢和外周区域表达， 在疼痛处理和情绪调节中很重要哪些δ OR在解剖学上对调节 三叉神经血管的病理生理学目前尚不清楚。本提案的一个目标是确定以下方面的作用： 中枢与外周δ阿片受体在三叉神经血管痛的发生和治疗中的作用为此 目的，我们将使用新的条件性敲除（cKO）小鼠与δ阿片受体删除特定的中央 和周边地区。我们将研究这些特定敲除在NTG模型中的作用， 三叉神经血管疼痛和负性情绪，以及皮质扩散性抑制。我们亦会探讨 δ激动剂抑制三叉神经血管疼痛的机制。降钙素基因相关肽 降钙素基因相关肽（CGRP）在三叉神经血管疼痛的诱导和维持中起着关键作用，主要通过 从三叉神经节投射的外周传入神经。本提案的另一个目的是确定 当动物被注射时，CGRP表达神经节上δ OR的表达，以及CGRP释放的变化， 首次出现三叉神经血管疼痛，长期接受δ受体激动剂治疗。这些研究将共同提供 更深入地了解δ OR如何影响三叉神经血管疼痛，从而促进新的 治疗这种疾病的化合物。