BACKGROUND & AIMS: CONTEXT:Naltrexone hydrochloride treatment for alcohol dependence works for some individuals but not for everyone. Asn40Asp, a functional polymorphism of the mu-opioid receptor gene (OPRM1), might predict naltrexone response. OBJECTIVE:To evaluate whether individuals with alcoholism who are heterozygous (Asp40/Asn40) or homozygous (Asp40/Asp40) for the OPRM1 Asp40 allele respond better to naltrexone. DESIGN:Pharmacogenetic analysis conducted between January 1, 2001, and January 31, 2004. SETTING:Eleven academic sites in the COMBINE Study. PARTICIPANTS:Recently abstinent volunteers who met all 3 of the following conditions: (1) DSM-IV criteria for primary alcohol dependence; (2) participation in the COMBINE Study; and (3) availability of DNA. INTERVENTIONS:Alcoholic subjects were treated for 16 weeks with 100 mg of naltrexone hydrochloride (234 Asn40 homozygotes and 67 with at least 1 copy of the Asp40 allele) or placebo (235 Asn40 homozygotes and 68 with at least 1 copy of the Asp40 allele). All participants received medical management (MM) alone or with combined behavioral intervention (CBI). MAIN OUTCOME MEASURES:Time trends in percentage of days abstinent, percentage of heavy drinking days, and rates of good clinical outcome. RESULTS:Alcoholic subjects with an Asp40 allele receiving MM alone (no CBI) had an increased percentage of days abstinent (P = .07) and a decreased percentage of heavy drinking days (P = .04) if treated with naltrexone vs placebo, while those with the Asn40/Asn40 genotype showed no medication differences. If treated with MM alone and naltrexone, 87.1% of Asp40 carriers had a good clinical outcome, compared with only 54.8% of individuals with the Asn40/Asn40 genotype (odds ratio, 5.75; confidence interval, 1.88-17.54), while, if treated with placebo, 48.6% of Asp40 carriers and 54.0% of individuals with the Asn40/Asn40 genotype had a good clinical outcome (interaction between medication and genotype, P = .005). No gene x medication interactions were observed in those treated with both MM and CBI. CONCLUSIONS:These results confirm and extend the observation that the functionally significant OPRM1 Asp40 allele predicts naltrexone treatment response in alcoholic individuals. This relationship might be obscured, however, by other efficacious treatments. OPRM1 genotyping in alcoholic individuals might be useful to assist in selecting treatment options. TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT00006206.

背景与目标： 语境：盐酸纳曲酮治疗酒精依赖症对某些人有效，但并非对所有人都有效。 Asn40Asp是mu阿片受体基因（OPRM1）的功能性多态性，可能预测纳曲酮的反应。
目的：评估对于OPRM1 Asp40等位基因为杂合性（Asp40 / Asn40）或纯合性（Asp40 / Asp40）的酒精中毒患者对纳曲酮的反应是否更好。
设计：在2001年1月1日至2004年1月31日之间进行了药物遗传学分析。
地点：COMBINE研究中的11个学术站点。
参与者：最近戒断的志愿者，其符合以下所有三个条件：（1）DSM-IV原发性酒精依赖标准； （2）参与组合研究； （3）DNA的可用性。
干预措施：用100 mg盐酸纳曲酮（234例Asn40纯合子和67例具有至少1份Asp40等位基因）或安慰剂（235例Asn40纯合子和68例具有至少1份Asp40等位基因）治疗酒精中毒受试者16周。所有参与者均接受单独的医学管理（MM）或联合行为干预（CBI）。
主要观察指标：禁酒日百分比，重度饮酒天数百分比和良好临床结果发生率的时间趋势。
结果：如果接受纳曲酮和安慰剂治疗，仅接受MM（无CBI）的Asp40等位基因的酒精饮料受试者的禁酒日百分比（P = .07）和重度饮酒天数百分比（P = .04）降低，而具有Asn40 / Asn40基因型的患者没有药物差异。如果单独使用MM和纳曲酮治疗，则87.1％的Asp40携带者具有良好的临床结果，而只有54.8％的Asn40 / Asn40基因型个体（优势比为5.75；置信区间为1.88-17.54），而如果接受治疗使用安慰剂时，有48.6％的Asp40携带者和54.0％的Asn40 / Asn40基因型个体具有良好的临床预后（药物与基因型之间的相互作用，P = 0.005）。 MM和CBI均未观察到基因x药物相互作用。
结论：这些结果证实并扩展了观察结果，即功能上重要的OPRM1 Asp40等位基因可预测酒精中毒者的纳曲酮治疗反应。但是，其他有效的治疗方法可能会掩盖这种关系。酒精中毒者的OPRM1基因分型可能有助于选择治疗方案。
试验注册：clinicaltrials.gov标识符：NCT00006206。

