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Hemiplegic migraine (HM) is a rare form of migraine characterized by the presence of a motor and other types of aura. HM can be sporadic or familial. Familial hemiplegic migraine (FHM) is an autosomal dominant disorder, classified into 3 subtypes, based on the gene involved (CACNA1A in FHM1, ATP1A2 in FHM2 and SCN1A in FHM3). The clinical presentation is highly heterogeneous and some attacks may be severe. We report the clinical characteristics and genetic analysis of 12 patients belonging to a family with CACNA1A-p.Thr501Met gene mutation.
Learn More >Neuropathic pain (NP) is a clinical symptom that accompanies many diseases. We investigated the effect of receptor-interacting protein kinase 3 (RIP3)-regulated necroptosis on NP, and explore its relationship with microglia, in order to provide a theoretical basis for further research and provide new insights into the treatment of NP. In this study, the spared nerve injury (SNI) model was used along with intervention with necrostatin and the inhibitor of necroptosis necrostatin-1 (Nec-1). Pain behavior tests were performed 1 and 3 days before the nerve injury (or sham) operation, and on days 1, 3, 5, 7, 10 and 14 after the operation. The spinal cord tissues were collected for detection of RIP3 expression and distribution, changes in the number of microglia cells, activation of necroptosis, and the level of pro-inflammatory factors. Collected spinal cord tissues were analysed using western blot, immunohistochemistry, immunofluorescence, immunoprecipitation assays and ELISA, respectively. We found that, compared with the sham group, the expression of RIP3 protein in the spinal cord of rats in the SNI group increased from 3 days to 14 days after surgery. Immunofluorescence staining showed that RIP3 was co-expressed with the microglia and the number of microglia increased significantly in the SNI model group. The results of immunoprecipitation assays suggested that a RIP3-mediated necroptosis pathway promotes NP. After treatment with Nec-1, the expression of RIP3 protein and the number of microglia was significantly reduced, and the expression levels of TNF-α, IL-1β and IL-6 in spinal dorsal horns were significantly decreased. These results indicate that RIP3 promotes necroptosis to increase the occurrence of NP via microglia.
Learn More >Biofeedback is effective in treating migraines. It is believed to have a beneficial effect on autonomous nervous system activity and render individuals resilient to stressors that may trigger a migraine. However, widespread use of biofeedback is hampered by the need for a trained therapist and specialized equipment. Emerging digital health technology, including smartphones and wearables (mHealth), enables new ways of administering biofeedback. Currently, mHealth interventions for migraine appear feasible, but development processes and usability testing remain insufficient.
Learn More >Allergic inflammation is often the result of a dysregulated Th2 immune response, IgE production, and the release of allergic mediators such as histamine or leukotrienes (LTs) by basophils and mast cells (MCs). Allergic diseases can manifest as acute allergic reactions (anaphylaxis), or as chronic allergic inflammation in chronic urticaria, allergic rhinitis, allergic asthma, and atopic dermatitis (AD). Common allergic symptoms such as sneezing, airway mucus secretion, and chronic itch are caused by interactions between immune cells and sensory neurons in the inflamed tissue.
Learn More >Opioid analgesics are essential in clinical practice, but their excessive use is associated with addiction risk. Increases in opioid prescription rates have fuelled an epidemic of opioid addiction in the USA, making statistics on medical opioid use a critical warning signal. A dramatic 150% increase in Swedish opioid access 2001-2013 was recently reported based on data from the International Narcotics Control Board (INCB; Berterame et al. 2016) in conflict with other studies of opioid use in the Nordic countries. This article aims to analyse to what degree published INCB statistics on opioids in Scandinavia (Denmark, Norway and Sweden) reflect actual medical use and study the methodological reasons for putative discrepancies.
Learn More >Multiple factors are involved in the physiology and variability of postsurgical pain, a great part of which can be explained by genetic and environmental factors and their interaction. Epigenetics refers to the mechanism by which the environment alters the stability and expression of genes. We conducted a scoping review to examine the available evidence in both animal models and clinical studies on epigenetic mechanisms involved in regulation of postsurgical and chronic postsurgical pain.
Learn More >Loss of function mutations of SCN1A, the gene coding for the voltage-gated sodium channel NaV1.1, cause different types of epilepsy, whereas gain of function mutations cause sporadic and familial hemiplegic migraine type 3 (FHM-3). However, it is not clear yet how these opposite effects can induce paroxysmal pathological activities involving neuronal networks' hyperexcitability that are specific of epilepsy (seizures) or migraine (cortical spreading depolarization, CSD). To better understand differential mechanisms leading to the initiation of these pathological activities, we used a two-neuron conductance-based model of interconnected GABAergic and pyramidal glutamatergic neurons, in which we incorporated ionic concentration dynamics in both neurons. We modeled FHM-3 mutations by increasing the persistent sodium current in the interneuron and epileptogenic mutations by decreasing the sodium conductance in the interneuron. Therefore, we studied both FHM-3 and epileptogenic mutations within the same framework, modifying only two parameters. In our model, the key effect of gain of function FHM-3 mutations is ion fluxes modification at each action potential (in particular the larger activation of voltage-gated potassium channels induced by the NaV1.1 gain of function), and the resulting CSD-triggering extracellular potassium accumulation, which is not caused only by modifications of firing frequency. Loss of function epileptogenic mutations, on the other hand, increase GABAergic neurons' susceptibility to depolarization block, without major modifications of firing frequency before it. Our modeling results connect qualitatively to experimental data: potassium accumulation in the case of FHM-3 mutations and facilitated depolarization block of the GABAergic neuron in the case of epileptogenic mutations. Both these effects can lead to pyramidal neuron hyperexcitability, inducing in the migraine condition depolarization block of both the GABAergic and the pyramidal neuron. Overall, our findings suggest different mechanisms of network hyperexcitability for migraine and epileptogenic NaV1.1 mutations, implying that the modifications of firing frequency may not be the only relevant pathological mechanism.
Learn More >Previous studies suggest that adenosine A receptors (AR) modulate the processing of pain. The aim of this study was to characterize the distribution of AR in nociceptive tissues and to evaluate whether targeting AR with the partial agonist capadenoson may reduce neuropathic pain in mice. The cellular distribution of AR in dorsal root ganglia (DRG) and the spinal cord was analyzed using fluorescent in situ hybridization. In behavioral experiments, neuropathic pain was induced by spared nerve injury or intraperitoneal injection of paclitaxel, and tactile hypersensitivities were determined using a dynamic plantar aesthesiometer. Whole-cell patch-clamp recordings were performed to assess electrophysiological properties of dissociated DRG neurons. We found AR to be expressed in populations of DRG neurons and dorsal horn neurons involved in the processing of pain. However, administration of capadenoson at established in vivo doses (0.03-1.0 mg/kg) did not alter mechanical hypersensitivity in the spared nerve injury and paclitaxel models of neuropathic pain, whereas the standard analgesic pregabalin significantly inhibited the pain behavior. Moreover, capadenoson failed to affect potassium currents in DRG neurons, in contrast to a full AR agonist. Despite expression of AR in nociceptive neurons, our data do not support the hypothesis that pharmacological intervention with partial AR agonists might be a valuable approach for the treatment of neuropathic pain.
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