The development of a mouse model of mTBI-induced post-traumatic migraine, and identification of the delta opioid receptor as a novel therapeutic target

Background Post-traumatic headache is the most common and long-lasting impairment observed following mild traumatic brain injury, and frequently has migraine-like characteristics. The mechanisms underlying progression from mild traumatic brain injury to post-traumatic headache are not fully understood. The aim of this study was to develop a mouse model of post-traumatic headache and identify mechanisms and novel targets associated with this disorder. Methods We combined the closed head weight-drop method and the nitroglycerin chronic migraine model. To induce mild traumatic brain injury, a weight was dropped onto intact crania of mildly anesthetized mice, and mechanical responses to chronic-intermittent administration of nitroglycerin, a human migraine trigger, were determined at multiple time points post-injury. Results Low dose nitroglycerin (0.1 mg/kg) evoked acute periorbital and hind paw allodynia in both mild traumatic brain injury and sham animals. However, only mild traumatic brain injury mice developed chronic hypersensitivity to low dose nitroglycerin. Migraine medications, sumatriptan and topiramate, inhibited post-traumatic headache-associated allodynia. In addition, the delta opioid receptor agonist, SNC80, also blocked post-traumatic headache-associated allodynia. Finally, we examined the expression of calcitonin gene-related peptide within this model and found that it was increased in trigeminal ganglia two weeks post-mild traumatic brain injury. Conclusions Overall, we have established a mouse model of post-traumatic headache and identified the delta opioid receptor as a novel therapeutic target for this disorder.