BACKGROUND & AIMS: BACKGROUND:Pharmacotherapy of alcohol dependence (AD) is at an early stage of development; currently available medications have limited efficacy. It would be clinically valuable to identify, before initiation of a course of treatment, those patients who, based on genetic markers, are most likely to respond to a specific pharmacotherapy. A previous report suggested that a functional variant at the genetic locus encoding the mu opioid receptor (Asn40Asp) is such a marker, in short-term (3-month) treatment with the opioid-blocking drug naltrexone (NTX). METHODS:We studied polymorphic variants at each of the 3 opioid receptor genes--OPRM1, OPRD1, and OPRK1, which encode the mu, delta, and kappa opioid receptors, respectively--including the OPRM1 Asn40Asp variant--as predictors of response to NTX or placebo in 215 alcohol-dependent male subjects who participated in Veterans Affairs Cooperative Study 425, "Naltrexone in the Treatment of Alcohol Dependence." RESULTS:At the 3-month time point, treatment condition, age, and the pretreatment number of drinks per drinking day were all significant (p<0.05) predictors of the rate of relapse and time to relapse. Although NTX had no significant effect on relapse to heavy drinking in the overall sample in CSP 425, it significantly reduced relapse in the subgroup that provided DNA for analysis (i.e., the present study sample). There were no significant interactions between any individual single nucleotide polymorphisms studied and NTX treatment response. CONCLUSIONS:These results do not support association of the OPRM1 Asn40Asp polymorphism with NTX treatment response for AD.

背景与目标： 背景：酒精依赖（AD）的药物治疗尚处于发展初期。目前可用的药物疗效有限。在开始一个疗程之前，根据遗传标记确定最有可能对特定药物疗法产生反应的患者，在临床上具有重要的临床价值。先前的一份报告表明，在短期（3个月）使用阿片类药物阻断剂纳曲酮（NTX）治疗的情况下，编码mu阿片受体（Asn40Asp）的遗传基因座处的功能变异就是这样的标记。
方法：我们研究了3种阿片受体基因-OPRM1，OPRD1和OPRK1的多态变异体，它们分别编码mu，delta和kappa类阿片受体-包括OPRM1 Asn40Asp变异体-作为对反应的预测因子参加退伍军人事务合作研究425，“纳曲酮治疗酒精依赖性”的215名酒精依赖性男性受试者中的NTX或安慰剂。
结果：在三个月的时间点上，治疗条件，年龄和每个饮酒日的预处理次数均是复发率和复发时间的重要预测指标（p <0.05）。尽管NTX在CSP 425的整个样本中对重度饮酒的复发没有显着影响，但它显着降低了提供DNA进行分析的亚组（即本研究样本）的复发。在研究的任何单个单核苷酸多态性与NTX治疗反应之间没有显着的相互作用。
结论：这些结果不支持OPRM1 Asn40Asp多态性与AD的NTX治疗反应的关联。

BACKGROUND & AIMS: :Previous studies have shown significant associations between OPRK1 and susceptibility to opioid dependence and the relationships between libido dysfunction and insomnia among opium addicts who underwent methadone maintenance treatment. The authors investigated the single locus and haplotype association of rs997917, rs6985606, and rs6473797 with susceptibility to opioid addiction. Samples were selected among 202 healthy individuals and 202 opium addicts undergoing methadone maintenance treatment. Genomic DNA was extracted from the whole blood samples of all subjects through a salting out procedure. All three variants were genotyped in the studied subjects using Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR). The whole analysis process was performed using SNPAlyze and SPSS ver.20 software packages. According to the single locus analyses, rs997917 and rs6985606 represented significant associations with opium addiction under recessive (p = 0.0128) and co-dominant (p = 0.0001) inheritance models, respectively. The haplotypes C-T-C (Permutation p = 0.014) and C-T-T (Permutation p = 0.0002) were significantly associated with opioid dependence. Among methadone maintenance treatment individuals, rs997917 was significantly associated with insomnia in both allelic and genotypic levels (p = 0.0001 and p = 0.038, respectively). Furthermore, rs6985606 had the only significant association with the co-incidence of insomnia and libido dysfunction in the methadone maintenance treatment group (p = 0.038). The OPRK1 gene variants showed significant association with susceptibility to opioid dependence among Iranians.

