Rationale The alpha7 nicotinic acetylcholine receptor (nAChR) has been implicated as a target in modulating nicotine reward. However, the effect of pharmacological agents that have been shown to ...alter the channel properties of the alpha7 nAChR is not well understood in nicotine reward. Objectives This study aimed to investigate the impact of alpha7 nAChR pharmacological modulation on nicotine conditioned place preference (CPP) in mice by using positive allosteric modulators (PAMs) and a silent agonist. Methods The effect of the orthosteric alpha7 nAChR full agonist PNU282987 (1.3 and 9 mg/kg, s.c.), Type I alpha7 PAM NS1738 (1 and 10 mg/kg; i.p.), the Type II alpha7 PAM PNU120596 (0.3, 1, and 3 mg/kg, i.p.), and the alpha7 silent agonist NS6740 (1 and 3 mg/kg, i.p) on nicotine CPP was measured in mice. Mice were conditioned with either saline or nicotine (0.5 mg/kg) for 3 days in the CPP paradigm. Results The alpha7 full orthosteric agonist PNU282987 and the Type II alpha7 nAChR PAM PNU120596 reduced nicotine CPP, while the silent agonist NS6740 and Type I PAM NS1738 had no effect. The effects of PNU282987 and PNU120596 did not have an effect on morphine CPP. Conclusions Taken together, our results suggest that modulation of the alpha7 nAChR can play important roles in nicotine CPP in mice. In addition, the Type II alpha7 nAChR PAM PNU120596 attenuated nicotine reward suggesting that endogenous acetylcholine/choline tone is sufficient to reduce nicotine CPP. These findings highlight a beneficial effect of using alpha7 nAChR PAMs in nicotine reward.
Contexte
: La stimulation transcrânienne à courant direct (tDCS) a montré des résultats prometteurs dans le soulagement de différents types de douleur. Cette étude compare l’efficacité de trois ...sessions de tDCS anodale appliquée sur l’aire motrice primaire (M1) ou le cortex préfrontal dorsolatéral gauche (DLPFC) ou de sham sur la réduction de la douleur et la consommation totale d’opioïdes chez des patients postopératoires de chirurgie de la colonne vertébrale.
Matériel
: Soixante-sept des 75 patients éligibles pour une chirurgie postopératoire de la colonne vertébrale ont été répartis au hasard dans l’un des trois groupes expérimentaux. Le groupe A a reçu une tDCS anodale appliquée sur le cortex M1, le groupe B sur le cortex DLPF gauche (2 mA, 20 minutes), et le groupe C a reçu une tDCS sham, tous pendant trois jours postopératoires consécutifs. Les patients ont été évalués à l’aide d’une échelle visuelle analogique (EVA) et d’une échelle visuelle analogique adynamique (EVAA) au début de l’étude et à chacun des jours de traitement. La consommation totale de morphine sur les trois jours postopératoires a été évaluée.
Résultats
: L’Anova à mesures répétées à deux voies n’a montré aucune différence statistiquement significative de l’EVA au repos entre les trois groupes. Cependant, on a constaté une amélioration significative de la douleur (
p
< 0,001) dans l’EVAA dans les deux groupes actifs (groupes A et B) par rapport au groupe fictif (groupe C) dans la période postopératoire, sans différence significative entre les groupes actifs. La consommation de morphine a été significativement réduite dans les deux groupes actifs par rapport au groupe sham, mais il n’y avait pas de différence de consommation entre les groupes actifs.
Conclusion
: Il y a eu une réduction postopératoire significative de la consommation de morphine et des scores DVAS après trois sessions de tDCS active.
Impact
: La tDCS est un outil prometteur pour soulager la douleur dans le domaine de la chirurgie postopératoire de la colonne vertébrale.
