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/6 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.
Background The development of novel migraine therapies has been slow, in part because of the small number of clinically relevant animal models. We have recently developed a new mouse model of chronic migraine using chronic intermittent nitroglycerin, a known human migraine trigger. The objective of this study was to validate this model by testing known and potential migraine-preventive treatments. Methods Migraine therapies were administered to male and female mice for 11 days. On day 3, mice were tested with nitroglycerin every second day for nine days. Basal and nitroglycerin-evoked mechanical hypersensitivity was evaluated using von Frey filaments. Results Chronic intermittent nitroglycerin produced acute hyperalgesia with each administration, and progressive and sustained basal hypersensitivity. The established preventive migraine therapy propranolol effectively blocked the development of acute and chronic nitroglycerin-induced hyperalgesia, while valproate had no effect. Potential migraine-preventive therapies were also tested: Amiloride inhibited nitroglycerin-induced acute and chronic hyperalgesia; while memantine was ineffective. We also tested the acute migraine therapy sumatriptan, which did not alter nitroglycerin-induced hyperalgesia, but instead resulted in acute and chronic hyperalgesia similar to that observed following nitroglycerin administration. Conclusions This study establishes the chronic nitroglycerin model as an additional screening tool to test novel migraine-preventive therapies.
The ␦ opioid receptor (␦R) is a promising alternate target for pain management because ␦R agonists show decreased abuse potential compared with current opioid analgesics that target the opioid receptor. A critical limitation in developing ␦R as an analgesic target, however, is that ␦R agonists show relatively low efficacy in vivo, requiring the use of high doses that often cause adverse effects, such as convulsions. Here we tested whether intracellular retention of ␦R in sensory neurons contributes to this low ␦R agonist efficacy in vivo by limiting surface ␦R expression. Using direct visualization of ␦R trafficking and localization, we define a phosphatase and tensin homolog (PTEN)-regulated checkpoint that retains ␦R in the Golgi and decreases surface delivery in rat and mice sensory neurons. PTEN inhibition releases ␦R from this checkpoint and stimulates delivery of exogenous and endogenous ␦R to the neuronal surface both in vitro and in vivo. PTEN inhibition in vivo increases the percentage of TG neurons expressing ␦R on the surface and allows efficient ␦R-mediated antihyperalgesia in mice. Together, we define a critical role for PTEN in regulating the surface delivery and bioavailability of the ␦R, explain the low efficacy of ␦R agonists in vivo, and provide evidence that active ␦R relocation is a viable strategy to increase ␦R antinociception.
Background Nitric oxide (NO) has been heavily implicated in migraine. Nitroglycerin is a prototypic NO-donor, and triggers migraine in humans. However, nitroglycerin also induces oxidative/nitrosative stress and is a source of peroxynitrite - factors previously linked with migraine etiology. Soluble guanylyl cyclase (sGC) is the high affinity NO receptor in the body, and the aim of this study was to identify the precise role of sGC in acute and chronic migraine. Methods We developed a novel brain-bioavailable sGC stimulator (VL-102), and tested its hyperalgesic properties in mice. We also determined the effect of VL-102 on c-fos and calcitonin gene related peptide (CGRP) immunoreactivity within the trigeminovascular complex. In addition, we also tested the known sGC inhibitor, ODQ, within the chronic nitroglycerin migraine model. Results VL-102-evoked acute and chronic mechanical cephalic and hind-paw allodynia in a dose-dependent manner, which was blocked by the migraine medications sumatriptan, propranolol, and topiramate. In addition, VL-102 also increased c-fos and CGRP expressing cells within the trigeminovascular complex. Importantly, ODQ completely inhibited acute and chronic hyperalgesia induced by nitroglycerin. ODQ also blocked hyperalgesia already established by chronic nitroglycerin, implicating this pathway in migraine chronicity. Conclusions These results indicate that nitroglycerin causes migraine-related pain through stimulation of the sGC pathway, and that super-activation of this receptor may be an important component for the maintenance of chronic migraine. This work opens the possibility for negative sGC modulators as novel migraine therapies.
Overall, these results suggest that δ receptor agonists interact with arrestins in a ligand-specific manner, and tolerance to high- but not low-internalizing agonists are preferentially regulated by arrestin 2.
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