T-type calcium channels in chronic pain: mouse models and specific blockers

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Design of Phosphonated Imidazolium-Based Ionic Liquids Grafted on γ-Alumina: Potential Model for Hybrid Membranes

International audienceImidazolium bromide-based ionic liquids bearing phosphonyl groups on the cationic part were synthesized and grafted on gamma-alumina (gamma-Al2O3) powders. These powders were prepared as companion samples of conventional mesoporous gamma-alumina membranes, in order to favor a possible transfer of the results to supported membrane materials, which could be used for CO2 separation applications. Effective grafting was demonstrated using energy dispersive X-ray spectrometry (EDX), N2 adsorption measurements, fourier transform infrared spectroscopy (FTIR), and special attention was paid to 31P and 13C solid state nuclear magnetic resonance spectroscopy (NMR)

Spatiotemporal dynamics of 5-HT6 receptor ciliary localization during mouse brain development

International audienceThe serotonin 5-HT6 receptor (5-HT6R) is a promising target to improve cognitive symptoms of psychiatric diseases of neurodevelopmental origin, such as autism spectrum disorders and schizophrenia. However, its expression and localization at different stages of brain development remain largely unknown, due to the lack of specific antibodies to detect endogenous 5-HT6R. Here, we used transgenic mice expressing a GFP-tagged 5-HT6R under the control of its endogenous promoter (Knock-in) as well as embryonic stem cells expressing the GFP-tagged receptor to extensively characterize its expression at cellular and subcellular levels during development. We show that the receptor is already expressed at E13.5 in the cortex, the striatum, the ventricular zone, and to a lesser extent the subventricular zone. In adulthood, it is preferentially found in projection neurons of the hippocampus and cerebral cortex, in striatal medium-sized spiny neurons, as well as in a large proportion of astrocytes, while it is expressed in a minor population of interneurons. Whereas the receptor is almost exclusively detected in the primary cilia of neurons at embryonic and adult stages and in differentiated stem cells, it is located in the somatodendritic compartment of neurons from some brain regions at the neonatal stage and in the soma of undifferentiated stem cells. Finally, knocking-out the receptor induces a shortening of the primary cilium, suggesting that it plays a role in its function. This study provides the first global picture of 5-HT6R expression pattern in the mouse brain at different developmental stages. It reveals dynamic changes in receptor localization in neurons at the neonatal stage, which might underlie its key role in neuronal differentiation and psychiatric disorders of neurodevelopmental origin

Human serum albumin nanoparticles as nanovector carriers for proteins: Application to the antibacterial proteins “neutrophil elastase” and “secretory leukocyte protease inhibitor”

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Initial Steps toward the Development of Grafted Ionic Liquid Membranes for the Selective Transport of CO2

This work reports on a promising strategy for the development of novel grafted ionic liquid membranes (GILMs) in which phosphonate-based ILs are confined within the pores of a mesoporous γ-Al2O3 ceramic membrane by chemical grafting. The effect of both the chemical nature (i.e., alkyl versus ether) of the organic spacer chain and the presence of phosphonate coupling functions were evidenced as crucial parameters influencing CO2 transport through the membranes. The effectiveness of the grafting procedure yielding GILMs was clearly demonstrated by Fourier transform infrared spectroscopy and high resolution-magic angle spinning NMR, and attractive membrane performance was evidenced through both the CO2/N2 ideal selectivity (∼140) and CO2 permeability (∼130 Barrer)

Epigenetics Involvement in Oxaliplatin-Induced Potassium Channel Transcriptional Downregulation and Hypersensitivity

International audiencePeripheral neuropathy is the most frequent dose-limiting adverse effect of oxaliplatin. Acute pain symptoms that are induced or exacerbated by cold occur in almost all patients immediately following the first infusions. Evidence has shown that oxaliplatin causes ion channel expression modulations in dorsal root ganglia neurons, which are thought to contribute to peripheral hypersensitivity. Most dysregulated genes encode ion channels involved in cold and mechanical perception, noteworthy members of a sub-group of potassium channels of the K2P family, TREK and TRAAK. Downregulation of these K2P channels has been identified as an important tuner of acute oxaliplatin-induced hypersensitivity. We investigated the molecular mechanisms underlying this peripheral dysregulation in a murine model of neuropathic pain triggered by a single oxaliplatin administration. We found that oxaliplatin-mediated TREK-TRAAK downregulation, as well as downregulation of other K+ channels of the K2P and Kv families, involves a transcription factor known as the neuron-restrictive silencer factor (NRSF) and its epigenetic co-repressors histone deacetylases (HDACs). NRSF knockdown was able to prevent most of these K+ channel mRNA downregulation in mice dorsal root ganglion neurons as well as oxaliplatin-induced acute cold and mechanical hypersensitivity. Interestingly, pharmacological inhibition of class I HDAC reproduces the antinociceptive effects of NRSF knockdown and leads to an increased K+ channel expression in oxaliplatin-treated mice

The Low-Threshold Calcium Channel Cav3.2 Determines Low-Threshold Mechanoreceptor Function

