The Delta Opioid Receptor: A Therapeutic Target For Headache Disorders

Headache disorders are incredibly common, and those with a migraine-like phenotype are one of the most disabling neurological disorders. Despite the very high prevalence of headache disorders, therapeutic strategies are limited. The development of effective anti-migraine therapeutics is dependent on a thorough characterization of potential targets in preclinical animal models. In this thesis, I behaviorally and molecularly characterize the delta opioid receptor (DOR) as a promising therapeutic target for headache disorders. First, I show the development and characterization of a mouse model of post-traumatic headache. After pharmacological validation of this model, I used it to determine the anti-allodynic potential of DOR activation. Additionally, I characterized the effect of DOR activation in additional models of headache, including medication overuse headache, opioid-induced hyperalgesia, and the nitroglycerin (NTG) model of chronic migraine. Furthermore, I explore the unique interplay between the DOR, the pro-migraine peptide calcitonin gene-related peptide (CGRP), and the CGRP receptor, in the trigeminovascular system. Briefly, SNC80, a hallmark DOR agonist, reversed peripheral and cephalic hypersensitivity in the NTG mouse model of chronic migraine, post-traumatic headache, medication overuse headache, and opioid-induced hyperalgesia. Furthermore, chronic DOR activation prevented the development of basal hypersensitivity in the NTG model of chronic migraine and post-traumatic headache. To better understand how DOR activation regulates migraine-associated pain, I characterized the expression of the pro-migraine neuropeptide CGRP, receptor activity modifying protein 1 (RAMP1), calcitonin receptor-like receptor (CRLR), and the DOR within the trigeminal ganglia (TG) and the trigeminal nucleus caudalis (TNC). In the NTG model of chronic migraine, I found increased expression of CGRP and DOR within the TG and TNC. Interestingly, chronic DOR activation normalized increased CGRP expression, which suggests that both CGRP and DOR regulate aspects of migraine-associated pain. I also found a high co-expression of RAMP1, CRLR, and DOR within the TNC, which suggests that the DOR may interact with components of the CGRP receptor complex in some way to exert its anti-allodynic effects. Taken together, the results from this thesis demonstrate the powerful potential of DOR agonists for the treatment of headache disorders.