BACKGROUND & AIMS: BACKGROUND:Preference for fatty foods is a risk factor for obesity. It is a complex behaviour that involves the brain reward system and is regulated by genetic and environmental factors, such as the opioid receptor mu-1 gene (OPRM1) and prenatal exposure to maternal cigarette smoking (PEMCS). We examined whether OPRM1 and PEMCS interact in influencing fat intake and whether exposure-associated epigenetic modifications of OPRM1 may mediate this gene-environment interaction. METHODS:We studied adolescents from a French Canadian genetic founder population, half of whom were exposed prenatally to maternal cigarette smoking. Fat intake was assessed with a 24-hour food recall in the form of a structured interview conducted by a trained nutritionist. The OPRM1 variant rs2281617 was genotyped for the whole sample with the Illumina Human610-Quad and HumanOmniExpress BeadChips. Methylation of blood DNA was assessed at 21 CpGs across OPRM1 in a subset of the sample using the Illumina HumanMethylation450 BeadChip. RESULTS:We included 956 adolescents in our study. In the whole sample, OPRM1 (T carrier in rs2281617) was associated with lower fat intake (-1.6%, p = 0.017), and PEMCS was associated with higher fat intake (+1.6%, p = 0.005). OPRM1 and PEMCS interacted with each other (p = 0.003); the "protective" (fat intake-lowering) allele of OPRM1 was associated with lower fat intake in nonexposed (-3.2%, p < 0.001) but not in exposed individuals (+0.8%, p = 0.42). Further, PEMCS was associated with lower DNA methylation across multiple CpGs across OPRM1 in exposed versus nonexposed individuals (p = 0.031). LIMITATIONS:A limitation of our study was its cross-sectional design. CONCLUSION:Our study suggests that PEMCS may interact with OPRM1 in increasing fat preference. Silencing of the protective OPRM1 allele in exposed adolescents might be related to epigenetic modification of this gene.

背景与目标： 背景：偏爱脂肪食品是肥胖的危险因素。它是一种复杂的行为，涉及大脑奖励系统，并受遗传和环境因素（例如阿片受体mu-1基因（OPRM1））和产前暴露于母亲吸烟（PEMCS）的影响。我们检查了OPRM1和PEMCS是否在影响脂肪摄入方面相互作用，以及OPRM1的暴露相关表观遗传修饰是否可以介导这种基因-环境相互作用。
方法：我们研究了来自法国加拿大遗传创始人群体的青少年，其中一半在产前暴露于母亲吸烟。通过由受过训练的营养师进行的结构化访谈，通过24小时食物召回评估脂肪摄入量。使用Illumina Human610-Quad和HumanOmniExpress BeadChips对整个样品进行OPRM1变体rs2281617的基因分型。使用Illumina HumanMethylation450 BeadChip在样品的一个子集中，通过OPRM1以21 CpGs评估了血液DNA的甲基化。
结果：我们纳入了956名青少年。在整个样本中，OPRM1（rs2281617中的T携带者）与较低的脂肪摄入量相关（-1.6％，p = 0.017），而PEMCS与较高的脂肪摄入量相关（1.6％，p = 0.005）。 OPRM1和PEMCS相互影响（p = 0.003）；在未暴露的人群中，OPRM1的“保护性”（降低脂肪摄入量）等位基因与较低的脂肪摄入量相关（-3.2％，p <0.001），而在暴露的人群中则不相关（0.8％，p = 0.42）。此外，在暴露和未暴露的个体中，PEMCS与OPRM1的多个CpG的DNA甲基化程度较低相关（p = 0.031）。
局限性：我们研究的局限性在于其横截面设计。
结论：我们的研究表明，PEMCS可能与OPRM1相互作用，从而增加了脂肪的偏好。在暴露的青少年中保护性OPRM1等位基因的沉默可能与该基因的表观遗传修饰有关。

BACKGROUND & AIMS: :The largest proportion of methadone-associated deaths occurs during the drug induction phase. We analysed methadone-related fatalities for gene variations linked with methadone action. A significant association between high methadone concentrations and the CYP2B6*6 allele characteristic of the slow metabolizer phenotype was identified. We suggest that the risk of methadone fatality may be predetermined in part by the CYP2B6*6 allele. A significant correlation was also observed between post-mortem benzodiazepine concentrations and the OPRM1 A118G allele GA in methadone-related fatalities. Screening for these susceptibility variations prior to methadone prescription could assist in reducing the potential for serious adverse effects.

背景与目标： ：与美沙酮有关的死亡中，最大比例的死亡发生在药物诱导阶段。我们分析了与美沙酮作用相关的基因变异与美沙酮相关的致命性。发现高美沙酮浓度与慢代谢者表型的CYP2B6 * 6等位基因特征之间存在显着关联。我们建议美沙酮死亡的风险可能是由CYP2B6 * 6等位基因部分确定的。在与美沙酮有关的死亡中，死后苯二氮卓类药物的浓度与OPRM1 A118G等位基因GA之间也观察到显着相关性。在美沙酮处方前对这些药敏性变化进行筛查可以帮助减少发生严重不良反应的可能性。

BACKGROUND & AIMS: :Understanding the emotional reaction to loss, or frustration, is a critical problem for the field of mental health. Animal models of loss have pointed to the opioid system as a nexus of frustration, physical pain, and substance abuse. However, few attempts have been made to connect the results of animal models of loss to human behavior. Allelic differences in the human mu opioid receptor gene, notably the A118G single nucleotide polymorphism, have been linked to individual differences in pain sensitivity, depressive symptoms, and reward processing. The present study explored the relationship between A118G and behavior in two frustrating tasks in humans. Results showed that carriers of the mutant G-allele were slower to recover behavior following a reward downshift and abandoned a frustrating task earlier than those without the mutation. Additionally, G-carriers were more sensitive to physical pain. These results highlight the overlap between frustration and pain, and suggest that genetic variation in opioid tone may contribute to individual differences in vulnerability and resilience following emotional disturbances.

