Somatosensory profiling of patients undergoing alcohol withdrawal: Do neuropathic pain and sensory loss represent a problem?

Chronic heavy alcohol use is known to cause neurological complications such as peripheral neuropathy. Concerning the pathophysiology, few sural nerve and skin biopsy studies showed that small fibers might be selectively vulnerable to degeneration in alcohol-related peripheral neuropathy. Pain has rarely been properly evaluated in this pathology. The present study aims at assessing pain intensity, potential neuropathic characteristics as well as the functionality of both small and large nerve sensitive fibers. In this observational study, 27 consecutive adult patients, hospitalized for alcohol withdrawal and 13 healthy controls were recruited. All the participants underwent a quantitative sensory testing (QST) according to the standardized protocol of the German Research Network Neuropathic Pain, a neurological examination and filled standardized questionnaires assessing alcohol consumption and dependence as well as pain characteristics and psychological comorbidities. Nearly half of the patients (13/27) reported pain. Yet, pain intensity was weak, leading to a low interference with daily life, and its characteristics did not support a neuropathic component. A functional impairment of small nerve fibers was frequently described, with thermal hypoesthesia observed in 52% of patients. Patients with a higher alcohol consumption over the last 2 years showed a greater impairment of small fiber function. Patients report pain but it is however unlikely to be caused by peripheral neuropathy given the non-length-dependent distribution and the absence of neuropathic pain features. Chronic pain in AUD deserves to be better evaluated and managed as it represents an opportunity to improve long-term clinical outcomes, potentially participating to relapse prevention

Cortico-autonomic local arousals and heightened somatosensory arousability during NREMS of mice in neuropathic pain.

Frequent nightly arousals typical for sleep disorders cause daytime fatigue and present health risks. As such arousals are often short, partial, or occur locally within the brain, reliable characterization in rodent models of sleep disorders and in human patients is challenging. We found that the EEG spectral composition of non-rapid eye movement sleep (NREMS) in healthy mice shows an infraslow (~50 s) interval over which microarousals appear preferentially. NREMS could hence be vulnerable to abnormal arousals on this time scale. Chronic pain is well-known to disrupt sleep. In the spared nerve injury (SNI) mouse model of chronic neuropathic pain, we found more numerous local cortical arousals accompanied by heart rate increases in hindlimb primary somatosensory, but not in prelimbic, cortices, although sleep macroarchitecture appeared unaltered. Closed-loop mechanovibrational stimulation further revealed higher sensory arousability. Chronic pain thus preserved conventional sleep measures but resulted in elevated spontaneous and evoked arousability. We develop a novel moment-to-moment probing of NREMS vulnerability and propose that chronic pain-induced sleep complaints arise from perturbed arousability

A novel anxiogenic role for the delta opioid receptor expressed in GABAergic forebrain neurons.

BACKGROUND: The delta opioid receptor (DOR) is broadly expressed throughout the nervous system; it regulates chronic pain, emotional responses, motivation, and memory. Neural circuits underlying DOR activities have been poorly explored by genetic approaches. We used conditional mouse mutagenesis to elucidate receptor function in GABAergic neurons of the forebrain. METHODS: We characterized DOR distribution in the brain of Dlx5/6-CreXOprd1(fl/fl) (Dlx-DOR) mice and tested main central DOR functions through behavioral testing. RESULTS: The DOR proteins were strongly deleted in olfactory bulb and striatum and remained intact in cortex and basolateral amygdala. Olfactory perception, circadian activity, and despair-like behaviors were unchanged. In contrast, locomotor stimulant effects of SNC80 (DOR agonist) and SKF81297 (D1 agonist) were abolished and increased, respectively. The Dlx-DOR mice showed lower levels of anxiety in the elevated plus maze, opposing the known high anxiety in constitutive DOR knockout animals. Also, Dlx-DOR mice reached the food more rapidly in a novelty suppressed feeding task, despite their lower motivation for food reward observed in an operant paradigm. Finally, c-fos protein staining after novelty suppressed feeding was strongly reduced in amygdala, concordant with the low anxiety phenotype of Dlx-DOR mice. CONCLUSIONS: We demonstrate that DORs expressed in the forebrain mediate the described locomotor effect of SNC80 and inhibit D1-stimulated hyperactivity. Our data also reveal an unanticipated anxiogenic role for this particular DOR subpopulation, with a potential novel adaptive role. In emotional responses, DORs exert dual anxiolytic and anxiogenic roles, both of which may have implications in the area of anxiety disorders

Role of signalling molecules in behaviours mediated by the δ opioid receptor agonist SNC80

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142438/1/bph14131.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142438/2/bph14131-sup-0001-Supplementary-Data_S1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142438/3/bph14131_am.pd

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Gi/o-protein coupled receptors in the aging brain