La douleur est un problème courant chez les enfants. Des mesures pharmacologiques et non pharmacologiques sont utilisées pour la prendre en charge. Depuis quelques décennies, les opioïdes par voie ...orale sont populaires pour soulager la douleur modérée à grave. La codéine a longtemps été l'opioïde par voie orale le plus connu pour les enfants. Pour des raisons de sécurité, elle est désormais nettement moins accessible et moins employée. Divers autres opioïdes la remplacent, mais les données sur leur efficacité et leur sécurité sont limitées chez les enfants. L'oxycodone par voie orale emprunte les mêmes voies métaboliques que la codéine, mais sa pharmacocinétique est très variable. Les données sur la sécurité et l'efficacité de l'hydromorphone et du tramadol par voie orale chez les enfants sont également limitées. Lorsqu'on y recourt au lieu de la codéine, la morphine par voie orale est l'opiacé dont la sécurité et l'efficacité sont les mieux démontrées chez les enfants. Des recherches devront être réalisées pour explorer d'autres approches relatives aux médicaments opioïdes et non opioïdes, afin d'orienter les traitements analgésiques fondés sur des données probantes qui soulageront la douleur modérée à grave chez les enfants. Mots-clés : hydromorphone; morphine; oxycodone; tramadol
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Morphine is a widely used opioid for treatment of moderate to severe pain, but large interindividual variability in patient response and no clear guidance on how to optimise morphine ...dosage regimen complicates treatment strategy for clinicians. Population pharmacokinetic–pharmacodynamic models can be used to quantify dose–response relationships for the population as well as interindividual and interoccasion variability. Additionally, relevant covariates for population subgroups that deviate from the typical population can be identified and help clinicians in dose optimisation.
This review provides a detailed overview of the published human population pharmacokinetic–pharmacodynamic studies for morphine analgesia in addition to basic drug disposition and pharmacological properties of morphine and its analgesic active metabolite, morphine-6-glucuronide, that may help identify future covariates.
Furthermore, based on simulations from key pharmacokinetic–pharmacodynamic models, the contribution of morphine-6-glucuronide to the analgesic response in patients with renal insufficiency was investigated. Simulations were also used to examine the impact of effect-site equilibration half-life on time course of response. Lastly, the impact of study design on the likelihood of determining accurate pharmacodynamic parameters for morphine response was evaluated.
Morphine-6-glucuronide (M6G) is a strong µ-receptor agonist with higher affinity than morphine itself. It has been suggested that M6G contributes to the analgesic effect after administration of ...morphine, but the extent of its contribution remains unclear.
In order to elucidate the relative contribution of both drugs to the overall analgesic effect mediated by the µ-receptor, published data on µ-receptor binding, plasma protein binding, concentrations preferably area under the concentration–time curve (AUC) of morphine and M6G in blood or cerebrospinal fluid (CSF), or concentration ratios were used to calculate free CSF concentration corrected for receptor binding for each compound. To compare different routes of administration, free CSF concentrations of M and M6G corrected for potency were added and compared with oral administration.
Based on AUC data, there is a major contribution of M6G to the overall analgesic effect; the mean contributions being estimated as 96.6%, 85.6%, 85.4%, and 91.3% after oral, s.c., i.v., and rectal administration of morphine, respectively. In patients with renal insufficiency, 97.6% of the analgesic effect is caused by M6G when morphine is given orally. Owing to accumulation of M6G over time in these patients, morphine may be regarded as a prodrug.
When administering morphine to patients, the analgesic effect is mainly caused by M6G instead of morphine itself, irrespective of the route of administration. Therefore, the patient's kidney function plays a key role in determining the optimal daily dose of morphine.
Inadequately treated acute and chronic pain remains a major cause of suffering and dissatisfaction in pain therapy. A cause for the variable success of pharmacologic pain therapy is the different ...genetic disposition of patients to develop pain or to respond to analgesics. The patient's phenotype may be regarded as the result of synergistic or antagonistic effects of several genetic variants concomitantly present in an individual. Variants modulate the risk of developing painful disease or its clinical course (e.g., migraine, fibromyalgia, low back pain). Other variants modulate the perception of pain (e.g., OPRM1 or GCH1 variants conferring modest pain protection by increasing the tone of the endogenous opioid system or decreasing nitric oxide formation). Other polymorphisms alter pharmacokinetic mechanisms controlling the local availability of active analgesic molecules at their effector sites (e.g., decreased CYP2D6 related prodrug activation of codeine to morphine). In addition, genetic variants may alter pharmacodynamic mechanisms controlling the interaction of the analgesic molecules with their target structures (e.g., opioid receptor mutations). Finally, opioid dosage requirements may be increased depending on the risk of drug addiction (e.g., DRD2 polymorphisms decreasing the functioning of the dopaminergic reward system). With the complex nature of pain involving various mechanisms of nociception, drug action, drug pharmacology, pain disease and possibly substance addiction, a multigenic or even genome wide approach to genetics could be required to base individualized pain therapy on the patient's genotype.