The T-type calcium channel Cav3.2 emerges as a key regulator of sensory functions, but its expression pattern within primary afferent neurons and its contribution to modality-specific signaling remain obscure. Here, we elucidate this issue using a unique knockin/flox mouse strain wherein Cav3.2 is replaced by a functional Cav3.2-surface-ecliptic GFP fusion. We demonstrate that Cav3.2 is a selective marker of two major low-threshold mechanoreceptors (LTMRs), Aδ- and C-LTMRs, innervating the most abundant skin hair follicles. The presence of Cav3.2 along LTMR-fiber trajectories is consistent with critical roles at multiple sites, setting their strong excitability. Strikingly, the C-LTMR-specific knockout uncovers that Cav3.2 regulates light-touch perception and noxious mechanical cold and chemical sensations and is essential to build up that debilitates allodynic symptoms of neuropathic pain, a mechanism thought to be entirely A-LTMR specific. Collectively, our findings support a fundamental role for Cav3.2 in touch/pain pathophysiology, validating their critic pharmacological relevance to relieve mechanical and cold allodynia

Oxaliplatin-induced cold hypersensitivity is due to remodeling of ion channels in nociseptors

L’oxaliplatine, largement utilisé dans le traitement du cancer colorectal, est susceptible d’induire précocement des dysesthésies pharyngées et des extrémités, majorées par l’exposition au froid. Il s’agit d’une toxicité cumulative et limitante. L’efficacité des traitements actuellement disponibles est médiocre, ce qui justifie d’évaluer de nouvelles approches pharmacologiques. Le but de ce travail est de développer un modèle de souris reproduisant cette hypersensibilité au froid afin d’en étudier les mécanismes physiopathologiques. Comme chez les patients, l’administration d’oxaliplatine entraîne une amplification importante de la perception du froid chez la souris. Nous montrons que ces symptômes sont médiés par les nocicepteurs exprimant le thermorécepteur TRPM8. D’un point de vue physiopathologique, l’oxaliplatine favorise l’excitabilité de ces nocicepteurs en diminuant l’expression de plusieurs canaux potassiques (TREK1 et TRAAK en particulier), et en augmentant l’expression de canaux pro excitateurs tels que les canaux cationiques activés par l’hyperpolarisation (HCN1 notamment). Ces constatations sont confortées, au niveau comportemental, par l’analyse de la lignée de souris invalidées pour TREK1 et TRAAK et par l’utilisation de l’ivabradine, un inhibiteur pharmacologique spécifique des canaux HCNs. L’ivabradine, déjà utilisé en clinique pour le traitement de l’insuffisance cardiaque, entraîne une suppression de l’hypersensibilité au froid induite par l’oxaliplatine. L’ensemble de ces résultats suggère que l’oxaliplatine exacerbe la perception du froid en remodelant le patron d’expression de plusieurs canaux ioniques qui coordonnent la réponse au froid. Ils constituent un rationnel pour l’évaluation de l’ivabradine dans le traitement des neuropathies induites par l’oxaliplatine.The hallmark of oxaliplatin-induced neuropathy is a hypersensibility to cold that develops in nearly all patients ultimately leading to cessation of this chemotherapy treatment. To date, classical pain management strategies have failed to alleviate these painful symptoms, and hence there is a need for developing new and efficient pharmacologic agents. Here we report that, as in patients, oxaliplatin mediates a clear development of exaggerated perception of cold temperatures in mice. These symptoms are mediated by nociceptors expressing the thermoreceptor TRPM8. Mechanistically, we find that oxaliplatin promotes excitability in nociceptors drastically lowering the expression of distinct potassium channels (TREK1, TRAAK) that act as excitability brakes for cold perception, and by increasing the expression of pro-excitatory channels such as the hyperpolarisation-activated channels (HCNs). These findings are corroborated by the analysis of the TREK1-TRAAK null mice, and by the use a specific HCN channel inhibitor abolishing the oxaliplatin-induced cold hypersensibility. Collectively, these results suggest that oxaliplatin exacerbates cold perception in cold sensing neurons by transcriptionally remodeling a combination of ionic conductances that together shape the final response to cold. A direct promising clinical consequence of these findings for patients would be that the HCN inhibitor ivabradine could represent a tailored treatment for oxaliplatin-induced neuropathy

Oxaliplatin‐induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors

International audienceCold hypersensitivity is the hallmark of oxaliplatin-induced neuropathy, which develops in nearly all patients under this chemotherapy. To date, pain management strategies have failed to alleviate these symptoms, hence development of adapted analgesics is needed. Here, we report that oxaliplatin exaggerates cold perception in mice as well as in patients. These symptoms are mediated by primary afferent sensory neurons expressing the thermoreceptor TRPM8. Mechanistically, oxaliplatin promotes over-excitability by drastically lowering the expression of distinct potassium channels (TREK1, TRAAK) and by increasing the expression of pro-excitatory channels such as the hyperpolarization-activated channels (HCNs). These findings are corroborated by the analysis of TREK1-TRAAK null mice and use of the specific HCN inhibitor ivabradine, which abolishes the oxaliplatin-induced cold hypersensibility. These results suggest that oxali-platin exacerbates cold perception by modulating the transcription of distinct ionic conductances that together shape sensory neuron responses to cold. The translational and clinical implication of these findings would be that ivabradine may represent a tailored treatment for oxaliplatin-induced neuropathy