Mechanisms of Chronic Migraine and the Development of Novel Therapeutic Targets for this Disorder

Chronic migraine is an extremely common disorder that greatly impacts the quality of life of the sufferer. Chronic migraine affects up to 2% of the general population and within the United States alone accounts for almost 3 millions Americans. Despite the high prevalence for this disorder and the recent breakthroughs that have been achieved, therapeutic strategies for the treatment of migraine are still limited. With the recent addition of the calcitonin gene related peptide (CGRP) antibodies some patients with chronic migraine who previously had poor response to available migraine pharmaceutics finally experienced a reduction in headache days per month. While these advancements are great and show the therapeutic potential that can be gained from exploring migraine pathophysiology there is still not a migraine therapeutic that is effective in all people nor is there a cure to migraine. Gaining a better understanding about the pathophysiology of chronic migraine would allow for more effective therapeutic options to treat this population. In this thesis I have uncovered a greater understanding of migraine pathophysiology and characterized novel treatment options for chronic migraine. Under the scope of discovering the pathophysiology of migraine I have characterized a neuronal cytoarchitectural basis for migraine chronification. I further established the use of histone deacetylase 6 (HDAC6) inhibitors as a novel treatment target for chronic migraine and migraine aura. I further expanded these findings to reveal other cytoarchitectural changes associated with chronic migraine and another chronic pain disorder, chronic regional pain syndrome (CRPS). I also demonstrated that a non-convulsant delta opioid receptor agonist could effectively relieve chronic migraine associated symptoms and reduce cortical spreading depression events. Many chronic neuropsychiatric conditions are implicated as having alterations in neuroplasticity. Chronic pain disorders have been found to not be an exception and many have changes in the cytoarchitecture in both humans and rodent models. In this thesis I demonstrate that chronic migraine is correlated with changes in neuronal cytoarchitecture. Following a chronic intermittent nitroglycerin (NTG) model I observed reduced neuronal complexity in the trigeminal nucleus caudalis, periaqueductal gray, and somatosensory cortex, regions that are important for migraine processing. These results are the first of their kind to demonstrate altered neuronal cytoarchitecture correlating with a chronic migraine model. Furthermore, the chronic NTG model resulted in chronic basal hyperalgesia that was reversible through treatment with an HDAC6 inhibitor. HDAC6 inhibition also caused increased neuronal complexity correlating with reduced allodynia. A second mechanistically distinct model examining migraine aura, cortical spreading depression, also showed decreased neuronal complexity in the somatosensory cortex and trigeminal nucleus caudalis. HDAC6 inhibition was able to prevent these cytoarchitectural changes and reduce susceptibility to cortical spreading depression. Building on these findings we found further disruption of the cytoarchitecture in other key migraine and pain related brain regions. Changes in cytoarchitecture were also detected in another model, chronic regional pain syndrome. Finally in this thesis I further demonstrated the promising potential of using delta opioid receptor agonists for the treatment of migraine. The non-convulsant delta opioid receptor agonist, KNT-127, reduced the number of cortical spreading depression events and reversed established basal hyperalgesia following the chronic NTG model. Collectively, the results presented in this thesis demonstrate a better understanding of the pathophysiology of chronic migraine as well as further development of therapeutic targets for treatment of this disorder.