背景与目标： ：了解对丧失或沮丧的情绪反应，是心理健康领域的一个关键问题。动物模型的丧失指出阿片样物质系统是沮丧，身体疼痛和药物滥用的纽带。但是，很少有人尝试将动物损失模型的结果与人类行为联系起来。人mu阿片受体基因的等位基因差异，特别是A118G单核苷酸多态性，与疼痛敏感性，抑郁症状和奖励过程的个体差异有关。本研究探讨了人类两个令人沮丧的任务中A118G与行为之间的关系。结果表明，突变的G-等位基因的携带者在奖励降档后恢复行为的速度较慢，并且比没有突变的携带者更早地放弃了令人沮丧的任务。此外，G载体对身体疼痛更敏感。这些结果突出了挫折感和疼痛之间的重叠，并表明阿片类药物基调的遗传变异可能会导致情绪障碍后个体的脆弱性和适应力差异。

BACKGROUND & AIMS: :The μ-opioid receptor (MOR) is the primary target of methadone and buprenorphine. The primary neuronal transcript of the OPRM1 gene, MOR-1, contains a ~13 kb 3' untranslated region with five common haplotypes in European-Americans. We analyzed the effects of these haplotypes on the percentage of opioid positive urine tests in European-Americans (n=582) during a 24-week, randomized, open-label trial of methadone or buprenorphine/naloxone (Suboxone) for the treatment of opioid dependence. A single haplotype, tagged by rs10485058, was significantly associated with patient urinalysis data in the methadone treatment group. Methadone patients with the A/A genotype at rs10485058 were less likely to have opioid-positive urine drug screens than those in the combined A/G and G/G genotypes group (relative risk=0.76, 95% confidence intervals=0.73-0.80, P=0.0064). Genotype at rs10485058 also predicted self-reported relapse rates in an independent population of Australian patients of European descent (n=1215) who were receiving opioid substitution therapy (P=0.003). In silico analysis predicted that miR-95-3p would interact with the G, but not the A allele of rs10485058. Luciferase assays indicated miR-95-3p decreased reporter activity of constructs containing the G, but not the A allele of rs10485058, suggesting a potential mechanism for the observed pharmacogenetic effect. These findings suggest that selection of a medication for opioid dependence based on rs10485058 genotype might improve outcomes in this ethnic group.

背景与目标： ：μ阿片受体（MOR）是美沙酮和丁丙诺啡的主要靶标。 OPRM1基因的主要神经元转录物MOR-1包含一个〜13 kb 3'非翻译区，在欧美人中有五种常见的单倍型。我们在美沙酮或丁丙诺啡/纳洛酮（Suboxone）治疗阿片类药物的24周随机，开放标签试验中，分析了这些单倍型对欧洲裔美国人（n = 582）阿片类药物阳性尿检百分比的影响依赖。在美沙酮治疗组中，一个由rs10485058标记的单倍型与患者尿液分析数据显着相关。具有A / A基因型rs10485058的美沙酮患者比具有A / G和G / G联合基因型组的患者接受阿片类药物阳性尿液筛查的可能性更低（相对风险= 0.76，95％置信区间= 0.73-0.80， P ＝ 0.0064）。 rs10485058的基因型还预测了接受阿片类药物替代治疗的欧洲裔澳大利亚独立患者（n = 1215）的自我报告的复发率（P = 0.003）。在计算机分析中预测，miR-95-3p将与rs10485058的G等位基因相互作用，但不会与之相互作用。萤光素酶分析表明，miR-95-3p降低了含有rs10485058的G等位基因的构建体的报告基因活性，提示观察到的药理作用的潜在机制。这些发现表明，基于rs10485058基因型的阿片类药物依赖药物的选择可能会改善该族群的结局。

BACKGROUND & AIMS: :Recent studies in psychoneuroimmunology have indicated that proinflammatory cytokines cause several diseases and behaviors that overlap symptomatically with depression. It is known that the endogenous opioid peptide beta-endorphin regulates proinflammatory cytokine secretion from peripheral immune cells via mu-opioid receptor-dependent mechanisms. Therefore, it is possible that the functional polymorphism of the mu-opioid receptor gene (OPRM1, SNP: A118G) influences peripheral circulating proinflammatory cytokine levels and the health-related quality of life (QOL) even in healthy populations. In this study, we compared the serum concentrations of several proinflammatory cytokines (interleukin-2 (IL-2), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma)) and the health-related QOL between OPRM1 genotypes. Interestingly, serum concentrations of IL-6, TNF-alpha, and IFN-gamma were significantly lower and the general health score was significantly higher in carriers of the G allele, who show a strong binding of beta-endorphin to the mu-opioid receptor as compared to individuals without the G allele. Correlation analysis indicated that the general health score was negatively correlated with the IL-6 serum concentration. These results suggest that the sensitive endogenous opioid system in carriers of the G allele may suppress proinflammatory cytokine secretion from peripheral immune cells; consequently, it may influence the health perception.

背景与目标： 心理神经免疫学的最新研究表明，促炎性细胞因子会导致多种疾病和行为，与抑郁症在症状上重叠。已知内源性阿片肽β-内啡肽通过μ阿片受体依赖性机制调节周围免疫细胞的促炎细胞因子分泌。因此，即使在健康人群中，μ阿片受体基因（OPRM1，SNP：A118G）的功能多态性也可能影响外周循环促炎细胞因子水平和健康相关的生活质量（QOL）。在这项研究中，我们比较了几种促炎细胞因子（白介素2（IL-2），白介素6（IL-6），肿瘤坏死因子α（TNF-alpha）和干扰素-γ（IFN-α）的血清浓度。 γ）和OPRM1基因型之间与健康相关的QOL。有趣的是，G等位基因携带者的血清IL-6，TNF-α和IFN-γ浓度显着降低，而总体健康评分显着更高，这些携带者表现出β-内啡肽与μ阿片受体的强烈结合与没有G等位基因的个体相比。相关分析表明，总体健康评分与IL-6血清浓度呈负相关。这些结果表明，G等位基因携带者中敏感的内源性阿片样物质系统可能抑制外周免疫细胞的促炎细胞因子分泌。因此，它可能会影响健康感知。

