Assessment of the Effects of Dietary Vitamin D Levels on Olanzapine-Induced Metabolic Side Effects: Focus on the Endocannabinoidome-Gut Microbiome Axis.

Vitamin D deficiency is associated with poor mental health and dysmetabolism. Several metabolic abnormalities are associated with psychotic diseases, which can be compounded by atypical antipsychotics that induce weight gain and insulin resistance. These side-effects may be affected by vitamin D levels. The gut microbiota and endocannabinoidome (eCBome) are significant regulators of both metabolism and mental health, but their role in the development of atypical antipsychotic drug metabolic side-effects and their interaction with vitamin D status is unknown. We studied the effects of different combinations of vitamin D levels and atypical antipsychotic drug (olanzapine) exposure on whole-body metabolism and the eCBome-gut microbiota axis in female C57BL/6J mice under a high fat/high sucrose (HFHS) diet in an attempt to identify a link between the latter and the different metabolic outputs induced by the treatments. Olanzapine exerted a protective effect against diet-induced obesity and insulin resistance, largely independent of dietary vitamin D status. These changes were concomitant with olanzapine-mediated decreases in Trpv1 expression and increases in the levels of its agonists, including various N-acylethanolamines and 2-monoacylglycerols, which are consistent with the observed improvement in adiposity and metabolic status. Furthermore, while global gut bacteria community architecture was not altered by olanzapine, we identified changes in the relative abundances of various commensal bacterial families. Taken together, changes of eCBome and gut microbiota families under our experimental conditions might contribute to olanzapine and vitamin D-mediated inhibition of weight gain in mice on a HFHS diet.

Capsaicin 8% dermal patch in clinical practice: an expert opinion.

INTRODUCTION: Neuropathic pain (NP) is caused by a lesion or disease of the somatosensory system, which can severely impact patients' quality of life. The current-approved treatments for NP comprise of both centrally acting agents and topical drugs, including capsaicin 8% dermal patches, which is approved for the treatment of peripheral NP. AREAS COVERED: The authors summarize literature data regarding capsaicin use in patients who suffer from NP and discuss the clinical applications of this topical approach. EXPERT OPINION: Overall, the capsaicin 8% dermal patch is as effective in reducing pain intensity as other centrally active agents (i.e. pregabalin). Some studies have also reported fewer systemic side effects, a faster onset of action and superior treatment satisfaction compared with systemic agents. In our opinion, capsaicin 8% dermal patches also present additional advantages, such as a good systemic tolerability, the scarcity of adverse events, the possibility to combine it with other agents, and a good cost-effective profile. It is important to note that, as the mechanism of action of capsaicin 8% is the 'defunctionalization' of small afferent fibers through interaction with TRPV1 receptors, the peripheral expression of this receptor on nociceptor fibers, is crucial to predict patient's response to treatment.

Transient Receptor Potential Vanilloid 4 and Serum Glucocorticoid-regulated Kinase 1 Are Critical Mediators of Lung Injury in Overventilated Mice In Vivo.

BACKGROUND: Mechanical ventilation can cause lung endothelial barrier failure and inflammation cumulating in ventilator-induced lung injury. Yet, underlying mechanotransduction mechanisms remain unclear. Here, the authors tested the hypothesis that activation of the mechanosensitive Ca channel transient receptor potential vanilloid (TRPV4) by serum glucocorticoid-regulated kinase (SGK) 1 may drive the development of ventilator-induced lung injury. METHODS: Mice (total n = 54) were ventilated for 2 h with low (7 ml/kg) or high (20 ml/kg) tidal volumes and assessed for signs of ventilator-induced lung injury. Isolated-perfused lungs were inflated with continuous positive airway pressures of 5 or 15 cm H2O (n = 7 each), and endothelial calcium concentration was quantified by real-time imaging. RESULTS: Genetic deficiency or pharmacologic inhibition of TRPV4 or SGK1 protected mice from overventilation-induced vascular leakage (reduction in alveolar protein concentration from 0.84 ± 0.18 [mean ± SD] to 0.46 ± 0.16 mg/ml by TRPV4 antagonization), reduced lung inflammation (macrophage inflammatory protein 2 levels of 193 ± 163 in Trpv4 vs. 544 ± 358 pmol/ml in wild-type mice), and attenuated endothelial calcium responses to lung overdistension. Functional coupling of TRPV4 and SGK1 in lung endothelial mechanotransduction was confirmed by proximity ligation assay demonstrating enhanced TRPV4 phosphorylation at serine 824 at 18% as compared to 5% cyclic stretch, which was prevented by SGK1 inhibition. CONCLUSIONS: Lung overventilation promotes endothelial calcium influx and barrier failure through a mechanism that involves activation of TRPV4, presumably due to phosphorylation at its serine 824 residue by SGK1. TRPV4 and SGK1 may present promising new targets for prevention or treatment of ventilator-induced lung injury.

Low-cost functional plasticity of TRPV1 supports heat tolerance in squirrels and camels.