背景与目标： ：以前的研究表明，接受美沙酮维持治疗的鸦片成瘾者中OPRK1与阿片类药物依赖性的易感性以及性欲障碍和失眠之间的关系密切。作者研究了rs997917，rs6985606和rs6473797与阿片类药物成瘾的易感性的单一基因座和单倍型关联。从接受美沙酮维持治疗的202名健康个体和202名鸦片成瘾者中选择样本。通过盐析法从所有受试者的全血样品中提取基因组DNA。使用扩增难治性突变系统-聚合酶链反应（ARMS-PCR）在研究对象中对所有三个变体进行基因分型。整个分析过程使用SNPAlyze和SPSS ver.20软件包执行。根据单基因座分析，rs997917和rs6985606分别与隐性（p = 0.0128）和共同主导（p = 0.0001）遗传模型下的鸦片成瘾显着相关。单倍型C-T-C（排列p = 0.014）和C-T-T（排列p = 0.0002）与阿片样物质依赖性显着相关。在美沙酮维持治疗个体中，rs997917与等位基因和基因型水平的失眠显着相关（分别为p = 0.0001和p = 0.038）。此外，在美沙酮维持治疗组中，rs6985606与失眠和性欲功能障碍的同时发生仅有显着关联（p = 0.038）。 OPRK1基因变异与伊朗人对阿片类药物依赖性的敏感性显着相关。

BACKGROUND & AIMS: :Variations in OPRK1, which encodes the kappa-opioid receptor, are associated with the risk for alcohol dependence. Sequencing DNAs with higher and lower risk haplotypes revealed an insertion/deletion (indel) with a net addition of 830 bp located 1986 bp upstream of the translation start site (1389 bp upstream of the transcription start site). We demonstrated that the upstream region extending from -1647 to -10 bp or from -2312 to -10 bp (relative to the translation start site) could function as a promoter in transient transfection assays. We then determined that the presence of the indel reduced transcriptional activity by half. We used a PCR assay to genotype individuals in 219 multiplex alcohol-dependent families of European American descent for the presence or absence of this indel. Family-based association analyses detected significant evidence of association of this insertion with alcoholism; the longer allele (with the indel), which had lower expression, is associated with higher risk for alcoholism. This indel is, therefore, a functional regulatory variation likely to explain at least part of the association of OPRK1 with alcohol dependence.

背景与目标： ：编码RK-阿片受体的OPRK1的变异与酒精依赖的风险有关。具有较高和较低风险单倍型的DNA测序显示插入/缺失（插入缺失），在翻译起始位点上游1986 bp（转录起始位点上游1389 bp）处净增加了830 bp。我们证明上游区域从-1647延伸到-10 bp或从-2312延伸到-10 bp（相对于翻译起始位点）可以在瞬时转染测定中起启动子的作用。然后，我们确定indel的存在使转录活性降低了一半。我们使用PCR分析法对欧洲裔的219个多重酒精依赖家族的个体进行基因分型，以确定是否存在此indel。基于家庭的关联分析发现了明显的证据表明这种插入与酒精中毒有关；具有较低表达的较长等位基因（具有插入缺失）与酒精中毒的风险较高相关。因此，该插入缺失是功能性调节变异，可能至少解释了OPRK1与酒精依赖性的关联的至少一部分。

BACKGROUND & AIMS: :The kappa opioid receptor (KOR) plays a role in stress responsivity, opiate withdrawal and responses to cocaine. KOR activation by its endogenous ligand dynorphin A(1-17) decreases basal and drug-induced striatal levels of dopamine. The complete structure of the human KOR gene (hOPRK1) has not been previously determined. This study: (i) characterized the genomic structure of the hOPRK1 gene; (ii) identified single nucleotide polymorphisms (SNPs) in the hOPRK1 gene; and (iii) investigated possible associations of these variants with vulnerability to develop heroin addiction. Analysis of 5'-RACE cDNA clones revealed the presence of a novel exon 1 ranging in length from 167 to 251 nucleotides in the 5' 5'-untranslated region of the hOPRK1 mRNA. We found that the hOPRK1 gene has four major exons and three introns, similar to rodent OPRK1 genes. Direct sequencing of amplified DNA containing all four exons and intron 1 of the hOPRK1 gene were evaluated for polymorphisms in 291 subjects (145 former heroin addicts and 146 controls). Twelve SNPs were identified, nine novel variants and three previously reported SNPs. Using logistic regression with opioid dependence as the dependent variable, the 36G>T SNP exhibited a point-wise significant association (P = 0.016) with disease status. The number of haplotypes seen in the three ethnic groups were nine, six and five for African-Americans, Caucasians, and Hispanics, respectively, with corresponding significance levels for differences in haplotype frequencies between cases and controls of P = 0.0742, 0.1015 and 0.0041. Combining ethnicities by Fisher's method yields an empirical significance level of P = 0.0020.