BACKGROUND & AIMS: BACKGROUND:Among adolescent novice smokers, craving is often the first, and is the most reported, symptom of nicotine dependence. Until now, little has been known about the development of craving symptoms in novice smokers. The aim of this study was to identify specific genetic (i.e., DRD2 Taq1A, DRD4 48 bp VNTR, and OPRM1 A118G polymorphisms) and environmental mechanisms that underlie the emergence of both cue-induced and cognitive craving among adolescent novice smokers. METHOD:A five-wave longitudinal, genetically-informed survey study was conducted with intervals of four months. The sample included 376 early adolescent smokers (12-13 years of age at baseline). Self-report questionnaires were completed regarding smoking behavior, observed parental smoking behavior, and both cue-induced and cognitive craving. RESULTS:Data were analyzed with a latent growth curve approach. For both cue-induced and cognitive craving, significant interaction effects were found for DRD2 Taq1A with parental smoke exposure. A1-allele carriers did not seem to be influenced by the environment with regard to craving development. Adolescents who are homozygous for the A2-allele and who are more exposed to parental smoking experience the highest levels of both types of craving over time. No significant interaction effects were found between parental smoke exposure and DRD4 48 bp VNTR or OPRM1 A118G. CONCLUSIONS:Previous studies identified DRD2 Taq1A A1-allele carriers as vulnerable to developing nicotine dependence. However, this study showed that parental smoking increased the chances of developing dependence more rapidly for early adolescents who are considered to be less sensitive to the rewarding effects of nicotine according to their DRD2 Taq1A genotype. It is thus especially important that these young people not be exposed to smoking in their social environment.

背景与目标： 背景：在青少年新手吸烟者中，渴望通常是尼古丁依赖的首发症状，也是报道最多的症状。直到现在，对于新手吸烟者的渴望症状的发展还知之甚少。这项研究的目的是确定特定的遗传因素（即DRD2 Taq1A，DRD4 48 bp VNTR和OPRM1 A118G多态性）和环境机制，这些机制是青春期新手吸烟者因提示和认知渴望而出现的。
方法：以遗传信息为基础的五波纵向调查，每四个月进行一次。该样本包括376名青少年早期吸烟者（基线年龄为12-13岁）。完成了关于吸烟行为，观察到的父母吸烟行为以及提示和认知渴望的自我报告调查表。
结果：数据采用潜伏增长曲线法进行了分析。对于提示诱导的和认知的渴望，发现DRD2 Taq1A与父母的烟雾接触具有显着的相互作用。在渴望发展方面，A1等位基因携带者似乎不受环境的影响。随着时间的流逝，对于A2-等位基因纯合的青少年和更容易接受父母吸烟的青少年，两种类型的渴望的水平最高。父母的烟雾暴露与DRD4 48 bp VNTR或OPRM1 A118G之间没有发现显着的相互作用。
结论：先前的研究确定DRD2 Taq1A A1等位基因携带者易受尼古丁依赖的发展。然而，这项研究表明，父母吸烟对于那些根据其DRD2 Taq1A基因型对尼古丁的奖励作用不那么敏感的早期青少年增加了更快发展依赖性的机会。因此，尤其重要的是，这些年轻人不要在其社交环境中接触吸烟。

BACKGROUND & AIMS: BACKGROUND:Emerging evidence has shown that the most common polymorphism (A118G; rs1799971 A>G) in the μ-opioid receptor (OPRM1) gene may influence the response to labor analgesia, but individually published studies showed inconclusive results. OBJECTIVE:This meta-analysis aimed to derive a more precise estimation of the effects of the OPRM1 A118G polymorphism on epidural analgesia with fentanyl during labor. METHODS:A literature search was conducted on PubMed, Embase, Web of Science, and China BioMedicine databases before April 1st, 2013. The crude standardized mean difference (SMD) or odds ratio (OR) with 95% confidence interval (CI) was calculated. RESULTS:Six clinical studies were included with a total 838 women who received epidural analgesia with fentanyl during labor. The meta-analysis results indicated that women carrying the G allele (AG+GG) of the OPRM1 A118G polymorphism required less fentanyl doses to achieve adequate pain relief compared with those with the AA homozygote (SMD=-0.24, 95% CI [-0.44, -0.03], p=0.022). The 118G variant was associated with a decreased ED50 of fentanyl for labor analgesia (SMD=-1.56, 95% CI [-1.97, -1.15], p<0.001). The analgesia satisfaction in women carrying the G allele (AG+GG) was higher than those with the AA homozygote (SMD=0.22, 95% CI [0.05, 0.39], p=0.012). However, there were no statistically significant differences between an AA homozygote and a G carrier (AG+GG) in the incidence of nausea and vomiting (OR=1.99, 95% CI [0.88, 4.52], p=0.101). CONCLUSION:In conclusion, the current meta-analysis indicates that women carrying the G allele (AG+GG) of OPRM1 A118G polymorphism may have a good response to epidural analgesia with fentanyl during labor. The OPRM1 A118G polymorphism may help predict individuals' response to epidural labor analgesia and so optimize postoperative pain control.

