Implication du système ubiquitine protéasome dans le noyau accumbens lors de l'élaboration et du maintien de comportements addictifs induits par les opioïdes

L'addiction est définie comme l'usage compulsif d'une substance en dépit de ses conséquences néfastes. Les propriétés renforçantes des drogues d'abus conduisent à une usurpation pathologique des circuits neuronaux servant aux apprentissages appétitifs. Ces neuro-adaptations, telles que la plasticité synaptique et les changements morphologiques des neurones, partagent de nombreuses similarités avec les mécanismes mis en jeu lors de la formation d'une mémoire à long terme. Dans l'hippocampe de rongeurs, la dégradation protéique par le système ubiquitine protéasome (SUP) joue un rôle primordial dans la plasticité synaptique et la formation de la mémoire. Cependant l'activité du SUP n'est pas restreinte à la plasticité hippocampique et à la mémoire mais est aussi impliquée dans les adaptations cellulaires induites par un traitement morphinique à long terme sur des cultures de neuroblastomes. Au vu de ces similarités, le point majeur restant à élucider est donc quelle est l'implication du SUP dans l'établissement des propriétés renforçantes des drogues d'abus in vivo. Le noyau accumbens (NAcc), un important point de convergence du circuit de la récompense, joue un rôle majeur dans ces propriétés renforçantes et participe à la transition entre un usage contrôlé et un usage compulsif des drogues. Le but de ce travail était donc d'évaluer la nécessité du SUP dans le NAcc de rongeurs lors du développement de comportements induits par les opioïdes. Nous avons dans un premier temps vérifié qu'une injection de morphine in vivo induisait bien une dégradation protéique dans le NAcc. Nous avons ensuite déterminé quelles étaient les conséquences de l'inhibition de la dégradation protéique, grâce à des injections locales de lactacystine, un inhibiteur du SUP, dans le NAcc, pendant l'établissement d'un grand nombre de paradigmes expérimentaux couramment utilisés pour tester les propriétés renforçantes des drogues. Ce travail nous a donc permis de définir clairement un rôle primordial de la dégradation protéique dans le NAcc lors de l'acquisition de comportements dirigés par les des effets renforçants opioïdes menant à l'addiction.Addiction is defined as a compulsive use of a substance despite negative consequences. High reinforcing properties of drugs of abuse lead to pathological usurpation of neural processes that normally serve reward-related learning. In recent years, it was shown that the transition to addiction depends on plastic changes in the reward system. These neuro-adaptations, such as synaptic plasticity and changes in neuronal morphology, share many similarities with mechanisms involved in long-term memory (LTM). In the hippocampus of rodents, protein degradation by the ubiquitin proteasome system (UPS) plays a crucial role in synaptic plasticity and memory. Nevertheless UPS activity is not restricted to hippocampal plasticity and long-term memory storage but is also involved in cellular adaptations induced by long-term morphine treatments in neuroblastoma cultures. An important question is, therefore, whether the UPS is necessary for the in vivo reinforcing properties of drugs of abuse. The nucleus accumbens (NAcc), an important point of convergence in the reward circuitry, plays a major role in the reinforcing properties of drugs of abuse and participate in the transition from recreational to compulsive drug use. The purpose of the present work was therefore to evaluate the necessity of UPS in the NAcc for the development of opiate-induced behaviors in rodents. First, we investigated whether injection of morphine in vivo could induce protein degradation in the NAcc. Then, our strategy was to determine the effects of protein degradation blockade by locally injecting lactacystin, a proteasome inhibitor, in the NAcc during the establishment of a wide range of standard behavioral paradigms commonly used to test morphine reinforcement. This strategy allowed us to provide compelling evidence for a role of protein degradation in the NAcc in the establishment of goal-directed behaviors induced by opiate reinforcing effects that lead to addiction

A trigger for opioid misuse: Chronic pain and stress dysregulate the mesolimbic pathway and kappa opioid system