The ability to sense heat is crucial for survival. Increased heat tolerance may prove beneficial by conferring the ability to inhabit otherwise prohibitive ecological niches. This phenomenon is widespread and is found in both large and small animals. For example, ground squirrels and camels can tolerate temperatures more than 40 °C better than many other mammalian species, yet a molecular mechanism subserving this ability is unclear. Transient receptor potential vanilloid 1 (TRPV1) is a polymodal ion channel involved in the detection of noxious thermal and chemical stimuli by primary afferents of the somatosensory system. Here, we show that thirteen-lined ground squirrels (Ictidomys tridecemlineatus) and Bactrian camels (Camelus ferus) express TRPV1 orthologs with dramatically reduced temperature sensitivity. The loss of sensitivity is restricted to temperature and does not affect capsaicin or acid responses, thereby maintaining a role for TRPV1 as a detector of noxious chemical cues. We show that heat sensitivity can be reengineered in both TRPV1 orthologs by a single amino acid substitution in the N-terminal ankyrin-repeat domain. Conversely, reciprocal mutations suppress heat sensitivity of rat TRPV1, supporting functional conservation of the residues. Our studies suggest that squirrels and camels co-opt a common molecular strategy to adapt to hot environments by suppressing the efficiency of TRPV1-mediated heat detection at the level of somatosensory neurons. Such adaptation is possible because of the remarkable functional flexibility of the TRPV1 molecule, which can undergo profound tuning at the minimal cost of a single amino acid change.

Stochastic model of endothelial TRPV4 calcium sparklets: effect of bursting and cooperativity on EDH.

We examined the endothelial transient receptor vanilloid 4 (TRPV4) channel's vasodilatory signaling using mathematical modeling. The model analyzes experimental data by Sonkusare and coworkers on TRPV4-induced endothelial Ca(2+) events (sparklets). A previously developed continuum model of an endothelial and a smooth muscle cell coupled through microprojections was extended to account for the activity of a TRPV4 channel cluster. Different stochastic descriptions for the TRPV4 channel flux were examined using finite-state Markov chains. The model also took into consideration recent evidence for the colocalization of intermediate-conductance calcium-activated potassium channels (IKCa) and TRPV4 channels near the microprojections. A single TRPV4 channel opening resulted in a stochastic localized Ca(2+) increase in a small region (i.e., few µm(2) area) close to the channel. We predict micromolar Ca(2+) increases lasting for the open duration of the channel sufficient for the activation of low-affinity endothelial KCa channels. Simulations of a cluster of four TRPV4 channels incorporating burst and cooperative gating kinetics provided quantal Ca(2+) increases (i.e., steps of fixed amplitude), similar to the experimentally observed Ca(2+) sparklets. These localized Ca(2+) events result in endothelium-derived hyperpolarization (and SMC relaxation), with magnitude that depends on event frequency. The gating characteristics (bursting, cooperativity) of the TRPV4 cluster enhance Ca(2+) spread and the distance of KCa channel activation. This may amplify the EDH response by the additional recruitment of distant KCa channels.

Neuromodulatory and anti-inflammatory ingredient for sensitive skin: in vitro assessment.

The manifestation of sensitive skin occurs as a consequence of increased permeability of the Stratum corneum, besides the involvement of neuro-immune-endocrine system. In this study, we evaluated the effects of an active ingredient SensC on the production of neuropeptides substance P (SP), enkephalin and ß-endorphin; eicosanoids prostaglandin E2 (PGE2) and leukotriene B4 (LTB4); histamine, transient receptor potential vanilloid subfamily member 1 (TRPV1), and envelope proteins filaggrin and involucrin, using an in vitro model of human cell culture. Our results demonstrated that treatment of keratinocyte cultures with SensC prevented the increase of all evaluated inflammatory mediators induced by interleukin-1 alpha (IL-1α). As the same way, SensC provides decrease in the synthesis of TRPV1. Regarding the synthesis of envelope proteins, SensC promoted increases for filaggrin and involucrin levels, when compared to control group. Considering the absence of appropriate treatment, the availability of ingredients, such as SensC, with antiinflammatory and protective barrier properties can be a significant tool for preventing neurosensorial symptoms associated with sensitive skin.

New treatments for headache.

Migraine and cluster headache are primary headache disorders commonly encountered in clinical practice. Despite the profound disability caused by these primary headache disorders, available acute and preventive treatment options are limited. Recent understanding of headache pathophysiology has led to the development of new drug formulations and novel drug targets that are extremely promising. This article will highlight several of the new treatments that are currently under investigation including novel delivery mechanisms of already existing medications, calcitonin gene-related peptide (CGRP) receptor antagonists, antibodies to CGRP and its receptor, serotonin receptor agonists, transient receptor potential vanilloid receptor modulators, orexin receptor antagonists, glial cell modulators, and neuromodulation. If data is supportive, these therapies will be welcome additions to the headache specialist's armamentarium.