背景与目标： 背景：新兴证据表明，μ阿片受体（OPRM1）基因中最常见的多态性（A118G; rs1799971 A> G）可能影响对分娩镇痛的反应，但个别发表的研究结果尚无定论。
目的：本荟萃分析旨在更准确地评估OPRM1 A118G基因多态性对芬太尼分娩时硬膜外镇痛的影响。
方法：在2013年4月1日之前在PubMed，Embase，Web of Science和中国生物医学数据库上进行文献检索。计算出具有95％置信区间（CI）的粗标准均差（SMD）或比值比（OR）。 。
结果：共进行了六项临床研究，共有838名在分娩期间接受芬太尼硬膜外镇痛的妇女。荟萃分析结果表明，与AA纯合子相比，携带OPRM1 A118G多态性的G等位基因（AG GG）的女性需要较少的芬太尼剂量才能获得足够的疼痛缓解（SMD = -0.24，95％CI [-0.44， -0.03]，p = 0.022）。 118G变体与用于分娩镇痛的芬太尼ED50降低有关（SMD = -1.56，95％CI [-1.97，-1.15]，p <0.001）。携带G等位基因（AG GG）的女性的镇痛满意度高于AA纯合子的女性（SMD = 0.22，95％CI [0.05，0.39]，p = 0.012）。但是，AA纯合子和G携带者（AG GG）在恶心和呕吐的发生率上没有统计学上的显着差异（OR = 1.99，95％CI [0.88，4.52]，p = 0.101）。
结论：总而言之，当前的荟萃分析表明，携带OPRM1 A118G多态性的G等位基因（AG GG）的妇女在分娩时对芬太尼硬膜外镇痛有良好的反应。 OPRM1 A118G基因多态性可以帮助预测个体对硬膜外分娩镇痛的反应，从而优化术后疼痛控制。

BACKGROUND & AIMS: OBJECTIVE:We previously examined the expression of specific C-terminal μ-opioid receptor (MOR) splice variants in human central nervous system cell types and HIV-infected brain tissue from individuals with neurocognitive impairment ± HIV encephalitis (HIVE). In the present study, we examined the N-terminal splice variant MOR-1K, which mediates excitatory cellular signaling. METHODS AND RESULTS:We found segregation of expression ranging from undetectable to seemingly exclusive across nervous system cell types compared to the pool of C-terminal MOR splice variants using the real-time polymerase chain reaction (RT-PCR). Expression of MOR-1K mRNA was also increased in HIV-infected individuals with combined neurocognitive impairment and HIVE compared with the other groups. MOR-1K expression correlated with the level of patient neurocognitive impairment, whereas the pool of C-terminal MOR splice variants did not. HIVE was also associated with increased expression of the inflammatory mediators MCP-1, MCP-2, and RANTES, but not the host HIV coreceptors CXCR4 and CCR5 or the CD4 receptor using qRT-PCR. Network analysis of microarray data from these same patients revealed filamin A (FLNA) as a possible interaction partner with MOR-1K, and FLNA gene expression was also found to be upregulated in HIVE using qRT-PCR. Overexpression of FLNA in HEK293 cells redistributed MOR-1K from intracellular compartments to the cell surface. CONCLUSION:These results suggest that HIVE, and neurocognitive impairment depending on its severity, are associated with enhanced MOR-1K signaling through both increased expression and trafficking to the cell surface, which may alter the contribution of MOR receptor isoforms and exacerbate the effects of MOR activation in neuroAIDS.

背景与目标： 目的：我们先前研究了神经认知功能减退HIV脑炎（HIVE）患者的中枢神经系统细胞类型和HIV感染的脑组织中特定的C末端μ阿片受体（MOR）剪接变体的表达。在本研究中，我们研究了介导兴奋性细胞信号传导的N末端剪接变体MOR-1K。
方法和结果：我们发现，与实时聚合酶链反应（RT-PCR）的C端MOR剪接变体池相比，跨神经系统细胞类型的表达分离范围从不可检测到看似排斥。与其他组相比，在合并了神经认知障碍和HIVE的HIV感染者中，MOR-1K mRNA的表达也增加了。 MOR-1K表达与患者神经认知功能障碍的水平相关，而C端MOR剪接变体库则不相关。使用qRT-PCR，HIVE还与炎症介质MCP-1，MCP-2和RANTES的表达增加相关，但与宿主HIV核心受体CXCR4和CCR5或CD4受体表达无关。对来自这些相同患者的微阵列数据的网络分析显示，纤维蛋白A（FLNA）可能与MOR-1K相互作用，并且使用qRT-PCR还发现FLE基因表达在HIVE中被上调。 FLNA在HEK293细胞中的过表达将MOR-1K从细胞内区室重新分布到细胞表面。
结论：这些结果表明，HIVE和神经认知损害​​取决于其严重程度，通过增加的表达和向细胞表面的运输来增强MOR-1K信号传导，这可能会改变MOR受体亚型的作用并加剧MOR的作用神经艾滋病的激活。

BACKGROUND & AIMS: :The gene encoding the mu opioid receptor, OPRM1, contains at least two polymorphisms affecting protein sequence in exon 1, Ala6Val and Asp40Asn. In previous studies, each variant has been reported to be associated with some form of drug dependence. Although past reports have not been consistent, they have also not considered comparable populations. The goals of the present study were to delineate allele and haplotype frequencies of these variants in a range of populations, and in drug- or alcohol-dependent subjects deriving from some of those populations. We developed new PCR-RFLP methods to detect both of these polymorphisms and studied them in control and substance-dependent populations of African American (AA), European American (EA) and Hispanic origin, and in a series of populations differing in geographic origin (Japanese, Ethiopians, Bedouins, and Ashkenazi Jews), 891 subjects overall. We designed primers flanking the DNA segment containing both polymorphisms, each primer creating a different artificial restriction site, such that a single PCR reaction can be completed, then divided, and the PCR product digested with either of two enzymes to reveal both polymorphisms. We found that allele frequencies for both polymorphic systems were significantly different between AA and EA subjects, and there was significant heterogeneity among the more extensive set of populations. Furthermore, there were no significant differences in allele frequency by diagnosis; that is, neither polymorphism appears to be a direct risk factor for substance dependence. Finally, we demonstrated linkage disequilibrium between the two exon 1 markers, and a previously described short tandem repeat (STR) marker.

