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导致药物过度使用头痛（MOH）。这是一 偏头痛相关症状和头痛的严重程度反常增加，这些症状和头痛是其他药物难以治疗的。 治疗。目前，MOH的一线治疗是停止药物治疗。然而，在禁欲期间， 患者继续遭受严重的偏头痛，并且大多数MOH患者返回这些药物 在第一年内。专门针对MOH的靶向治疗将导致更好的头痛管理， 提高患者生活质量。该赠款上一个供资周期的成就之一是 在多种头痛模型中测试δ阿片受体（δOR）激动剂，包括MOH模型。我们发现 δOR激活完全逆转了慢性药物治疗诱导的头部异常性疼痛，表明δOR 激动剂作为MOH的新治疗策略。在上一个资金周期，我们也进行了大规模的投放 无偏肽组筛选，以确定慢性偏头痛和MOH之间的重叠机制。我们 经鉴定，垂体腺苷酸环化酶激活多肽（PACAP）通过PAC 1受体结合， 这两种疾病之间的潜在联系;以及PACA Pergic系统可能明显参与疼痛 慢性药物暴露的促进作用。进一步分析我们还发现， δOR和PACAP或PAC 1之间的疼痛处理区域，包括在导水管周围灰质（PAG）和 三叉神经复合体本次更新的总体目标是在这些令人兴奋的发现的基础上， 激动剂通过抑制PACA麻痹系统缓解偏头痛和MOH。在目标1中，我们将测试G蛋白 偏性δOR激动剂在新的头部MOH模型中的临床意义，并确定它们是否导致 在这个模型中，这些研究将加强δOR治疗MOH药物开发的证据。在 目的2：我们将定位δOR与PACAP和PAC 1的共表达，并利用生物化学和 通过电生理测定来研究δOR如何调节PACA Pergic信号传导。最后，在目标3中， 在表达PACAP和PAC 1的细胞中产生δOR的条件性敲除，这将揭示行为性 δOR激动剂的作用通过PACA Pergic信号传导调节。在此提出的实验 应用程序是高度创新的，并使用多学科的方法。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的见解， 确定δOR激动剂是否通过抑制PACA Pergic系统起作用。此外，调制的 δOR的PACA麻痹系统可能是其他δOR行为效应的基础，包括情绪 调制和外周镇痛。