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: 10608549
• 负责人: Amynah Amir Ali Pradhan
• 金额: $ 47.57万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608549
• 关键词: Absence of pain sensation; Abstinence; Acute; Adenylate Cyclase; Affect; Agonist; Analgesic Overuse Headaches; Auras; Behavioral; Binding; Biochemical; Biological Assay; Brain region; Cells; Cephalic; Chronic; Clinical; Clinical Trials; Complex; Data; Disease; Effectiveness; Electrophysiology (science); Emotional; Funding; GTP-Binding Proteins; Genetic; Goals; Grant; Headache; Headache Disorders; Hot Spot; Immunohistochemistry; In Situ Hybridization; Individual; Knock-out; Link; Maps; Migraine; Modeling; Opioid; Opioid Receptor; Opioid agonist; PACAPR-1 protein; Pain; Patients; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Population; Post-Traumatic Headaches; Prevalence; Quality of life; Receptor Activation; Refractory; Role; Severities; Signal Transduction; Site; Source; Structure of trigeminal ganglion; System; Testing; Therapeutic; Trigeminal Nuclei; Trigeminal System; Viral; Work; abuse liability; allodynia; associated symptom; chronic pain; conditional knockout; delta opioid receptor; disability; drug development; efficacy evaluation; evidence base; experimental study; gamma-Aminobutyric Acid; inhibitor; innovation; insight; interdisciplinary approach; midbrain central gray substance; migraine treatment; novel; novel therapeutic intervention; pain processing; pain sensitivity; pituitary adenylate cyclase activating polypeptide; presynaptic; receptor; receptor expression; return to use; targeted treatment; therapeutic target; translational model; triptans

Chronic use of commonly used migraine therapies can lead to medication overuse headache (MOH). This is a paradoxical increase in severity of migraine-associated symptoms and headaches which are refractory to other treatments. Currently, the first-line treatment for MOH is drug cessation. However, during this abstinence period, patients continue to suffer from severe migraine, and a majority of MOH patients return to these medications within the first year. Targeted therapies specifically for MOH would result in better headache management and increased patient quality of life. One of the accomplishments of the previous funding cycle of this grant was to test δ opioid receptor (δOR) agonists in multiple headache models, including models of MOH. We found that δOR activation completely reversed cephalic allodynia induced by chronic medication treatment, revealing δOR agonists as a novel therapeutic strategy for MOH. In the previous funding cycle, we also performed a large scale unbiased peptidomic screen to identify overlapping mechanisms between chronic migraine and MOH. We identified pituitary adenylate cyclase activating polypeptide (PACAP) binding through PAC1 receptor as a potential link between these two disorders; and that the PACAPergic system may be distinctly involved in pain facilitation by chronic medication exposure. Upon further analysis we also found that there is high co-expression between δOR and PACAP or PAC1 in pain-processing regions, including in the periaqueductal grey (PAG) and trigeminal complex. The overall goal of this renewal is to build upon these exciting findings and determine if δOR agonists relieve migraine and MOH through inhibition of the PACAPergic system. In Aim 1, we will test G protein biased δOR agonists in novel translationally significant models of cephalic MOH and determine if they cause tolerance in this model. These studies will strengthen the evidence for drug development of δOR for MOH. In Aim 2 we will map the co-expression of δOR with PACAP and PAC1 and use biochemical and electrophysiological assays to investigate how δOR modulates PACAPergic signaling. Finally, in Aim 3 we will generate conditional knockouts of δOR in PACAP and PAC1 expressing cells, which will reveal if the behavioral effects of δOR agonists are regulated through PACAPergic signaling. The experiments proposed in this application are highly innovative and use a multidisciplinary approach. They will provide important insight on the effectiveness of δOR agonist as a therapeutic target for MOH and headache disorders more broadly and will determine if δOR agonists work through inhibition of the PACAPergic system. Further, the modulation of the PACAPergic system by δOR may be fundamental to other δOR behavioral effects, including emotional modulation and peripheral analgesia.

长期使用常用的偏头痛疗法可能会导致药物过度使用性头痛 (MOH)。这是一个 偏头痛相关症状和头痛的严重程度反常增加，而这些症状是其他药物难以治愈的 治疗。目前，MOH 的一线治疗是戒药。然而，在这段禁欲期间， 患者继续遭受严重偏头痛的困扰，大多数卫生部患者恢复使用这些药物 第一年内。专门针对 MOH 的靶向治疗将带来更好的头痛管理和 提高患者的生活质量。这笔赠款的上一个资助周期的成就之一是 在多种头痛模型（包括 MOH 模型）中测试 δ 阿片受体 (δOR) 激动剂。我们发现 δOR 激活完全逆转了慢性药物治疗引起的头部异常性疼痛，揭示了 δOR 激动剂作为 MOH 的一种新型治疗策略。在上一个融资周期中，我们也进行了大规模的 无偏肽组学筛选，以确定慢性偏头痛和 MOH 之间的重叠机制。我们 确定垂体腺苷酸环化酶激活多肽（PACAP）通过 PAC1 受体结合作为 这两种疾病之间的潜在联系； PACAPergic 系统可能明显参与疼痛 长期接触药物有促进作用。经过进一步分析，我们还发现存在高度共表达 疼痛处理区域中的 δOR 与 PACAP 或 PAC1 之间，包括导水管周围灰质 (PAG) 和 三叉神经复合体。这次更新的总体目标是建立在这些令人兴奋的发现的基础上，并确定 δOR 是否 激动剂通过抑制 PACAPergic 系统缓解偏头痛和 MOH。在目标 1 中，我们将测试 G 蛋白 在头颅 MOH 的新颖翻译显着模型中偏向 δOR 激动剂，并确定它们是否导致 该模型中的公差。这些研究将加强 δOR 治疗 MOH 药物开发的证据。在 目标 2 我们将绘制 δOR 与 PACAP 和 PAC1 的共表达图，并使用生化和 电生理学测定研究 δOR 如何调节 PACAPergic 信号传导。最后，在目标 3 中，我们将 在 PACAP 和 PAC1 表达细胞中产生 δOR 的条件敲除，这将揭示行为是否 δOR 激动剂的作用通过 PACAPergic 信号传导进行调节。本文提出的实验 应用程序具有高度创新性并采用多学科方法。他们将为 δOR 激动剂作为 MOH 和头痛疾病更广泛的治疗靶点的有效性提供重要见解，并将 确定 δOR 激动剂是否通过抑制 PACAPergic 系统发挥作用。此外，调制 δOR 的 PACAPergic 系统可能是其他 δOR 行为效应的基础，包括情绪 调节和外周镇痛。