Migraine is a prevalent neurological disease that is characterized by unpredictable episodic attacks of intense head pain. The underlying pathology involves sensitization and activation of the trigeminal system. Although non-invasive vagus nerve stimulation (nVNS) is recommended for the treatment of migraine, the abortive mechanism of action is not well-understood. The goal of this study was to compare the ability of nVNS and sumatriptan to inhibit trigeminal activation in two animal models of episodic migraine and to investigate the receptor mechanism of action of nVNS. Nocifensive head withdrawal response was investigated in adult male Sprague Dawley rats using von Frey filaments. To induce trigeminal nociceptor sensitization, complete Freund's adjuvant was injected in the trapezius muscle and trigeminal neurons were activated by exposure to a pungent odor or injection of the nitric oxide donor sodium nitroprusside. Some animals received nVNS or sumatriptan as treatment. Some animals were injected intracisternally with antagonists of GABA A , 5-HT3 or 5-HT7 receptors prior to nVNS since these receptors are implicated in descending modulation. While unsensitized animals exposed to the pungent odor or nitric oxide alone did not exhibit enhanced mechanical nociception, sensitized animals with neck muscle inflammation displayed increased trigeminal nocifensive responses. The enhanced nociceptive response to both stimuli was attenuated by nVNS and sumatriptan. Administration of antagonists of GABA A , 5-HT3, and 5-HT7 receptors in the upper spinal cord suppressed the anti-nocifensive effect of nVNS. Our findings suggest that nVNS inhibits trigeminal activation to a similar degree as sumatriptan in episodic migraine models via involvement of GABAergic and serotonergic signaling to enhance central descending pain modulation.

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Protein recycling is an essential cellular process involving endocytosis, intracellular trafficking, and exocytosis. In mammalian systems membrane lipids, including cholesterol, sphingolipids, and phospholipids, play a pivotal role in protein recycling. To address this role in budding yeast, Saccharomyces cerevisiae, we utilized GFP-Snc1, a v-SNARE protein serving as a fluorescent marker for faithfully reporting the recycling pathway. Here we demonstrate results that display moderate to significant GFP-Snc1 recycling defects upon overexpression or inactivation of phospholipid, ergosterol, and sphingolipid biosynthesis enzymes, indicating that the homeostasis of membrane lipid levels is prerequisite for proper protein recycling. By using a truncated version of GFP-Snc1 that cannot be recycled from the plasma membrane, we determined that abnormalities in Snc1 localization in membrane lipid overexpression or underexpression mutants are not due to defects in the synthetic/secretory pathway, but rather in the intracellular trafficking pathway. We found that membrane lipid imbalance resulted in an accumulation of the late endosome marker Vps10-GFP, indicating trafficking from the endosomes to the Golgi may be being hindered, preventing recycling to the plasma membrane. To elucidate the possible mechanism for this trafficking hindrance, we stained the actin cytoskeleton, then quantified the percentage of cells with visible actin cables. Compared to wild-type cells, membrane lipid mutant cells exhibited lower levels of actin cables, indicating the actin cytoskeleton is disrupted upon membrane lipid imbalance. Taken together, our results show that impairment of proper recycling may be due to disruption of the actin cytoskeleton, which causes trafficking hindrance between the endosomes and Golgi.

BackgroundThe risk factors neck muscle tension, prolonged jaw opening, and female gender are associated with developing temporomandibular disorders (TMD), which are characterized by persistent sensitization of trigeminal neurons and enhanced pain signaling. Dietary supplementation with a grape seed extract (GSE) can modulate expression of proteins that decrease neuronal excitability and trigeminal sensitization.MethodsMechanical nocifensive thresholds over the masseter were determined using von Frey filaments in male and female adult Sprague Dawley rats. To promote trigeminal sensitization, animals were injected with complete Freund’s adjuvant in the upper trapezius. After 8 days, animals were subjected to near maximal jaw opening and head withdrawal responses were determined for 28 days. Some animals received continuous supplementation with 0.5% GSE in their drinking water two weeks prior to trapezius injections.ResultsProlonged jaw opening increased the average number of nocifensive responses to mechanical stimuli for 14 days in males and females. However, trapezius inflammation prior to jaw opening promoted persistent mechanical sensitivity up to 28 days post‐jaw opening in females, while in males nociceptive levels were still elevated at day 21. Supplementation with GSE, which is enriched in polyphenols and exhibits antioxidant and COX‐2 activity, inhibited trigeminal nociception in response to jaw opening in both male and female sensitized animals.ConclusionsOur findings provide evidence that multiple risk factors contribute to the development of a prolonged state of trigeminal sensitization that is more severe in females and provide preclinical evidence that supplementation with GSE could be beneficial in the management of TMD.