背景与目标： ：编码阿片类阿片受体OPRM1的基因包含至少两个多态性，影响外显子1，Ala6Val和Asp40Asn中的蛋白质序列。在以前的研究中，已报道每种变体与某种形式的药物依赖性相关。尽管过去的报告不一致，但也没有考虑可比人群。本研究的目的是在一系列人群中以及在其中某些人群衍生的药物或酒精依赖性受试者中描绘这些变异的等位基因和单倍型频率。我们开发了新的PCR-RFLP方法来检测这两种多态性，并在非洲裔美国人（AA），欧美人（EA）和西班牙裔血统的控制和依赖物质的人群以及地理起源不同的一系列人群中进行了研究（日本人，埃塞俄比亚人，贝都因人和阿什肯纳兹犹太人），共有891个科目。我们设计了包含两个多态性的DNA片段侧翼的引物，每个引物创建了一个不同的人工限制性酶切位点，这样就可以完成一个PCR反应，然后将其分开，然后用两种酶之一消化PCR产物以揭示这两个多态性。我们发现，AA和EA受试者的两个多态性系统的等位基因频率都存在显着差异，并且在更广泛的人群中存在显着的异质性。此外，根据诊断，等位基因频率没有显着差异。也就是说，多态性似乎都不是物质依赖的直接危险因素。最后，我们证明了两个外显子1标记与先前描述的短串联重复（STR）标记之间的连锁不平衡。

BACKGROUND & AIMS: :Variations of the µ-opioid receptor gene OPRM1 have been shown to modulate pain perception with some evidence pointing towards a modulation of not only physical but also "psychological pain". In line with suggestions of a common neural network involved in the processing of physical pain and negative and distressing stimuli, like social rejection as a psychologically harmful event, we examined the influence of the A118G polymorphism on the neural processing of physical and non-physical pain. Using fMRI, we investigated a sample of 23 females with the more frequent AA genotype, and eight females with the relatively rare but more pain-sensitive AG genotype during electrical stimulation to the dorsum of the non-dominant hand. Non-physical pain was investigated using Cyberball, a virtual ball-tossing game, to induce experiences of non-self-dependent social rejection. A Go/NoGo task with an increased risk of self-dependent erroneous performance was used as a control task to investigate the effects of negative feedback as a more cognitive form of distress. Relative to A118G homozygous A-allele carriers, G-allele carriers showed significantly increased activation of the supplementary motor area/superior frontal gyrus and the precentral gyrus during electrical stimulation. Increased activation of the secondary sensorimotor cortex (SII) was found during social exclusion and during negative feedback. We demonstrate that brain regions particularly related to the somatosensory component of pain processing are modulated by variations in OPRM1. Influences were evident for both physical and psychological pain processing supporting the assumption of shared neural pathways.

背景与目标： ：μ阿片受体基因OPRM1的变化已显示出可调节疼痛感，一些证据表明不仅对生理上的而且对“心理上的疼痛”也有调节作用。根据涉及处理身体疼痛以及负面和令人沮丧的刺激的常见神经网络的建议（例如社会排斥是一种对心理有害的事件），我们研究了A118G多态性对身体和非身体疼痛的神经处理的影响。使用fMRI，我们在电刺激非优势手背的过程中调查了23位AA基因型频率更高的女性和8位相对罕见但对疼痛敏感的AG基因型的女性。使用虚拟投球游戏Cyber​​ball调查了非身体上的疼痛，以引发非自立型社会排斥的经历。自我控制错误行为风险增加的Go / NoGo任务被用作控制任务，以调查负反馈作为一种更痛苦的认知形式的影响。相对于A118G纯合的A等位基因携带者，G等位基因携带者在电刺激过程中显示补充运动区/上额回和中央前回的激活显着增加。在社交排斥和负反馈过程中，发现次级感觉运动皮层（SII）的激活增加。我们证明，与疼痛处理的体感成分特别相关的大脑区域受到OPRM1变异的调节。生理和心理疼痛处理的影响均很明显，这支持了共享神经通路的假设。

