Analysis of the anti-migraine effects of THC using home cage wheel running
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Migraine is a common neurological disorder characterized by severe headache and depression of normal activity. Despite its marked prevalence, migraine is poorly treated and no new anti-migraine agents have emerged in over 25 years. Two reasons for this lack of progress are the absence of clinically relevant behavioral outcomes for assessing migraine pain in rodents and a limited understanding of the underlying mechanisms. The purpose of this dissertation was to develop a clinically relevant method to assess migraine pain to evaluate the anti-migraine efficacy of ∆9-tetrahydrocannabinol (THC) in female rats. Activation of primary afferents via dural administration of allyl isothiocyanate (AITC) depressed home cage wheel running for three hours. Administration of the anti-migraine medication sumatriptan reversed AITC-induced depression of home cage wheel running. These observations are consistent with the migraine-induced decreases in activity in humans and subsequent recovery by sumatriptan. Chapter 3 shows that administration of THC also prevented migraine-depressed wheel running. This effect occurred only when rats were treated with THC immediately following AITC administration and not when administered 90 minutes before or after AITC. Administration of cannabinoid type-1 and type-2 receptor antagonists revealed that the anti-migraine effects of THC were mediated by activation of the cannabinoid type-1 receptor. Chapter 4 examined whether THC efficacy is maintained with repeated administration. THC prevented migraine-depressed wheel running in rats whether they were pretreated with THC or vehicle for 2.5 days. In contrast, morphine transiently prevented migraine-depressed wheel running in rats pretreated with saline, but not morphine for 2.5 days. Moreover, migraine-depressed wheel running was exacerbated in rats pretreated with morphine compared to rats pretreated with THC or vehicle. The present studies reveal three findings: 1) Depression of home cage wheel running is an objective and clinically relevant method to assess migraine pain in rats; 2) Administration of THC can prevent migraine-depressed wheel running via CB1 receptor activation; and 3) Repeated THC administration does not exacerbate migraine pain or produce antinociceptive tolerance. These novel findings suggest that THC may be an effective migraine treatment.