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

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.