BACKGROUND & AIMS: BACKGROUND:Postoperative pain management remains a challenge for clinicians due to unpredictable patient responses to opioid therapy. Some of this variability may result from single nucleotide polymorphisms (SNPs) of the human opioid mu-1 receptor (OPRM1) that modify receptor binding or signal transduction. The OPRM1 variant with the highest frequency is the A118G SNP. However, previous studies have produced inconsistent results regarding the clinical effects of A118G on opioid response. We hypothesized that measurement of serum opioid concentrations, in addition to determining total opioid consumption, may provide a more precise method of assessing the effects of A118G on analgesic response. The current study evaluated the relationship of analgesia, side effects, total hydrocodone consumption, quantitative serum hydrocodone and hydromorphone concentrations, and A118G SNP in postoperative patients following Cesarean section. METHODS:158 women scheduled for Cesarean section were enrolled prospectively in the study. The patients had bupivacaine spinal anesthesia for surgery and received intrathcal morphine with the spinal anesthetic or parenteral morphine for the first 24 hours after surgery. Thereafter, patients received hydrocodone/acetaminophen for postoperative pain control. On postoperative day 3, venous blood samples were obtained for OPRM1 A118G genotyping and serum opioid concentrations. RESULTS:131 (82.9%) of the subjects were homozygous for the 118A allele of OPRM1 (AA) and 27 (17.1%) carried the G allele (AG/GG). By regression analysis, pain relief was significantly associated with total hydrocodone dose in the AA group (P = 0.01), but not in the AG/GG group (P = 0.554). In contrast, there was no association between pain relief and serum hydrocodone concentration in either group. However, pain relief was significantly associated with serum hydromorphone concentration (a metabolite of hydrocodone) in the AA group (P = 0.004), but not in the AG/GG group (P = 0.724). Conversely, side effects were significantly higher (P < 0.04) in the AG/GG group (mean = 6.4) than in the AA group (mean = 4.4), regardless of adjustment for BMI, pain level, or total dose of hydrocodone. CONCLUSION:This study found a correlation between pain relief and total hydrocodone dose in patients homozygous for the 118A allele (AA) of the OPRM1 gene, but not in patients with the 118G allele (AG/GG). However, pain relief in 118A patients did not correlate with serum hydrocodone concentrations, but rather with serum hydromorphone levels, the active metabolite of hydrocodone. This suggests that pain relief with hydrocodone may be due primarily to hydromorphone. Although pain relief did not correlate with opioid dose in AG/GG patients, they had a higher incidence of opioid side effects. The correlations identified in this study may reflect the fact that serum opioid concentrations were measured directly, avoiding the inherent imprecision associated with relying solely on total opioid consumption as a determinant of opioid effectiveness. Thus, measurement of serum opioid concentrations is recommended when assessing the role of OPRM1 variants in pain relief. This study supports pharmacogenetic analysis of OPRM1 in conjunction with serum opioid concentrations when evaluating patient responses to opioid therapy.

背景与目标： 背景：由于患者对阿片类药物治疗的反应无法预测，术后疼痛管理仍然是临床医生面临的挑战。这种可变性中的某些可能是由于人类阿片样物质mu-1受体（OPRM1）的单核苷酸多态性（SNP）改变了受体结合或信号转导。频率最高的OPRM1型号是A118G SNP。但是，先前的研究在A118G对阿片样物质反应的临床效果方面产生不一致的结果。我们假设测量血清阿片类药物的浓度，除了确定阿片类药物的总消耗量外，还可以提供一种更精确的方法来评估A118G对镇痛作用的影响。本研究评估了剖宫产术后患者的镇痛，副作用，氢可酮总消耗量，血清氢可酮和氢吗啡酮定量浓度以及A118G SNP的关系。
方法：158名预定剖腹产的妇女被纳入研究对象。患者接受布比卡因脊柱麻醉以进行手术，并且在手术后的最初24小时内接受鞘内注射吗啡和脊髓麻醉剂或肠胃外吗啡。此后，患者接受氢可酮/对乙酰氨基酚进行术后疼痛控制。术后第3天，获得静脉血样本以进行OPRM1 A118G基因分型和血清阿片样物质浓度。
结果：131名受试者（82.9％）与OPRM1（AA）的118A等位基因是纯合的，其中27名（17.1％）带有G等位基因（AG / GG）。通过回归分析，在AA组中疼痛缓解与氢可酮的总剂量显着相关（P = 0.01），而在AG / GG组中则没有（P = 0.554）。相反，两组的疼痛缓解和血清氢可酮浓度之间均无关联。但是，AA组（P = 0.004）而血清氢吗啡酮浓度（氢可酮的代谢产物）与疼痛缓解显着相关（P = 0.004），而AG / GG组则没有（P = 0.724）。相反，无论BMI，疼痛程度或氢可酮总量如何调整，AG / GG组（平均= 6.4）的副作用均显着高于AA组（平均= 4.4）（P = 0.04）。
结论：本研究发现，对于OPRM1基因118A等位基因（AA）纯合的患者，止痛与总氢可酮剂量之间存在相关性，而对于118G等位基因（AG / GG）的患者而言，止痛与总氢可酮剂量之间没有相关性。然而，118A患者的疼痛缓解与血清氢可酮浓度无关，而与血清氢吗啡酮水平（氢可酮的活性代谢产物）相关。这表明氢可酮缓解疼痛可能主要归因于氢吗啡酮。尽管在AG / GG患者中疼痛缓解与阿片类药物剂量无关，但他们具有更高的阿片类药物副作用发生率。在这项研究中确定的相关性可能反映了直接测量血清阿片类药物浓度的事实，避免了仅依赖于总阿片类药物的消耗量来确定阿片类药物有效性的内在不精确性。因此，在评估OPRM1变异体在缓解疼痛中的作用时，建议测量血清阿片类药物的浓度。这项研究在评估患者对阿片类药物治疗的反应时，结合血清阿片类药物浓度支持OPRM1的药物遗传学分析。

BACKGROUND & AIMS: :Genomic duplications spanning Xq28 are associated with a spectrum of phenotypes, including anxiety and autism. The minimal region shared among affected individuals includes MECP2 and IRAK1, although it is unclear which gene when overexpressed causes anxiety and social behavior deficits. We report that doubling MECP2 levels causes heightened anxiety and autism-like features in mice and alters the expression of genes that influence anxiety and social behavior, such as Crh and Oprm1. To test the hypothesis that alterations in these two genes contribute to heightened anxiety and social behavior deficits, we analyzed MECP2 duplication mice (MECP2-TG1) that have reduced Crh and Oprm1 expression. In MECP2-TG1 animals, reducing the levels of Crh or its receptor, Crhr1, suppressed anxiety-like behavior; in contrast, reducing Oprm1 expression improved abnormal social behavior. These data indicate that increased MeCP2 levels affect molecular pathways underlying anxiety and social behavior and provide new insight into potential therapies for MECP2-related disorders.