Noninvasive vagus nerve stimulation suppressed persistent trigeminal nociception in a chronic headache model similarly to morphine and may provide a safe, nonaddictive abortive therapy for chronic headache.

Carbon nanomaterials (CNMs), which include carbon nanotubes (CNTs) and their derivatives, have diverse technological and biomedical applications. The potential toxicity of CNMs to cells and tissues has become an important emerging question in nanotechnology. To assess the toxicity of CNTs and fullerenol C60(OH)24, we in the present work used the budding yeast Saccharomyces cerevisiae, one of the simplest eukaryotic organisms that share fundamental aspects of eukaryotic cell biology. We found that treatment with CNMs, regardless of their physical shape, negatively affected the growth rates, end-point cell densities and doubling times of CNM-exposed yeast cells when compared to unexposed cells. To investigate potential mechanisms behind the CNMs-induced growth defects, we performed RNA-Seq dependent transcriptional analysis and constructed global gene expression profiles of fullerenol C60(OH)24- and CNT-treated cells. When compared to non-treated control cells, CNM-treated cells displayed differential expression of genes whose functions are implicated in membrane transporters and stress response, although differentially expressed genes were not consistent between CNT- and fullerenol C60(OH)24-treated groups, leading to our conclusion that CNMs could serve as environmental toxic factors to eukaryotic cells.

Migraine is associated with peripheral and central sensitization of the trigeminal system and dysfunction of descending pain modulation pathways. Recently, dietary inclusion of grape seed extract (GSE) was shown to inhibit mechanical nociception in a preclinical model of chronic temporomandibular joint disorder, a condition often comorbid with migraine, with the antinociceptive effect mediated, in part, by activation of 5-HT3/7 and GABAB receptors. This study further investigated the mechanisms by which GSE inhibits mechanical nociception in a preclinical model of episodic migraine. Hyperalgesic priming of female and male Sprague Dawley rats was induced by three consecutive daily two-hour episodes of restraint stress. Seven days after the final restraint stress, rats were exposed to pungent odors from an oil extract that contains the compound umbellulone, which stimulates CGRP release and induces migraine-like pain. Some animals received dietary supplementation of GSE in their drinking water beginning one week prior to restraint stress. Changes in mechanical sensitivity in the orofacial region and hindpaw were determined using von Frey filaments. To investigate the role of the endocannabinoid receptors in the effect of GSE, some animals were injected intracisternally with the CB1 antagonist AM 251 or the CB2 antagonist AM 630 prior to odor inhalation. Changes in CGRP expression in the spinal trigeminal nucleus (STN) in response to stress, odor and GSE supplementation were studied using immunohistochemistry. Exposure of stress-primed animals to the odor caused a significant increase in the average number of withdrawal responses to mechanical stimulation in both the orofacial region and hindpaw, and the effect was significantly suppressed by daily supplementation with GSE. The anti-nociceptive effect of GSE was inhibited by intracisternal administration of antagonists of CB1 and CB2 receptors. GSE supplementation inhibited odor-mediated stimulation of CGRP expression in the STN in sensitized animals. These results demonstrate that GSE supplementation inhibits trigeminal pain signaling in an injury-free model of migraine-like pain via activation of endocannabinoid receptors and repression of CGRP expression centrally. Hence, we propose that GSE may be beneficial as a complementary migraine therapeutic.