Abstract
Delta opioid receptor (DOR) agonists have been identified as a promising novel therapy for headache disorders. DORs are broadly expressed in several peripheral and central regions important for pain processing and mood regulation; and it is unclear which receptors regulate headache associated symptoms. In a model of chronic migraine-associated pain using the human migraine trigger, nitroglycerin, we observed increased expression of DOR in cortex, hippocampus, and striatum; suggesting a role for these forebrain regions in the regulation of migraine. To test this hypothesis, we used conditional knockout mice with DORs deleted from forebrain GABAergic neurons (Dlx-DOR), and investigated the outcome of this knockout on the effectiveness of the DOR agonist SNC80 in multiple headache models. In DOR loxP controls SNC80 blocked the development of acute and chronic cephalic allodynia in the chronic nitroglycerin model, an effect that was lost in Dlx-DOR mice. In addition, the anti-allodynic effects of SNC80 were lost in a model of opioid induced hyperalgesia/medication overuse headache in Dlx-DOR conditional knockouts. In a model reflecting negative affect associated with migraine, SNC80 was only effective in loxP controls and not Dlx-DOR mice. Similarly, SNC80 was ineffective in the cortical spreading depression model of migraine aura in conditional knockout mice. Taken together, these data indicate that forebrain DORs are necessary for the action of DOR agonists in relieving headache-related symptoms and suggest that forebrain regions may play an important role in migraine modulation.
Highlights
Delta opioid receptor (DOR) agonists have been identified as a promising novel therapy for headache disorders
SNC80 was found to inhibit allodynia associated with post-traumatic headache, medication overuse headache (MOH) induced by overuse of sumatriptan, and OIH12,13
Effect of NTG on DOR‐eGFP expression. δ receptors are abundantly expressed in forebrain regions such as the hippocampus, somatosensory cortex, and striatum
Summary
Delta opioid receptor (DOR) agonists have been identified as a promising novel therapy for headache disorders. In a model of chronic migraine-associated pain using the human migraine trigger, nitroglycerin, we observed increased expression of DOR in cortex, hippocampus, and striatum; suggesting a role for these forebrain regions in the regulation of migraine To test this hypothesis, we used conditional knockout mice with DORs deleted from forebrain GABAergic neurons (Dlx-DOR), and investigated the outcome of this knockout on the effectiveness of the DOR agonist SNC80 in multiple headache models. In a conditional knockout mouse with δ receptors deleted from peripheral voltage-gated sodium channel N av1.8-expressing neurons ( Nav1.8-DOR), δ agonist-induced anti-hyperalgesic effects were abolished in the Complete Freund’s Adjuvant (CFA) and the sciatic nerve ligation models[17,18] These data indicate that peripheral δ receptors are critical for regulating peripheral inflammatory and neuropathic pain, respectively. In a migraine model the peripherally restricted opioid antagonist N-methylnaltrexone failed to block SNC80-induced inhibition of NTG-evoked thermal hyperalgesia, suggesting a role for central δ receptors in migraine-associated pain[9]
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