Cells translate extracellular signals to regulate processes such as differentiation, metabolism and proliferation, via transmembranar receptors. G protein-coupled receptors (GPCRs) belong to the largest family of transmembrane receptors, with over 800 members in the human species. Given the variety of key physiological functions regulated by GPCRs, these are main targets of existing drugs. During normal aging, alterations in the expression and activity of GPCRs have been observed. The central nervous system (CNS) is particularly affected by these alterations, which results in decreased brain functions, impaired neuroregeneration, and increased vulnerability to neuropathologies, such as Alzheimer's and Parkinson diseases. GPCRs signal via heterotrimeric G proteins, such as Go, the most abundant heterotrimeric G protein in CNS. We here review age-induced effects of GPCR signaling via the Gi/o subfamily at the CNS. During the aging process, a reduction in protein density is observed for almost half of the Gi/o-coupled GPCRs, particularly in age-vulnerable regions such as the frontal cortex, hippocampus, substantia nigra and striatum. Gi/o levels also tend to decrease with aging, particularly in regions such as the frontal cortex. Alterations in the expression and activity of GPCRs and coupled G proteins result from altered proteostasis, peroxidation of membranar lipids and age-associated neuronal degeneration and death, and have impact on aging hallmarks and age-related neuropathologies. Further, due to oligomerization of GPCRs at the membrane and their cooperative signaling, down-regulation of a specific Gi/o-coupled GPCR may affect signaling and drug targeting of other types/subtypes of GPCRs with which it dimerizes. Gi/o-coupled GPCRs receptorsomes are thus the focus of more effective therapeutic drugs aiming to prevent or revert the decline in brain functions and increased risk of neuropathologies at advanced ages.This work was supported by Fundação para a Ciência e Tecnologia, Centro 2020 and Portugal 2020, the COMPETE program, QREN, and the European Union (FEDER program) via the GoBack project (PTDC/CVT-CVT/32261/2017), the pAGE program (Centro-01-0145-FEDER-000003), and Institute for Biomedicine iBiMED (UID/BIM/04501/2013; UID/BIM/04501/2019).publishe

Étude des fonctions du récepteur opioïde delta exprimé dans le cerveau antérieur grâce à une approche de knockout conditionnel

Delta opioid receptors (DORs) are G-protein coupled receptors belonging to the opioid system, which play a central role in chronic pain and emotional responses. DORs are strongly expressed in olfactory bulb, cortex, striatum, basolateral nucleus of the amygdala and pons nuclei. Using constitutive gene knockout, we have previously demonstrated the role of DORs in reducingchronic pain (Gaveriaux-Ruff, Nozaki et al. 2011), anxiety-related behaviors and impulsivity(Olmstead,Ouagazzal et al. 2009), regulating locomotor activity (Filliol, Ghozland et al. 2000) and facilitating context learning (Le Merrer, Faget et al. 2012; Le Merrer, Rezai et al. 2013), Although these functions are well-established, neuronal networks and mechanisms underlying DOR-regulated behaviors remain poorly understood. The aim of this thesis work was to identify neuronal populations and brain circuits that support DOR functions. Recent evidence showed that DOR is highly expressed in GABAergic neurons (Scherrer et al.. 2006;Erbs et al., 2012; Rezai et al.. 2012). We therefore developed a conditional knockout mouse line (Dlx-DOR)by breeding floxed DOR gene (Oprd1) with a transgenic Dlx-5/6-Cre mouse line (Monorv et al., 2006) in order to produce a specific deletion of DOR in GABAergic neurons of the forebrain. We first determined brain distribution of delta receptors in Dlx-DOR at mRNA and protein levels. Then, behavioral analysis were performed to assess whether DORs expressed in forebrain GABAergic neurons contribute to the regulation of emotional contrai, locomotor activity as well as epileptogenic effect of SNC80, the prototypal DOR agonist. Finally, we initiated a project focused on DORs detected at the level of BLA.Les récepteurs opioïde delta (DORs) sont des récepteurs couplés aux protéines G et sont fortement exprimés au niveau du bulbe olfactif, du cortex, du striatum, du noyau basolateral de l'amygdala et des noyaux du pons (Mansour et al., 1995; Le Merrer et al., 2009). Les souris mutantes de première génération (souris knockout, délétion totale du gène) ont déjà permis de démontrer que DOR joue un rôle critique dans le contrôle de la douleur chronique (Gavériaux-Ruff et al., 2011), la régulation de l’activité motrice et des réponses émotionnelles (Filliol et al ., 2000) et l’association drogue-contexte (Le Merrer et al., 2011). Le but de notre étude est d’identifier les circuits neuronaux dans lesquels les DORs contrôlent les processus émotionnels et cognitifs. Nous avons développé une lignée de souris de deuxième génération, dans laquelle les récepteurs sont supprimés spécifiquement dans les neurones GABAergiques du cerveau antérieur. Nous avons ensuite étudié le rôle des DORs exprimés par ces neurones dans les réponses émotionnelles, locomotrices et la sensibilité aux crises épileptiques

Traitement des gonalgies en antalgie interventionnelle [Interventional pain management for knee pain.]

Arthritis is the main cause of knee pain among adults over 50 years old. Prosthetic surgery is the ultimate treatment, however percutaneous interventional pain management is a good alternative treatment for patients who are not eligible for an operation or for those who experiment persistent pain after surgery. Intra-articular corticosteroids or hyaluronic acid injections have a mild effect which is limited in time. Nerve ablation treatment using radiofrequency or cryotherapy may have longer lasting analgesic effects superior than 6 months. Finally, regenerative medicine, meaning platelet-rich plasma or mesenchymal stem cells, seems a very promising treatment by improving pain and mobility for a longer period

Testing brown lemurs (Eulemur fulvus) on the reverse-reward contingency task without a modified procedure.

International audienceA common paradigm used to study inhibitory control is the reverse-reward contingency task in which the subject is presented with a choice between two different quantities of food and is rewarded with the non-chosen item. Most animals have problems inhibiting their impulsive choice towards the larger quantity, and need correction procedures to master the reverse-reward task. Recent studies have nonetheless shown that rhesus macaques and white crowned mangabeys were able to master the task without correction procedures after a large number of trials were applied. We previously demonstrated that, similar to other primates tested under the reverse-reward contingency task, lemurs initially showed an impulsive bias towards the larger quantity of food. But following introduction of a large-or-none contingency, all the subjects learned to reliably select the smaller quantity in order to gain access to the larger one. Here, we assessed the possibility that, similar to rhesus macaques and mangabeys, lemurs could master the reverse-reward task, without a modified procedure, by presenting a large number of trials. One of 5 subjects was able to master the task and then generalize performance to novel food arrays