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导致药物过度使用头痛（MOH）。这是一个