Agonists at the micro-opioid receptor are known to produce potent analgesic responses in the clinical setting, therefore, an increased understanding of the molecular interactions of ligands at this ...receptor could lead to improved analgesics. As historically morphine has been shown to be a poor recruiter of beta-arrestin in recombinant cell systems and this can be overcome by the co-expression of GRK2, we investigated the effects of GRK2 co-expression, in a recombinant micro-opioid receptor cell line, on ligand affinity and intrinsic activity in both beta-arrestin recruitment and .sup.35 SGTPgammaS binding assays. We also investigated the effect of receptor depletion in the beta-arrestin assay. GRK2 co-expression increased both agonist Emax and potency in the beta-arrestin assay. The increase in agonist potency could not be reversed using receptor depletion, supporting that the effects were due to a novel receptor conformation not system amplification. We also observed a small but significant effect on agonist K.sub.L values. Potency values in the .sup.35 SGTPgammaS assay were unchanged; however, inverse agonist activity became evident with GRK2 co-expression. We conclude that this is direct evidence that the micro-opioid receptor is an allosteric protein and the co-expression of signalling molecules elicits changes in its conformation and thus ligand affinity. This has implications when describing how ligands interact with the receptor and how efficacy is determined.
Opioid use for long-term pain management is limited by adverse side effects, such as hyperalgesia and negative affect. Neuroinflammation in the brain and spinal cord is a contributing factor to the ...development of symptoms associated with chronic opioid use. Recent studies have described a link between neuroinflammation and behavior that is mediated by a gut-brain signaling axis, where alterations in indigenous gut bacteria contribute to several inflammation-related psychopathologies. As opioid receptors are highly expressed within the digestive tract and opioids influence gut motility, we hypothesized that systemic opioid treatment will impact the composition of the gut microbiota. Here, we explored how opioid treatments, and cessation, impacts the mouse gut microbiome and whether opioid-induced changes in the gut microbiota influences inflammation-driven hyperalgesia and impaired reward behavior. Male C57Bl6/J mice were treated with either intermittent or sustained morphine. Using 16S rDNA sequencing, we describe changes in gut microbiota composition following different morphine regimens. Manipulation of the gut microbiome was used to assess the causal relationship between the gut microbiome and opioid-dependent behaviors. Intermittent, but not sustained, morphine treatment was associated with microglial activation, hyperalgesia, and impaired reward response. Depletion of the gut microbiota via antibiotic treatment surprisingly recapitulated neuroinflammation and sequelae, including reduced opioid analgesic potency and impaired cocaine reward following intermittent morphine treatment. Colonization of antibiotic-treated mice with a control microbiota restored microglial activation state and behaviors. Our findings suggest that differing opioid regimens uniquely influence the gut microbiome that is causally related to behaviors associated with opioid dependence.
Cell-derived exosomes have been demonstrated to be efficient carriers of small RNAs to neighbouring or distant cells, highlighting the preponderance of exosomes as carriers for gene therapy over ...other artificial delivery tools. In the present study, we employed modified exosomes expressing the neuron-specific rabies viral glycoprotein (RVG) peptide on the membrane surface to deliver opioid receptor mu (MOR) siRNA into the brain to treat morphine addiction. We found that MOR siRNA could be efficiently packaged into RVG exosomes and was associated with argonaute 2 (AGO2) in exosomes. These exosomes efficiently and specifically delivered MOR siRNA into Neuro2A cells and the mouse brain. Functionally, siRNA-loaded RVG exosomes significantly reduced MOR mRNA and protein levels. Surprisingly, MOR siRNA delivered by the RVG exosomes strongly inhibited morphine relapse via the down-regulation of MOR expression levels. In conclusion, our results demonstrate that targeted RVG exosomes can efficiently transfer siRNA to the central nervous system and mediate the treatment of morphine relapse by down-regulating MOR expression levels. Our study provides a brand new strategy to treat drug relapse and diseases of the central nervous system.
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