背景与目标： ：κ阿片受体（KOR）在应激反应，阿片戒断和对可卡因的反应中起作用。 KOR激活通过其内源性配体强啡肽A（1-17）降低基础和药物引起的纹状体多巴胺水平。人KOR基因（hOPRK1）的完整结构以前尚未确定。这项研究：（i）鉴定了hOPRK1基因的基因组结构； （ii）在hOPRK1基因中鉴定出单核苷酸多态性（SNP）； （iii）研究了这些变异与海洛因成瘾易感性之间的可能联系。 5'-RACE cDNA克隆的分析表明，在hOPRK1 mRNA的5'5'非翻译区中存在长度为167至251个核苷酸的新型外显子1。我们发现hOPRK1基因具有四个主要外显子和三个内含子，与啮齿动物OPRK1基因相似。在291名受试者（145名前海洛因成瘾者和146名对照）中，对包含hOPRK1基因的所有四个外显子和内含子1的扩增DNA的直接测序进行了多态性评估。鉴定出十二个SNP，九个新变体和三个先前报道的SNP。使用阿片类药物依赖性作为因变量的逻辑回归，36G> T SNP与疾病状况呈逐点显着相关性（P = 0.016）。在这三个族裔群体中，非裔美国人，白种人和西班牙裔分别看到的单倍型数量分别为九，六和五，对于病例与对照之间的单倍型频率差异，相应的显着性水平为P = 0.0742、0.1015和0.0041。通过费舍尔方法将种族组合在一起，得出的经验显着性水平为P = 0.0020。

BACKGROUND & AIMS: :Chronic inflammation may contribute to neuropsychological impairments in individuals with HIV, and modulation of this inflammatory response by opiate receptor ligands is important in light of the prevalence of drug use in HIV populations. Exogenous MOR and KOR agonists have differential effects on central nervous system (CNS) immunity and, while some data suggest KOR agonists are immunosuppressive, the KOR agonist dynorphin has been shown to stimulate human monocyte chemotaxis. In this study, we examined mRNA levels of endogenous opioid receptors OPRK1 and OPRM1, prodynorphin (PDYN), macrophage scavenger receptor CD163, and microglia/macrophage marker CD68 in the caudate and anterior cingulate of postmortem brains from HIV-positive and HIV-negative subjects. Brain tissues of HIV-infected (n = 24) and control subjects (n = 15) were obtained from the Manhattan HIV Brain Bank. Quantification of the gene mRNA was performed using SYBR Green RT-PCR. CD68 and CD163 were increased in HIV-positive (HIV+) compared to HIV-negative (HIV-) individuals in both brain regions. There were higher OPRK1 (P <0.005), and lower PDYN mRNA (P <0.005) levels in the anterior cingulate of HIV+ compared to HIV- subjects. This difference between the clinical groups was not found in the caudate. There was no difference in the levels of OPRM1 mRNA between HIV+ and HIV- subjects. Using linear regression analysis, we examined the relationship of OPRK1 and PDYN mRNA levels in the HIV+ subjects with seven cognitive domain T scores of a neuropsychological test battery. Within the HIV+ subjects, there was a positive correlation between anterior cingulate PDYN mRNA levels and better T-scores in the motor domain. Within the HIV+ subjects there were also positive correlations of both OPRK1 and PDYN mRNA levels with the anti-inflammatory marker CD163, but not with proinflammatory CD68 levels. In this setting, decreased PDYN mRNA may reflect a homeostatic mechanism to reduce monocyte migration, accompanied by compensatory increases in the cognate receptor (KOR) to dampen pro-inflammatory responses. It is possible that enhanced neuroprotection and better motor performance are associated with higher levels of dynorphin and the recruitment of neuroprotective CD163-positive macrophages. Further studies are needed to test this hypothesis.

