Mangutov Elizaveta, Dripps Isaac, Siegersma Kendra, Zhang Yanping, Bocian Rebecca, Asif Sarah, Halbesma Timothy, Witkowski Wiktor, Pradhan Amynah A
Center for Clinical Pharmacology, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, USA.
Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA.
Br J Pharmacol. 2025 Apr;182(7):1630-1643. doi: 10.1111/bph.17424. Epub 2025 Jan 10.
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.
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.
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.
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.
垂体腺苷酸环化酶激活多肽（PACAP）是一种可引发人类偏头痛的物质，正成为偏头痛治疗的靶点。δ-阿片受体（δ-受体）是偏头痛治疗的一个新靶点，但其作用机制尚不清楚。本研究的目的是使用具有临床意义剂量的PACAP建立小鼠PACAP性头痛模型；确定该模型中δ-受体激活的作用；并研究δ-受体、PACAP和PACAP-PAC1受体的共表达情况。
检测低剂量急性和慢性PACAP引起的头部痛觉过敏。在此模型中测试了一种曲坦类药物（舒马曲坦）和一种降钙素基因相关肽（CGRP）受体拮抗剂（olcegepant）。在PACAP和CGRP诱导的头痛模型中测试了δ-受体激动剂SNC80。使用原位杂交法测定PACAP、PAC1、CRLR和δ-受体的表达。
低剂量的PACAP产生剂量依赖性的急性和慢性头部痛觉过敏，舒马曲坦可阻断，但olcegepant不能阻断。PAC1拮抗剂（M65）不抑制CGRP诱导的痛觉过敏。在偏头痛相关区域，PAC1和CRLR转录本有中度共表达。SNC80可阻断PACAP和CGRP诱导的痛觉过敏。在所检测的脑区中，PACAP和δ-受体有低水平共表达。然而，在体感皮层、海马和三叉神经尾核中，PAC1和δ-受体有高水平共表达。
我们建立了一个具有转化意义的PACAP诱导性头痛模型，其机制与CGRP不同。δ-受体的激活可阻断PACAP和CGRP诱导的痛觉过敏，且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。
