Delta opioid receptor regulation of calcitonin gene-related peptide dynamics in the trigeminal complex

Migraine is highly prevalent and is the sixth leading cause worldwide for years lost to disability. Therapeutic options specifically targeting migraine are limited, and delta opioid receptor (DOP) agonists were recently identified as a promising pharmacotherapy. The mechanisms by which DOPs regulate migraine are currently unclear. Calcitonin gene-related peptide (CGRP) has been identified as an endogenous migraine trigger and plays a critical role in migraine initiation and susceptibility. The aim of this study was to determine the behavioral effects of DOP agonists on the development of chronic migraine-associated pain and to investigate DOP coexpression with CGRP and CGRP receptor (CGRPR) in the trigeminal system. Chronic migraine-associated pain was induced in mice through repeated intermittent injection of the known human migraine trigger, nitroglycerin. Chronic nitroglycerin resulted in severe chronic cephalic allodynia which was prevented with cotreatment of the DOP-selective agonist, SNC80. In addition, a corresponding increase in CGRP expression in the trigeminal ganglia and trigeminal nucleus caudalis was observed after chronic nitroglycerin, an augmentation that was blocked by SNC80. Moreover, DOP was also upregulated in these head pain-processing regions following the chronic migraine model. Immunohistochemical analysis of the trigeminal ganglia revealed coexpression of DOP with CGRP as well as with a primary component of the CGRPR, RAMP1. In the trigeminal nucleus caudalis, DOP was not coexpressed with CGRP but was highly coexpressed with RAMP1 and calcitonin receptor-like receptor. These results suggest that DOP agonists inhibit migraine-associated pain by attenuating CGRP release and blocking pronociceptive signaling of the CGRPR.