背景与目标： ：慢性炎症可能会导致HIV感染者的神经心理损害，并且鉴于HIV人群中的药物滥用情况，鸦片受体配体对这种炎症反应的调节非常重要。外源性MOR和KOR激动剂对中枢神经系统（CNS）免疫具有不同的作用，尽管一些数据表明KOR激动剂具有免疫抑制作用，但KOR激动剂强啡肽已显示出刺激人单核细胞趋化性。在这项研究中，我们检查了来自HIV阳性和HIV阴性受试者的死后脑尾状和前扣带状内源性阿片受体OPRK1和OPRM1，前降冰片（PDYN），巨噬细胞清除剂受体CD163和小胶质/巨噬细胞标记CD68的mRNA水平。 。 HIV感染者（n = 24）和对照对象（n = 15）的脑组织是从Manhattan HIV Brain Bank获得的。使用SYBR Green RT-PCR对基因mRNA进行定量。与两个脑区的HIV阴性（HIV-）个体相比，HIV阳性（HIV）的CD68和CD163升高。与受试者相比，HIV的前扣带中有较高的OPRK1（P <0.005）和较低的PDYN mRNA（P <0.005）水平。在尾状体中未发现临床组之间的这种差异。 HIV和HIV受试者之间的OPRM1 mRNA水平没有差异。使用线性回归分析，我们用一个神经心理学测试电池的七个认知域T分数检查了HIV受试者中OPRK1和PDYN mRNA水平的关系。在HIV感染者中，前扣带回PDYN mRNA水平与运动区较好的T分数之间存在正相关。在HIV感染者中，OPRK1和PDYN mRNA水平也与抗炎标记CD163呈正相关，而与促炎CD68则无正相关。在这种情况下，PDYN mRNA的减少可能反映了一种稳态机制，以减少单核细胞迁移，并伴随着同源受体（KOR）的代偿性增加，以抑制促炎反应。增强的神经保护作用和更好的运动表现可能与强啡肽水平升高和神经保护性CD163阳性巨噬细胞募集有关。需要进一步的研究来检验这个假设。

BACKGROUND & AIMS: BACKGROUND:Despite proven heritability, little is known about the genetic architecture of mood disorders. Although a number of family and case-control studies have examined the genetics of mood disorders, none have carried out joint linkage-association studies and sought to validate the results with gene expression analyses in an independent cohort. METHODS:We present findings from a large candidate gene study that combines linkage and association analyses using families and singletons, providing a systematic candidate gene investigation of mood disorder. For this study, 876 individuals were recruited, including 83 families with 313 individuals and 563 singletons. This large-scale candidate gene analysis included 130 candidate genes implicated in addictive and other psychiatric disorders. These data showed significant genetic associations for 28 of these candidate genes, although none remained significant after correction for multiple testing. To evaluate the functional significance of these 28 candidate genes in mood disorders, we examined the transcriptional profiles of these genes within the dorsolateral prefrontal cortex and anterior cingulate for 21 cases with mood disorders and 25 nonpsychiatric controls, and carried out a pathway analysis to identify points of high connectivity suggestive of particular molecular pathways that may be dysregulated. RESULTS:Two primary gene candidates were supported by the linkage-association, gene expression profiling, and network analysis: neurotrophic tyrosine kinase receptor, type 2 (NTRK2), and the opioid receptor, κ1 (OPRK1). CONCLUSION:This study supports a role for NTRK2 and OPRK1 signaling in the pathophysiology of mood disorder. The unique approach incorporating evidence from multiple experimental and computational modalities enhances confidence in these findings.

背景与目标： 背景：尽管遗传力得到证实，但对情绪障碍的遗传结构知之甚少。尽管许多家庭和病例对照研究已经检查了情绪障碍的遗传学，但没有一项进行联合连锁关联研究，并试图通过独立队列中的基因表达分析来验证结果。
方法：我们提出了一项来自大型候选基因研究的发现，该研究结合了使用家族和单身人士的连锁和关联分析，为情绪障碍提供了系统的候选基因研究。这项研究招募了876个人，包括83个家庭，其中313个人和563单身人士。这项大规模的候选基因分析包括130项与成瘾性和其他精神疾病有关的候选基因。这些数据显示了其中28个候选基因的显着遗传关联，尽管在进行多次测试校正后，这些关联都没有显着性。为了评估这28个候选基因在情绪障碍中的功能意义，我们检查了21例情绪障碍和25个非精神病患者的背外侧前额叶皮层和前扣带回中这些基因的转录谱，并进行了通路分析以识别点高连通性表明可能失调的特定分子途径。
结果：两个主要的候选基因得到了连锁关联，基因表达谱和网络分析的支持：神经营养型酪氨酸激酶受体2型（NTRK2）和阿片受体κ1（OPRK1）。
结论：本研究支持NTRK2和OPRK1信号传导在情绪障碍的病理生理中的作用。独特的方法结合了来自多种实验和计算方式的证据，增强了对这些发现的信心。