背景与目标： ：跨越Xq28的基因组重复与一系列表型有关，包括焦虑症和自闭症。在受影响的个体之间共享的最小区域包括MECP2和IRAK1，尽管不清楚哪个基因过表达会导致焦虑和社交行为缺陷。我们报告说，将MECP2水平提高一倍会引起小鼠焦虑和自闭症样症状的加剧，并改变影响焦虑和社交行为的基因的表达，例如Crh和Oprm1。为了检验以下假设：这两个基因的改变会加剧焦虑和社交行为缺陷，我们分析了Crh和Oprm1表达降低的MECP2复制小鼠（MECP2-TG1）。在MECP2-TG1动物中，降低Crh或其受体Crhr1的水平可抑制焦虑样行为；相反，减少Oprm1表达可改善异常社交行为。这些数据表明，增加的MeCP2水平会影响潜在的焦虑和社交行为的分子途径，并为与MECP2相关的疾病的潜在疗法提供新的见解。

BACKGROUND & AIMS: :Activation of mesolimbic mu-opioid receptors by their endogenous ligand, β-endorphin, can mediate the rewarding effects of alcohol. However, there is conflicting evidence on the relationship between the mu-opioid receptor (OPRM1) A118G single nucleotide polymorphism (SNP) and alcohol dependence risk. Preclinical evidence suggests that sex and sex hormone-dependent prenatal brain organization may interact with the opioid system to influence alcohol drinking behavior. We genotyped 200 alcohol-dependent patients and 240 healthy individuals for the OPRM1 A118G SNP and measured serum β-endorphin level at recruitment and after acute withdrawal. We then determined the association between these factors and alcohol dependence risk and 24-month outcome in the context of both sex and second-to-fourth digit lengths ratio (2D:4D) - a biomarker of prenatal sex hormone levels. The OPRM1 A118G AA genotype associated with elevated risk of alcohol-related hospital readmission, more readmissions, and fewer days until first readmission in male patients only. After normalizing patient 2D:4D against control 2D:4D, we found that normalized 2D:4D ratios were lower in male 118G patients than male AA patients, suggesting prenatal androgens interact with OPRM1 to influence alcohol dependence risk. In addition, β-endorphin levels after acute withdrawal correlated negatively with withdrawal severity in females but not in males, which may indicate β-endorphin protects against withdrawal-induced stress in a sex-specific manner.

背景与目标： ：中枢边缘类阿片受体通过其内源性配体β-内啡肽的激活可以介导酒精的有益作用。但是，关于μ阿片受体（OPRM1）A118G单核苷酸多态性（SNP）与酒精依赖风险之间的关系有相互矛盾的证据。临床前证据表明，性和依赖性激素的产前大脑组织可能与阿片样物质系统相互作用，从而影响饮酒行为。我们对200名酒精依赖患者和240名健康个体的OPRM1 A118G SNP进行了基因分型，并在募集时和急性停药后测量了血清β-内啡肽水平。然后，我们在性别和第二至第四位数长度比（2D：4D）的背景下确定了这些因素与酒精依赖风险和24个月结局之间的关联-产前性激素水平的生物标记。仅男性患者中，OPRM1 A118G AA基因型与酒精相关的医院再次入院，更多的再次入院和更少的天数相关。在将患者2D：4D与对照2D：4D标准化后，我们发现男性118G患者的标准化2D：4D比率低于男性AA患者，这表明产前雄激素与OPRM1相互作用会影响酒精依赖风险。另外，急性戒断后的β-内啡肽水平与女性的戒断严重程度呈负相关，而与男性无关，这可能表明β-内啡肽以性别特异性的方式保护免受戒断诱发的压力。

BACKGROUND & AIMS: :Evidence gained from animals and humans suggests that the encephalic opioid system might be involved in the development of drug addiction through its role in reward. Our aim is to assess the influence of genetic variations in the opioid receptor mu 1 on alcohol and tobacco consumption in a Spanish population. 763 unrelated individuals (465 women, 298 men) aged 18-85 years were recruited between October 2011 and April 2012. Participants were requested to answer a 35-item questionnaire on tobacco and alcohol consumption, as well as to complete the AUDIT and Fagerström tests. Individuals were genotyped for three polymorphisms in the opioid receptor mu 1 (OPRM1) gene, using a TaqMan protocol. In males, the rs10485057 polymorphism was associated with total pure ethanol intake and with the risk of being an alcohol consumer. Also, this polymorphism was significantly associated with higher Fagerström scores. Rs1799971 had a different influence on adaptive and maladaptive patterns of alcohol use. Despite the limited sample size, our study might enrich current knowledge on patterns of alcohol use, because it encompasses both extreme and adaptive phenotypes, providing thus a wider perspective on this subject.

背景与目标： ：从动物和人类获得的证据表明，脑阿片样物质系统可能通过其在奖励中的作用而参与了药物成瘾的发展。我们的目的是评估阿片类药物受体mu 1的遗传变异对西班牙人群烟酒消费的影响。在2011年10月至2012年4月之间，招募了763名年龄在18-85岁之间的无关个体（465名女性，298名男性）。参与者被要求回答有关烟酒消费的35项问卷，并完成AUDIT和Fagerström测试。使用TaqMan协议，对个体的阿片受体mu 1（OPRM1）基因中的三个多态性进行基因分型。在男性中，rs10485057多态性与总的纯乙醇摄入量和饮酒的风险有关。而且，这种多态性与较高的Fagerström分数显着相关。 Rs1799971对适应性和不良适应性饮酒模式有不同的影响。尽管样本量有限，但我们的研究可能会丰富有关酒精使用模式的最新知识，因为它涵盖了极端表型和适应性表型，因此为该主题提供了更广阔的视野。