Delta opioid receptor agonists are effective for multiple types of headache disorders

Abstract

ABSTRACT Headaches are highly disabling and are among the most common neurological disorders worldwide. Despite the high prevalence of headache, therapeutic options are limited. We recently identified the delta opioid receptor (DOR) as an emerging therapeutic target for migraine. In this study, we examined the effectiveness of a hallmark DOR agonist, SNC80, in disease models reflecting diverse headache disorders including: chronic migraine, post‐traumatic headache (PTH), medication overuse headache by triptans (MOH), and opioid‐induced hyperalgesia (OIH). To model chronic migraine C57BL/6J mice received chronic intermittent treatment with the known human migraine trigger, nitroglycerin. PTH was modeled by combining the closed head weight drop model with the nitroglycerin model of chronic migraine. For MOH and OIH, mice were chronically treated with sumatriptan or morphine, respectively. The development of periorbital and peripheral allodynia was observed in all four models; and SNC80 significantly inhibited allodynia in all cases. In addition, we also determined if chronic daily treatment with SNC80 would induce MOH/OIH, and we observed limited hyperalgesia relative to sumatriptan or morphine. Together, our results indicate that DOR agonists could be effective in multiple headache disorders, despite their distinct etiology, thus presenting a novel therapeutic target for headache. HighlightsDelta opioid receptor activation inhibits migraine, post‐traumatic headache, and medication overuse headache.Mu opioid receptor agonists can produce opioid induced hyperalgesia, which is inhibited by delta opioid receptor agonist.Chronic treatment with delta opioid receptor agonist produces limited medication overuse headache relative to sumatriptan.