BACKGROUND & AIMS: :Genetic polymorphisms have been shown to affect opioid requirement for pain relief. However, true genetic effect is often difficult to assess due to underlying pain conditions and placebo effects. The goal of this study was to understand how common polymorphisms affect opioid effects while controlling for these factors. A randomized, double-blind, placebo-controlled study was implemented to assess how opioid effects are modulated by COMT (rs6269, rs4633, rs4848, rs4680), OPRM1 (A118G), and OPRK1 (rs1051660, rs702764, rs16918875). One hundred and eight healthy subjects underwent experimental pain testing before and after morphine, butorphanol, and placebo (saline). Association analysis was performed between polymorphisms/haplotypes and opioid response, while correcting for race, gender, placebo effects, and multiple comparisons. Pressure pain was significantly associated with rs6269 and rs4633 following butorphanol. The AA genotype of rs4680 or A_T_C_A/ A_T_C_A (rs6269_rs4633_ rs4818_rs4680) diplotype of COMT, combined with the AG genotype of OPRM1 A118G, showed significantly increased pressure pain threshold from butorphanol. Opioid effects on pressure, ischemic, heat pain, and side effects were nominally associated with several SNPs and haplotypes. Effects were often present in one opioid but not the other. This indicates that these polymorphisms affect pain relief from opioids, and that their effects are opioid and pain modality specific.

背景与目标： ：遗传多态性已显示会影响阿片类药物缓解疼痛的需求。但是，由于潜在的疼痛状况和安慰剂作用，通常很难评估真正的遗传作用。这项研究的目的是了解常见的多态性如何在控制这些因素的同时影响阿片类药物的作用。已实施一项随机，双盲，安慰剂对照的研究，以评估COMT（rs6269，rs4633，rs4848，rs4680），OPRM1（A118G）和OPRK1（rs1051660，rs702764，rs16918875）如何调节阿片类药物的作用。 108名健康受试者在吗啡，布托啡诺和安慰剂（盐水）之前和之后进行了实验性疼痛测试。在校正种族，性别，安慰剂效应和多重比较的同时，在多态性/单倍型与阿片样物质反应之间进行了关联分析。布托啡诺后rs6269和rs4633与压力疼痛显着相关。 rs4680或A_T_C_A / A_T_C_A（rs6269_rs4633_ rs4818_rs4680）双倍体的AA基因型与OPRM1 A118G的AG基因型相结合，显示了丁烷酚的压力疼痛阈值明显增加。阿片类药物对压力，局部缺血，热痛和副作用的影响名义上与几种SNP和单倍型有关。一种阿片类药物常有作用，而另一种则无作用。这表明这些多态性影响阿片类药物的镇痛作用，并且其作用是阿片类药物和特定疼痛方式的结果。

BACKGROUND & AIMS: :Opioid receptors and their endogenous peptide ligands play important roles in neurotransmission and neuromodulation in response to addictive drugs such as heroin, cocaine, and alcohol. In an earlier study, we reported that variation in the genes encoding the kappa-opioid receptor (OPRK1) and its peptide ligand (PDYN) were associated with the risk for alcoholism. We continued our investigation of the role of the opioid system in alcohol dependence by analyzing the genes encoding the micro- and delta-opioid receptors and their peptide ligands. We analyzed 18 OPRM1 SNPs, 18 OPRD1 SNPs, 7 PENK SNPs, and 7 POMC SNPs in a sample of 1923 European Americans from 219 multiplex alcohol dependent families. Employing a family-based test of association, we found no evidence that these four genes were significantly associated with alcohol dependence. We also did not find association between these genes and illicit drug dependence. Secondary analyses employing the narrower phenotype of opioid dependence (83 affected individuals) demonstrated association with SNPs in PENK and POMC, but not in OPRM1 or OPRD1. Haplotype analyses provided further support for the association of PENK and POMC with opioid dependence. Therefore, our data provide no support for the idea that variations in OPRM1, OPRD1, PENK and POMC are associated with alcohol dependence or general illicit drug dependence, but variations in PENK and POMC appear to be associated with the narrower phenotype of opioid dependence in these families.

背景与目标： 阿片受体及其内源肽配体在对海洛因，可卡因和酒精等成瘾药物的反应中，在神经传递和神经调节中起重要作用。在较早的研究中，我们报道了编码κ阿片受体（OPRK1）及其肽配体（PDYN）的基因变异与酗酒风险有关。我们通过分析编码微阿片受体和δ阿片受体及其肽配体的基因，继续研究阿片样物质系统在酒精依赖中的作用。我们在来自219个多重酒精依赖家庭的1923个欧洲美国人的样本中分析了18个OPRM1 SNP，18个OPRD1 SNP，7个PENK SNP和7个POMC SNP。使用基于家庭的关联测试，我们没有发现这四个基因与酒精依赖显着相关的证据。我们还没有发现这些基因与非法药物依赖性之间的关联。使用较窄的阿片类药物依赖表型（83个受影响的个体）进行的次要分析表明，PENK和POMC中与SNP相关，而OPRM1或OPRD1中与SNP不相关。单倍型分析为将PENK和POMC与阿片类药物依赖性相关提供了进一步的支持。因此，我们的数据不支持以下观点：OPRM1，OPRD1，PENK和POMC的变异与酒精依赖或一般非法药物依赖有关，但PENK和POMC的变异似乎与这些患者中阿片样物质依赖的较窄表型有关。家庭。