Assessment of the biological similarity of three capsaicin analogs (Capsinoids) found in non-pungent chili pepper (CH-19 Sweet) fruits.

CH-19 Sweet is a newly found chili pepper breed bearing much less pungent fruits. Because CH-19 Sweet fruits were found to contain three analogs (capsinoids) of capsaicin, a major component of pungency of hot peppers (the analogs are capsiate or CST, dihydrocapsiate or DCT, and nordihydrocapsiate or NDCT), we assessed in this study the bio-potencies of these three capsinoids by comparing them with capsaicin. The three capsinoids bound to transient potential vanilloid 1 (TRPV1) receptors expressed in cultured cells and activated Ca(2+) influx in a concentration-dependent manner with similar magnitudes. In contrast to capsaicin, capsinoids at the same concentration induced virtually no nociceptive responses when applied to the eyes or the oral cavities of mice. Intravenous administration of capsaicin or 20-fold increased doses of each capsinoid to rats induced significant increases in plasma catecholamine levels. Orally administered, each capsinoid enhanced oxygen consumption in mice. Based on the present results, capsaicin and these three capsinoids should have similar bio-potency, though capsinoids do not generate pungency or sensory irritation.

Behavioral assessment and identification of a molecular marker in a salicylate-induced tinnitus in rats.

Tinnitus is a non-observable phantom sensation. As such, it is a difficult condition to investigate and, to date, no effective treatment has been developed. To approach this phantom sensation, we aimed to develop a rat behavioral model of tinnitus using salicylate, an active component of aspirin known to induce tinnitus. We also aimed to establish a molecular marker of tinnitus by assessing the expression of transient receptor potential cation channel superfamily V-1 (TRPV1) in the rat auditory pathway during salicylate-induced tinnitus. Animals were trained to perform "an active avoidance task": animals were conditioned by electrical footshock to move to the other side of the conditioning box when hearing a sound. Animals received a single injection of saline or salicylate (400 mg/kg i.p.) and false positive responses were measured 2 h after injection as the number of movements during a silent period. The number of responses in salicylate-treated animals was highest when the conditioned stimulus was 60 dB sound pressure level (SPL) and 16 kHz. This indicates that animals could feel tinnitus 2 h after salicylate injection, equivalent to that induced by 60 dB SPL and 16 kHz. By means of real-time PCR and western blot analysis, TRPV1 expression was significantly upregulated in spiral ganglion cells 2 h after salicylate injection and this upregulation together with the increase in the number of false positive responses was significantly suppressed by capsazepine (10 mg/kg i.p.), a specific antagonist of TRPV1. This suggests that salicylate could induce tinnitus through activation of TRPV1 in the rat auditory pathway.

Use of the novel Contact Heat Evoked Potential Stimulator (CHEPS) for the assessment of small fibre neuropathy: correlations with skin flare responses and intra-epidermal nerve fibre counts.

BACKGROUND: The Contact Heat Evoked Potential Stimulator (CHEPS) rapidly stimulates cutaneous small nerve fibres, and resulting evoked potentials can be recorded from the scalp. We have studied patients with symptoms of sensory neuropathy and controls using CHEPS, and validated the findings using other objective measures of small nerve fibres i.e. the histamine-induced skin flare response and intra-epidermal fibres (IEF), and also quantitative sensory testing (QST), a subjective measure. METHODS: In patients with symptoms of sensory neuropathy (n = 41) and healthy controls (n = 9) we performed clinical examination, QST (monofilament, vibration and thermal perception thresholds), nerve conduction studies, histamine-induced skin flares and CHEPS. Skin punch biopsies were immunostained using standard ABC immunoperoxidase for the nerve marker PGP 9.5 or the heat and capsaicin receptor TRPV1. Immunoreactive IEF were counted per length of tissue section and epidermal thickness recorded. RESULTS: Amplitudes of Adelta evoked potentials (muV) following face, arm or leg stimulation were reduced in patients (e.g. for the leg: mean +/- SEM - controls 11.7 +/- 1.95, patients 3.63 +/- 0.85, p = 0.0032). Patients showed reduced leg skin flare responses, which correlated with Adelta amplitudes (rs = 0.40, p = 0.010). In patient leg skin biopsies, PGP 9.5- and TRPV1-immunoreactive IEF were reduced and correlated with Adelta amplitudes (PGP 9.5, rs = 0.51, p = 0.0006; TRPV1, rs = 0.48, p = 0.0012). CONCLUSION: CHEPS appears a sensitive measure, with abnormalities observed in some symptomatic patients who did not have significant IEF loss and/or QST abnormalities. Some of the latter patients may have early small fibre dysfunction or ion channelopathy. CHEPS provides a clinically practical, non-invasive and objective measure, and can be a useful additional tool for the assessment of sensory small fibre neuropathy. Although further evaluation is required, the technique shows potential clinical utility to differentiate neuropathy from other chronic pain states, and provide a biomarker for analgesic development.