Pain and stress are protective mechanisms essential in avoiding harmful or threatening stimuli and ensuring survival. Despite these beneficial roles, chronic exposure to either pain or stress can lead to maladaptive hormonal and neuronal modulations that can result in chronic pain and a wide spectrum of stress-related disorders including anxiety and depression. By inducing allostatic changes in the mesolimbic dopaminergic pathway, both chronic pain and stress disorders affect the rewarding values of both natural reinforcers, such as food or social interaction, and drugs of abuse. Despite opioids representing the best therapeutic strategy in pain conditions, they are often misused as a result of these allostatic changes induced by chronic pain and stress. The kappa opioid receptor (KOR) system is critically involved in these neuronal adaptations in part through its control of dopamine release in the nucleus accumbens. Therefore, it is likely that changes in the kappa opioid system following chronic exposure to pain and stress play a key role in increasing the misuse liability observed in pain patients treated with opioids. In this review, we will discuss how chronic pain and stress-induced pathologies can affect mesolimbic dopaminergic transmission, leading to increased abuse liability. We will also assess how the kappa opioid system may underlie these pathological changes

Endogenous opioid systems alterations in pain and opioid use disorder

Decades of research advances have established a central role for endogenous opioid systems in regulating reward processing, mood, motivation, learning and memory, gastrointestinal function, and pain relief. Endogenous opioid systems are present ubiquitously throughout the central and peripheral nervous system. They are composed of four families, namely the μ (MOPR), κ (KOPR), δ (DOPR), and nociceptin/orphanin FQ (NOPR) opioid receptors systems. These receptors signal through the action of their endogenous opioid peptides β-endorphins, dynorphins, enkephalins, and nociceptins, respectfully, to maintain homeostasis under normal physiological states. Due to their prominent role in pain regulation, exogenous opioids-primarily targeting the MOPR, have been historically used in medicine as analgesics, but their ability to produce euphoric effects also present high risks for abuse. The ability of pain and opioid use to perturb endogenous opioid system function, particularly within the central nervous system, may increase the likelihood of developing opioid use disorder (OUD). Today, the opioid crisis represents a major social, economic, and public health concern. In this review, we summarize the current state of the literature on the function, expression, pharmacology, and regulation of endogenous opioid systems in pain. Additionally, we discuss the adaptations in the endogenous opioid systems upon use of exogenous opioids which contribute to the development of OUD. Finally, we describe the intricate relationship between pain, endogenous opioid systems, and the proclivity for opioid misuse, as well as potential advances in generating safer and more efficient pain therapies

Modulation of μ‐opioid receptor activation by acidic pH is dependent on ligand structure and an ionizable amino acid residue

Background and Purpose: Adverse side effects of conventional opioids can be avoided if ligands selectively activate peripheral opioid receptors in injured tissue. Injury and inflammation are typically accompanied by acidification. In this study, we examined influences of low pH and mutation of the ionizable amino acid residue H297(6.52) on mu-opioid receptor binding and signalling induced by the mu-opioid receptor ligands fentanyl, DAMGO, and naloxone. Experimental Approach: HEK 293 cells stably transfected with mu-opioid receptors were used to study opioid ligand binding, [S-35]-GTP gamma S binding, and cAMP reduction at physiological and acidic pH. We used mu-opioid receptors mutated at H297(6.52) to A (MOR-H297(6.52)A) to delineate ligand-specific interactions with H297(6.52). Key Results: Low pH and the mutant receptor MOR-H297(6.52)A impaired naloxone binding and antagonism of cAMP reduction. In addition, DAMGO binding and G-protein activation were decreased under these conditions. Fentanyl-induced signalling was not influenced by pH and largely independent of H297(6.52). Conclusions and Implications: Our investigations indicate that low pH selectively impairs mu-opioid receptor signalling modulated by ligands capable of forming hydrogen bonds with H297(6.52). We propose that protonation of H297(6.52) at acidic pH reduces binding and subsequent signalling of such ligands. Novel agonists targeting opioid receptors in injured tissue might benefit from lack of hydrogen bond formation with H297(6.52)