BACKGROUND & AIMS: :Heroin and methamphetamine (METH) addiction continues to be a major social, economic and therapeutic problem worldwide. The opioid pathway may mediate the effects of addictive drugs. However, the potential correlation between the κ1 opioid receptor (OPRK1) and drug addiction has not yet been characterized. The aim of the present study was to investigate the potential association between methylation of the OPRK1 promoter and substance abuse. Bisulfite pyrosequencing technology was used to determine the levels of OPRK1 promoter methylation in 60 drug abusers (30 heroin and 30 METH addicts) and 52 controls, observed to exhibit no significant differences in age or gender. The results indicated that levels of OPRK1 promoter methylation were significantly higher in drug addicts when compared with controls (P=2.43×10-4). Significant correlations between OPRK1 promoter methylation and the length and frequency of drug use were also observed in male heroin addicts (length: r=0.661, P=0.007; frequency: r=-0.684, P=0.005). In addition, a luciferase reporter gene assay indicated that the OPRK1 promoter fragment was able to regulate gene expression (fold change between two groups >32.12, P≤0.0001). In conclusion, results of the present study indicate that methylation of the OPRK1 promoter contributes to the pathophysiology of drug addiction.

背景与目标： 海洛因和甲基苯丙胺（METH）成瘾仍然是全球范围内的主要社会，经济和治疗问题。阿片类药物途径可能介导成瘾药物的作用。然而，κ1阿片受体（OPRK1）和药物成瘾之间的潜在相关性尚未被表征。本研究的目的是研究OPRK1启动子的甲基化与药物滥用之间的潜在联系。使用亚硫酸氢盐焦磷酸测序技术确定60名吸毒者（30名海洛因和30名METH吸毒者）和52名对照的OPRK1启动子甲基化水平，观察到它们在年龄或性别上均无显着差异。结果表明，吸毒成瘾者的OPRK1启动子甲基化水平明显高于对照组（P = 2.43×10-4）。在男性海洛因成瘾者中，还观察到OPRK1启动子甲基化与吸毒时间和频率之间存在显着相关性（长度：r = 0.661，P = 0.007；频率：r = -0.684，P = 0.005）。另外，荧光素酶报告基因测定表明OPRK1启动子片段能够调节基因表达（两组之间的倍数变化> 32.12，P≤0.0001）。总之，本研究的结果表明OPRK1启动子的甲基化有助于药物成瘾的病理生理。

BACKGROUND & AIMS: BACKGROUND:Pain clinicians have always been challenged by the variability of response to pain treatment. Differences in the degree of pain stimulation and pain sensitivity, weight and age differences, prior opioid use and tolerance, as well as the differences in bioavailability of various opioid formulations have been cited as causes for the wide variability in analgesia seen with opioids. Genetics may explain the variability of responses and help to predict more effective (or less dangerous) medication choices and doses. Genetics may also help to predict the response to specific opioids and antidepressants. OBJECTIVES:In this review article, we discuss the genetic influence of nociception, analgesia, and hyoanalgesia. The CYP450 enzymes involved in the metabolism and activity of opioids and adjuvant analgesics are genetically controlled, as are the opioid receptors and a variety of brain chemistries. METHODS:This article discusses the specific pain implications of genetic variations in CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A7, OPRM1, OPRK1, OPRD1, COMT, GABA, UGT, MC1R, GCH1, ABCB1, P-glycoprotein, 5HTR1A, 5HTR2A, MTHFR, CACNA2D2, and 5-HTTLPR. RESULTS:Recent research findings suggest the relationship between genetic predisposition and clinical behavior, including the risk of opioid misuse and addiction. While urine drug testing may hint at genetic issues regarding opioid metabolism, cheek swab DNA testing has become economically viable, and we review the current and future genetic pain issues that may influence the decisions that pain clinicians make every day. CONCLUSION:Genetic testing may explain and predict many of the clinical responses seen with opioids and adjuvant medications, and may help the clinician identify those patients at genetic risk of opioid misuse and addiction.

