Activation of δ-opioid receptors blocks allodynia in a model of headache induced by PACAP

IF 6.8 2区医学 Q1 PHARMACOLOGY & PHARMACY

British Journal of Pharmacology Pub Date : 2025-01-10 DOI:10.1111/bph.17424

Elizaveta Mangutov, Isaac Dripps, Kendra Siegersma, Yanping Zhang, Rebecca Bocian, Sarah Asif, Timothy Halbesma, Wiktor Witkowski, Amynah A. Pradhan

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Abstract

Background and purpose

Pituitary adenylate cyclase activating polypeptide (PACAP) is a human migraine trigger that is being targeted for migraine. The δ-opioid receptor (δ-receptor) is a novel target for the treatment of migraine, but its mechanism remains unclear. The goals of this study were to develop a mouse PACAP-headache model using clinically significant doses of PACAP; determine the effects of δ-receptor activation in this model; and investigate the co-expression of δ-receptors, PACAP and PACAP-PAC1 receptor.

Experimental approach

Cephalic allodynia to low doses of acute and chronic PACAP were tested. A triptan (sumatriptan) and a CGRP receptor antagonist (olcegepant) were tested in this model. The δ-receptor agonist SNC80 was tested in PACAP and CGRP-induced headache models. Expression of PACAP, PAC1, CRLR and δ-receptors was determined using in situ hybridisation.

Key results

Low doses of PACAP produced dose-dependent acute and chronic cephalic allodynia, blocked by sumatriptan but not by olcegepant. The PAC1 antagonist (M65) did not inhibit CGRP-induced allodynia. There was moderate co-expression of PAC1 and CRLR transcripts in migraine-related regions. SNC80 blocked PACAP- and CGRP-induced allodynia. There was low co-expression of PACAP and δ-receptors in brain regions measured. However, there was high co-expression of PAC1 and δ-receptors in somatosensory cortex, hippocampus and trigeminal nucleus caudalis.

Conclusion and implications

We developed a translationally significant model of PACAP-induced headache, which was mechanistically distinct from CGRP. Activation of δ-receptors blocked PACAP- and CGRP-induced allodynia, and δ-receptors were highly co-expressed with the PACAP-ergic system. Future studies will examine the functional relationship between δ-receptors and PAC1.

Abstract Image

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δ-阿片受体的激活可阻断PACAP诱导的头痛模型的异常性疼痛。

背景和目的：垂体腺苷酸环化酶激活多肽（PACAP）是一种针对偏头痛的人类偏头痛触发因子。δ-阿片受体（δ受体）是治疗偏头痛的新靶点，但其作用机制尚不清楚。本研究的目的是使用临床显著剂量的PACAP建立小鼠PACAP-头痛模型；确定δ受体激活对模型的影响；研究δ-受体、PACAP和PACAP- pac1受体的共表达。实验方法：检测低剂量急慢性PACAP对头侧异常性疼痛的影响。在该模型中检测曲坦类药物（舒马匹坦）和CGRP受体拮抗剂（olcegetant）。δ受体激动剂SNC80在PACAP和cgrp诱导的头痛模型中进行检测。采用原位杂交法检测PACAP、PAC1、CRLR和δ-受体的表达。关键结果：低剂量PACAP可产生剂量依赖性急慢性头性异常痛，可被舒马匹坦阻断，但不能被丙孕酮阻断。PAC1拮抗剂（M65）不能抑制cgrp诱导的异常性疼痛。PAC1和CRLR转录本在偏头痛相关区域有中度共表达。SNC80阻断PACAP-和cgrp诱导的异常性疼痛。PACAP和δ-受体在脑区低共表达。而PAC1和δ-受体在体感觉皮层、海马和三叉神经尾核中有较高的共表达。结论和意义：我们建立了一个具有翻译意义的pacap诱导的头痛模型，其机制与CGRP不同。δ-受体的激活阻断了PACAP-和cgrp诱导的异常性疼痛，δ-受体与PACAP-能系统高度共表达。未来的研究将探讨δ-受体与PAC1之间的功能关系。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

British Journal of Pharmacology 医学-药学

CiteScore

15.40

自引率

12.30%

发文量

270

审稿时长

2.0 months

期刊介绍： The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.