Heteromerization Modulates mu Opioid Receptor Functional Properties in vivo

Mu opioid receptors modulate a large number of physiological functions. They are in particular involved in the control of pain perception and reward properties. They are also the primary molecular target of opioid drugs and mediate their beneficial analgesic effects, euphoric properties as well as negative side effects such as tolerance and physical dependence. Importantly, mu opioid receptors can physically associate with another receptor to form a novel entity called heteromer that exhibits specific ligand binding, signaling, and trafficking properties. As reviewed here, in vivo physical proximity has now been evidenced for several receptor pairs, subsequent impact of heteromerization on native mu opioid receptor signaling and trafficking identified and a link to behavioral changes established. Selective targeting of heteromers as a tool to modulate mu opioid receptor activity is therefore attracting growing interest and raises hopes for innovative therapeutic strategies

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Nicotine withdrawal in selectively bred high and low nicotine preferring rat lines

WOS: 000352173200015PubMed ID: 25687373Background: We have generated high- and low-nicotine preferring (high-NP, low-NP) rat lines using voluntary oral nicotine intake as the selection criterion. After nine generations, the estimated realized heritability for high intake was 0.26. The aim of the current study is to compare how nicotine withdrawal varies between these two lines. This new analysis would help elucidate if nicotine withdrawal and intake share common genetic mechanisms. Methods: After exposing male and female Sprague Dawley rats (F-8 generation) to six weeks of nicotine exposure, nicotine was withdrawn. Somatic signs of withdrawal, locomotor activity, and weight were measured at 16 and 40 h. One week after withdrawal, resumption of nicotine intake was determined. Results: The High-NP line had higher nicotine intake before and after withdrawal than the Low-NP line. High-NP rats were more active than Low-NP rats, and locomotor activity decreased during withdrawal; this decrease was more pronounced in the High-NP line. High-NP rats gained more weight during withdrawal than Low-NP rats. Escape attempts decreased during withdrawal in all groups, but overall females demonstrated more escape attempts than males. The other somatic signs of withdrawal were higher during withdrawal compared to baseline and more pronounced in females. Conclusions: Selection for nicotine preference affected nicotine intake, locomotion and weight, suggesting the heritability of these traits. However, despite differences in nicotine preference and intake, high-NP and low-NP rats showed similar withdrawal responses: escape attempts decreased and somatic signs increased. Withdrawal responses of females were more pronounced than males suggesting sex differences in the negative affect induced by nicotine withdrawal. The major finding of this novel analysis is showing that nicotine preference does not predict withdrawal symptoms. This finding, together with sex differences observed during withdrawal, may contribute to a better understanding of nicotine dependence and have translational value in developing more effective strategies for smoking cessation. (C) 2015 Elsevier Inc All rights reserved

Gene expression of pro-opiomelanocortin and melanocortin receptors is regulated in the hypothalamus and mesocorticolimbic system following nicotine administration

WOS: 000392790300013PubMed ID: 27890744Pro-opiomelanocortin (POMC)-derived peptides and their receptors have been shown to play important roles in natural and drug-induced reward and reinforcement. Reward process may involve the regulation of POMC gene expression and the gene expression of POMC-derived peptide receptors. The present study investigated the alterations observed in the transcript levels of POMC, melanocortin 3 (MC3R), melanocortin 4 (MC4R) and mu-opioid receptors (MOR) in the hypothalamus and mesocorticolimbic system during nicotine exposure. Rats were injected subcutaneously for 5 days with one of the three doses (0.2, 0.4 or 0.6 mg/kg/day, free base) of nicotine and were decapitated one hour after a challenge dose on the sixth day. mRNA levels of POMC in the hypothalamus, MC3R in the ventral tegmental area (VTA), MC4R and MOR in the medial prefrontal cortex (mPFC), nucleus accumbens, dorsal striatum, amygdala, lateral hypothalamic area and VTA were measured by quantitative real-time PCR. Our results showed that treatment with 0.6 mg/kg/day nicotine upregulated POMC mRNA in the hypothalamus and MC4R mRNA in the mPFC. Additionally, all three nicotine doses increased MC3R mRNA expression in the VTA. On the other hand, none of the nicotine doses altered MOR mRNA levels in the mesocorticolimbic system and associated limbic structures. These results suggest that nicotine may enhance melanocortin signaling in the mesocorticolimbic system and this alteration may be an important mechanism mediating nicotine reward. (C). 2016 Elsevier Ireland Ltd. All rights reserved.Ege University Scientific Research Projects CommissionEge University [2015-BAUM-002]This work was supported financially by Ege University Scientific Research Projects Commission (Research Fund Grant 2015-BAUM-002). The funding source had no involvement in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication

Stressing the importance of choice - validity of a preclinical free-choice high-caloric diet paradigm to model behavioral, physiological, and molecular adaptations during human diet-induced obesity and metabolic dysfunction

Humans have engineered a dietary environment that has driven the global prevalence of obesity and several other chronic metabolic diseases to pandemic levels. To prevent or treat obesity and associated comorbidities, it is crucial that we understand how our dietary environment, especially in combination with a sedentary lifestyle and daily-life stress, can dysregulate energy balance and promote the development of an obese state. Substantial mechanistic insight into the maladaptive adaptations underlying caloric overconsumption and excessive weight gain has been gained by analyzing brains from rodents that were eating prefabricated nutritionally-complete pellets of high-fat diet (HFD). Although long-term consumption of HFDs induces chronic metabolic diseases, including obesity, they do not model several important characteristics of the modern-day human diet. For example, prefabricated HFDs ignore the (effects of) caloric consumption from a fluid source, do not appear to model the complex interplay in humans between stress and preference for palatable foods, and, importantly, lack any aspect of choice. Therefore, our laboratory uses an obesogenic free-choice high-fat high-sucrose (fc-HFHS) diet paradigm that provides rodents with the opportunity to choose from several diet components, varying in palatability, fluidity, texture, form, and nutritive content. Here we review recent advances in our understanding how the fc-HFHS diet disrupts peripheral metabolic processes and produces adaptations in brain circuitries that govern homeostatic and hedonic components of energy balance. Current insight suggests that the fc-HFHS diet has good construct and face validity to model human diet-induced chronic metabolic diseases, including obesity, as it combines the effects of food palatability and energy density with the stimulating effects of variety and choice. We also highlight how behavioral, physiological, and molecular adaptations might differ from those induced by prefabricated HFDs that lack an element of choice. Finally, advantages and disadvantages of using the fc-HFHS diet for preclinical studies will be discussed. This article is protected by copyright. All rights reserved

Long-term efficacy and safety of eculizumab in Japanese patients with generalized myasthenia gravis: A subgroup analysis of the REGAIN open-label extension study

The terminal complement inhibitor eculizumab was shown to improve myasthenia gravis-related symptoms in the 26-week, phase 3, randomized, double-blind, placebo-controlled REGAIN study (NCT01997229). In this 52-week sub-analysis of the open-label extension of REGAIN (NCT02301624), eculizumab's efficacy and safety were assessed in 11 Japanese and 88 Caucasian patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis. For patients who had received placebo during REGAIN, treatment with open-label eculizumab resulted in generally similar outcomes in the Japanese and Caucasian populations. Rapid improvements were maintained for 52 weeks, assessed by change in score from open-label extension baseline to week 52 (mean [standard error]) using the following scales (in Japanese and Caucasian patients, respectively): Myasthenia Gravis Activities of Daily Living (−2.4 [1.34] and − 3.3 [0.65]); Quantitative Myasthenia Gravis (−2.9 [1.98] and − 4.3 [0.79]); Myasthenia Gravis Composite (−4.5 [2.63] and − 4.9 [1.19]); and Myasthenia Gravis Quality of Life 15-item questionnaire (−8.6 [5.68] and − 6.5 [1.93]). Overall, the safety of eculizumab was consistent with its known safety profile. In this interim sub-analysis, the efficacy and safety of eculizumab in Japanese and Caucasian patients were generally similar, and consistent with the overall REGAIN population