背景与目标： 背景：疼痛临床医生一直受到对疼痛治疗反应的可变性的挑战。疼痛刺激和疼痛敏感性程度的差异，体重和年龄的差异，先前使用阿片类药物和耐受性的差异以及各种阿片类药物制剂的生物利用度差异被认为是阿片类药物镇痛广泛差异的原因。遗传学可以解释反应的变异性，并有助于预测更有效（或更危险）的药物选择和剂量。遗传学也可能有助于预测对特定阿片类药物和抗抑郁药的反应。
目的：在这篇综述文章中，我们讨论了伤害感受，镇痛和镇痛的遗传影响。涉及阿片类药物和辅助镇痛药的代谢和活性的CYP450酶，阿片受体和各种脑化学物质均受到基因控制。
方法：本文讨论CYP1A2，CYP2C8，CYP2C9，CYP2C19，CYP2D6，CYP2E1，CYP3A4，CYP3A7，OPRM1，OPRK1，OPRD1，COMT，GABA，UGT，MC1R，G1蛋白的遗传变异对特定疼痛的影响，5HTR1A，5HTR2A，MTHFR，CACNA2D2和5-HTTLPR。
结果：最近的研究结果表明遗传易感性与临床行为之间的关系，包括阿片类药物滥用和成瘾的风险。虽然尿液药物检测可能提示有关阿片类药物代谢的遗传问题，但颊拭子DNA检测已在经济上可行，我们将回顾当前和未来的遗传性疼痛问题，这些问题可能会影响临床医生每天做出的决定。
结论：基因检测可以解释和预测使用阿片类药物和辅助药物所见的许多临床反应，并可以帮助临床医生识别出有阿片类药物滥用和成瘾的遗传风险的患者。

BACKGROUND & AIMS: BACKGROUND AND OBJECTIVES:Drug addiction is a serious illness with deleterious functional and social consequences for both the affected individuals, their families, and society at large. In spite of the abundant research on substance dependence, there are few effective treatments for this disease. Given the crucial role of the endogenous opioid system in the development and maintenance of substance abuse disorders, this review focuses on the opioidergic system and examines the role of opioidergic genes in the treatment outcome of pharmacotherapies of alcohol, opioid, and cocaine addiction. METHODS:Scopus (all databases) and Pubmed were systematically searched with no language or year restrictions, up to July 2014, for studies that focused on the relationship between polymorphisms of opioidergic genes and the treatment outcome of pharmacotherapies of alcohol, opioid, and cocaine addictions. Selected search terms were opioid, gene, polymorphism, drug therapy, substance abuse, and response. RESULTS AND CONCLUSIONS:The genetic variability of μ-, δ- and κ-opioid receptors genes OPRM1, OPRD1, and OPRK1 modulates the efficacy of opioid antagonist treatments such as naltrexone and methadone, as well as the cocaine vaccine. Despite the number of promising reports, data from additional cohorts are needed to substantiate these findings. SCIENTIFIC SIGNIFICANCE:Gene variant profiling could help predict treatment response and assist in developing effective treatments for alcohol, opioid, and cocaine addiction.

背景与目标： 背景与目的：药物成瘾是一种严重的疾病，对受影响的个人，他们的家庭和整个社会都具有有害的功能和社会后果。尽管对物质依赖性进行了大量研究，但是对于这种疾病几乎没有有效的治疗方法。鉴于内源性阿片类药物系统在滥用药物的发生和维持中的关键作用，本综述着重于阿片类药物系统，并研究了阿片类药物基因在酒精，阿片类药物和可卡因成瘾药物治疗中的作用。
方法：直到2014年7月，系统地搜索Scopus（所有数据库）和Pubmed，没有语言或年份限制，研究重点在于阿片类药物基因多态性与酒精，阿片类药物和可卡因成瘾药物治疗结果之间的关系。选择的搜索词是阿片类药物，基因，多态性，药物治疗，药物滥用和反应。
结果与结论：μ，δ和κ阿片受体基因OPRM1，OPRD1和OPRK1的遗传变异性可调节纳曲酮和美沙酮等阿片拮抗剂治疗以及可卡因疫苗的疗效。尽管有大量有希望的报告，但仍需要来自其他队列的数据来证实这些发现。
科学意义：基因变异分析可以帮助预测治疗反应，并帮助开发有效的治疗酒精，阿片类药物和可卡因成瘾的方法。

