Characterization of a rat model of chronic headache

Migraine, a debilitating headache disorder, affects 1 in 5 women and 1 in 15 men. The diagnostic criteria for migraine include at least 5 migraine attacks and unilateral throbbing pain accompanied by phonophobia and sensitivity of the face to innocuous stimuli or facial allodynia. If migraine frequency increases to 15 or more attacks per month, the headache is classified as chronic migraine. The transition from episodic migraine to chronic migraine involves a clinical transformation – reversible increase in headache frequency, a physiological transformation – development of allodynia and sensitization and an anatomical transformation – development of anatomical abnormalities such as white matter lesions. Many animal models of migraine utilize a single inflammatory manipulation to illustrate pain pathways and model migraine symptoms such as allodynia. However, a major limitation to these models is that migraine is not an acute phenomenon. Our laboratory uses repeated inflammatory stimulation of the dura to model migraine. Following repeated nociceptor activation, rats demonstrate facial (periorbital) allodynia and phonophobia. The goal of this thesis is to characterize this animal model in the context of three transformations described in the evolution from episodic to chronic migraine. The physiological transformation is highlighted in chapters 2 and 3 and demonstrated by exacerbation of allodynia in response to the migraine trigger ethanol. Chapters 4 and 5 displayed blood brain barrier breakdown in rats following repeated inflammatory stimulation, fitting the anatomical transformation. The clinical transformation was modeled through prevention of allodynia and the sensitization process with minocycline, a tetracycline-derived antibiotic. This thesis provides evidence that our model is relevant to chronic migraine transformation in humans. In addition, we show that ethanol induced headache-like allodynia is mediated by adenosine and correlated with changes in extracellular GABA and glutamate in our model. We also demonstrate that blood brain barrier damage in our model of migraine may be correlated with astrocyte activation. These findings significantly impact the fields of headache research and alcohol addiction and suggest targets for clinical studies. Future directions include investigations of ethanol sensitivity and blood brain barrier abnormalities in chronic migraine patients.