Utilisation du test GeneXpert pour le diagnostic de la tuberculose au service des maladies infectieuses du CHNU de Fann

Introduction: Nous avons réalisé ce travail pour montrer notre expérience d’utilisation du GeneXpert et évaluer son apport dans la confirmation du diagnostic de la tuberculose. Méthodes: Etude prospective descriptive et analytique de janvier à Décembre 2013. Résultats: Quatre vingt quatorze patients ont bénéficié du geneXpert pour le dépistage de la tuberculose toute localisation confondue. Le geneXpert avait été positif dans 62% des cas. Les images radiologiques fortement évocatrices de tuberculose était associées à un geneXpert positif dans 25% des cas. La recherche de BAAR réalisée chez 55 patients était positive dans 9 cas (16%). Le geneXpert était positif sur 46 frottis négatif (54%)et dans 89% sur les frottis positifs. La prévalence de la tuberculose extrapulmonaire était de 34%. Le taux de positivité était variable en fonction du type de prélèvement. Deux cas de résistance à la rifampicine ont été détectées. Conclusion: Le geneXpert a été d’un grand apport pour le diagnostic de la tuberculose pulmonaire et extrapulmonaire mais la bacilloscopie reste incontournable.Pan African Medical Journal 2016; 2

Climatic Effects and Total Factor Productivity in U.S. Dairy Farming: An Empirical Analysis of Northeastern and Midwestern Counties between 1974 and 2012

Climate change refers to changes in temperature and precipitation patterns as well as increases in the occurrence of extreme events. In recent years, climate change has gained increasing attention from production economists; however, its effects on productivity have been largely ignored in the literature. Our study aims to address these shortcomings by implementing a Total Factor Productivity (TFP) analysis and decomposing TFP into climatic effect, output-oriented technical efficiency, technological progress, and output-oriented scale efficiency indexes. Our study focuses primarily on climatic effects on TFP growth on dairy farming in two traditional US dairy regions. We use U.S. county level data from 1974 to 2012 in the Northeast (NE) and Midwest (MW) to estimate stochastic production frontier models, which provide the basis for measuring TFP and its components. We find that the coefficients for winter and summer temperatures are highly significant and exhibit a positive and negative relationship with output, respectively. In the Northeast, TFP growth is highest in Cayuga County, NY (3.2%), while in the Midwest, Sanilac County in MI exhibits the highest TFP growth (2.6%). Our results also show that on average, per year summer temperatures have a negative contribution to TFP growth per annum while winter temperatures have a positive contribution to per annum output growth. Precipitation exhibits a mixed effect on TFP growth in both the Northeast and Midwest regions

A trigger for opioid misuse: Chronic pain and stress dysregulate the mesolimbic pathway and kappa opioid system

Pain and stress are protective mechanisms essential in avoiding harmful or threatening stimuli and ensuring survival. Despite these beneficial roles, chronic exposure to either pain or stress can lead to maladaptive hormonal and neuronal modulations that can result in chronic pain and a wide spectrum of stress-related disorders including anxiety and depression. By inducing allostatic changes in the mesolimbic dopaminergic pathway, both chronic pain and stress disorders affect the rewarding values of both natural reinforcers, such as food or social interaction, and drugs of abuse. Despite opioids representing the best therapeutic strategy in acute pain conditions, they are often misused as a result of these allostatic changes induced by chronic pain and stress. The kappa opioid receptor system is critically involved in these neuronal adaptations in part through its control of dopamine release in the nucleus accumbens. Therefore, it is likely that changes in the kappa opioid system following chronic exposure to pain and stress play a key role in increasing the misuse liability observed in pain patients treated with opioids. In this review, we will discuss how chronic pain and stress-induced pathologies can affect mesolimbic dopaminergic transmission, leading to increased abuse liability. We will also assess how the kappa opioid system may underlie these pathological changes

Etude en chambre conditionn e de la croissance de Vigna Glabres-cens (Marechal; Mascherija et Stainier)

SIGLEBSEB223508P / UCL - Université Catholique de LouvainBEBelgiu