The role of delta opioid receptors in trigeminovascular pain

项目摘要/摘要 美国有200多万人滥用处方药阿片类止痛药。其中一个 处方阿片类药物的主要原因是治疗三叉神经血管疼痛(偏头痛)；以及 这些治疗大多针对阿片受体。这些µ激动剂对 三叉神经血管疼痛，有助于疼痛从发作状态发展到慢性状态，并作为一种 处方药滥用的切入点。选择性激活δ阿片受体的药物有不同的 这些特性使它们成为当前使用的基于µ的疗法的有前途的替代品。我们最近做了 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慢性间歇治疗可引起急性和慢性痛觉过敏，δ可抑制这种作用 激动剂。此外，我们还表明，δ激动剂SNC80可以抑制皮质扩散抑制，a 与三叉神经血管疼痛相关的先兆的“黄金标准”模型。δ激动剂的研究进展 偏头痛取决于对δ激动剂在哪里以及如何抑制三叉神经血管性疼痛的更好理解 以及相关症状。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δOR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。这项提案的一个目标将是确定 中枢和外周δ阿片受体在三叉神经血管性疼痛的发生和治疗中的作用。为了这个 目的：我们将使用新的条件性基因敲除小鼠，其δ阿片受体在特定的中枢区域缺失。 和外围区域。我们将在NTG模型中检查这些特定基因敲除的影响 三叉神经血管性疼痛和负性情绪，以及皮质扩散性抑制。我们还将探索 δ激动剂抑制三叉神经血管性疼痛的机制。神经肽，降钙素基因相关肽 降钙素基因相关肽(CGRP)在三叉神经血管性疼痛的诱导和维持中起关键作用，主要通过 三叉神经节发出的外周传入纤维。这项提案的另一个目标是确定 降钙素基因相关肽在神经节的表达及降钙素基因相关肽释放的变化 天真，用于三叉神经血管疼痛，并长期使用δ激动剂治疗。总而言之，这些研究将提供一个 更深入地了解δOR如何影响三叉神经血管性疼痛，从而促进小说的发展 治疗这种疾病的化合物。

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.