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

Abstract

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.

Forebrain delta opioid receptors regulate the response of delta agonist in models of migraine and opioid-induced hyperalgesia

“…Recent evidence indicates that δ agonists may be effective in headache disorders more broadly. SNC80 was found to inhibit allodynia associated with post-traumatic headache, MOH induced by overuse of sumatriptan, and OIH 12 , 13 .…”

Pain, Motivation, Migraine, and the Microbiome: New Frontiers for Opioid Systems and Disease

“…Acute injection of this DOR agonist was also effective in a related model of chronic migraine induced by mild traumatic brain injury, otherwise known as posttraumatic migraine (Moye and Pradhan, 2017;Moye et al, 2019b). Importantly, long-term treatment with SNC80 also prevented the development of chronic migraine in this same model of posttraumatic headache (Moye et al, 2019a). These data suggest that DOR may be effective for both episodic headache and could also protect from the induction of headache chronicity.…”

Emerging Treatment Targets for Migraine and Other Headaches

“…SNC80 effectively inhibited cephalic allodynia in mouse models of chronic migraine, and medication overuse headache associated with triptans . In a model of post‐traumatic headache, acute SNC80 blocked established cephalic allodynia, and long‐term treatment with this δ agonist also prevented the chronification of post‐traumatic headache . In a model of opioid‐induced hyperalgesia, chronic morphine treatment produced a severe cephalic and peripheral allodynia that was inhibited by treatment with a δ agonist .…”

“…64 In a model of post-traumatic headache, acute SNC80 blocked established cephalic allodynia, 64 and long-term treatment with this δ agonist also prevented the chronification of post-traumatic headache. 65 In a model of opioid-induced hyperalgesia, chronic morphine treatment produced a severe cephalic and peripheral allodynia that was inhibited by treatment with a δ agonist. 64 This latter finding particularly supports the distinction between the µ and δ receptors, as chronic µ receptor stimulation by morphine resulted in a correlate of mediation overuse headache which could still be blocked by δ receptor activation.…”