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.