{"doi":"10.1111/bph.17424","title":"Activation of δ‐opioid receptors blocks allodynia in a model of headache induced by PACAP","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.","journal":"British Journal of Pharmacology","year":2025,"id":515810,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9672,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":309501,"name":"Isaac Dripps","orcid":null,"position":1,"is_corresponding":false},{"id":511565,"name":"Kendra Siegersma","orcid":"0000-0002-6578-5561","position":2,"is_corresponding":false},{"id":1220388,"name":"Yanping Zhang","orcid":"0009-0008-3171-6614","position":3,"is_corresponding":false},{"id":1186649,"name":"Rebecca Bocian","orcid":null,"position":4,"is_corresponding":false},{"id":903157,"name":"Sarah Asif","orcid":"0000-0001-7953-8206","position":5,"is_corresponding":false},{"id":1381190,"name":"Timothy Halbesma","orcid":null,"position":6,"is_corresponding":false},{"id":553584,"name":"Wiktor Witkowski","orcid":"0000-0002-0296-5055","position":7,"is_corresponding":false},{"id":307054,"name":"Amynah Pradhan","orcid":"0000-0001-9691-2976","position":8,"is_corresponding":false},{"id":903621,"name":"Elizaveta Mangutov","orcid":null,"position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T02:48:44.647022Z","pmid":"39797405","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}