The role of delta opioid receptors in trigeminovascular pain

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 偏头痛相关症状和头痛的严重程度矛盾地增加，这些症状和头痛对其他 治疗。目前，MOH的一线治疗是停药。然而，在这段禁欲时期， 患者继续遭受严重偏头痛的折磨，大多数MOH患者重新使用这些药物 在第一年内。专门针对MOH的靶向治疗将导致更好的头痛治疗和 提高了患者的生活质量。这笔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激活完全逆转慢性药物治疗所致的头痛症，揭示δOR 激动剂作为治疗MOH的新策略。在之前的融资周期中，我们也进行了大规模的 无偏倚的多肽筛选，以确定慢性偏头痛和MOH之间的重叠机制。我们 鉴定通过PAC1受体结合的垂体腺苷环化酶激活多肽 这两种疾病之间的潜在联系；PACAP能系统可能与疼痛明显相关 通过慢性药物暴露来促进。进一步分析，我们还发现存在高共表达 在疼痛处理区，包括在中脑导水管周围灰质(δ)和 三叉神经复合体。此次更新的总体目标是在这些令人兴奋的发现的基础上，确定δ或 激动剂通过抑制PACAP能系统来缓解偏头痛和MOH。在目标1中，我们将测试G蛋白 有偏倚的δ或激动剂在新的有翻译意义的头面部MOH模型中的作用，并确定它们是否导致 此模型中的容差。这些研究将加强δ或MOH药物开发的证据。在……里面 目的2定位δOR与PACAP和PAC1的共表达，并使用生化AND 电生理实验研究δ或如何调节PACAP能信号。最后，在目标3中，我们将 在PACAP和δ表达细胞中产生PAC1OR的条件敲除，这将揭示是否行为 δ或激动剂的作用是通过PACAP能信号调节的。这项研究中提出的实验 应用是高度创新的，并使用多学科的方法。它们将为δ或激动剂作为更广泛的MOH和头痛障碍的治疗靶点的有效性提供重要的见解，并将 确定δ或激动剂是否通过抑制PACAP能系统起作用。此外，调制 δ的δ或可能是其他PACA或行为影响的基础，包括情绪 调制和外周镇痛。

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.