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…
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