BACKGROUND & AIMS: :As the pre-dementia phase of Alzheimer disease, mild cognitive impairment (MCI) involves the onset and development of cognitive impairments. Opioid receptors play pivotal roles in the regulation of learning and cognition. Our study focused on the association of OPRK1 and OPRM1 methylation with MCI in Xinjiang Uygur and Han populations. DNA methylation was measured using bisulphite pyrosequencing method. Our results indicated OPRK1 was significantly hypermethylated in Xinjiang Han MCI females. Meanwhile, OPRM1 CpG1 hypermethylation and CpG2-4 hypomethylation were associated with MCI risk in Xinjiang Uygur and Han, respectively. Our study showed that OPRK1 and OPRM1 were significantly hypermethylated in Xinjiang (Northwest China) than Zhejiang (Southeast China) Han Chinese healthy controls. Our results showed that OPRK1 promoter methylation was related to gender, ethnicity, aging, and environmental changes, while OPRM1 promoter methylation was related to blood lipids and living regions. Dual-luciferase reporter gene assays revealed that promoter fragments of OPRK1 and OPRM1 were able to upregulate gene expression. In summary, our findings provided novel aspects of OPRK1 and OPRM1 methylation in Xinjiang Uygur and Han populations.

背景与目标： ：作为老年痴呆症的痴呆前期，轻度认知障碍（MCI）涉及认知障碍的发生和发展。阿片受体在调节学习和认知中起关键作用。我们的研究集中在新疆维吾尔族和汉族人群中OPRK1和OPRM1甲基化与MCI的关系。使用亚硫酸氢焦磷酸测序法测量DNA甲基化。我们的结果表明，OPRK1在新疆汉族MCI女性中明显超甲基化。同时，新疆维吾尔族和汉族人群中OPRM1 CpG1高甲基化和CpG2-4低甲基化分别与MCI风险相关。我们的研究表明，新疆（中国西北部）的OPRK1和OPRM1甲基化程度明显高于浙江（中国东南部）汉族健康对照。我们的结果表明，OPRK1启动子甲基化与性别，种族，衰老和环境变化有关，而OPRM1启动子甲基化与血脂和生活区有关。双荧光素酶报告基因检测表明，OPRK1和OPRM1的启动子片段能够上调基因表达。总之，我们的发现为新疆维吾尔族和汉族人群的OPRK1和OPRM1甲基化提供了新颖的方面。

BACKGROUND & AIMS: The endogenous opioid peptides have been reported to be involved in the regulation of reproductive physiology. Many of the studies conclude with sentences around the harmful effect of opioids in male fertility but, actually, there is only one study regarding the real fertility potential of spermatozoa that have been exposed to mu specific opioids. The aim of the present study was to see if the modulation of delta (OPRD1) and kappa (OPRK1) opioid receptors in mouse sperm during capacitation was able to vary the embryo production after in vitro fertilization (IVF). The presence of OPRD1 and OPRK1 in mouse mature spermatozoa was analyzed by RT-PCR and immunofluorescence. Incubating the sperm with, on one hand, the delta specific agonist DPDPE and/or antagonist naltrindole, and, on the other hand, the kappa specific agonist U-50488 and antagonist nor-binaltorphimine, we analyzed the involvement of OPRD1 and OPRK1 on IVF and preimplantational embryo development. We verified the presence of OPRD1 and OPRK1 in mouse mature spermatozoa, not only at the mRNA level but also at protein level. Moreover, the sperm incubation with DPDPE, before the IVF, had an effect on the fertilization rate of sperm and reduced the number of reached blastocysts, which was reverted by naltrindole. Instead, the use of the kappa agonist U-50488 and the antagonist nor-binaltophimine did not have any effect on the amount and the quality of the achieved blastocysts. Although nowadays the pure delta or kappa opioid ligands are not used for the clinic, clinical trials are being conducted to be used in the near future, so it would be interesting to know if the modulation of these receptors in sperm would generate any consequence in relation to fertilization capacity.

背景与目标： 据报道内源性阿片样物质肽参与生殖生理的调节。许多研究以关于阿片类药物对男性生育的有害影响的句子作为结尾，但实际上，只有一项研究涉及暴露于μ特定阿片类物质的精子的实际生育潜力。本研究的目的是观察在获能过程中小鼠精子中δ（OPRD1）和κ（OPRK1）阿片受体的调节是否能够改变体外受精（IVF）后的胚胎产量。通过RT-PCR和免疫荧光分析小鼠成熟精子中OPRD1和OPRK1的存在。一方面，将精子与δ特异性激动剂DPDPE和/或拮抗剂纳曲酮一起孵育，另一方面与κ特异性激动剂U-50488和拮抗剂去甲双萘酚胺一起孵育，我们分析了OPRD1和OPRK1对IVF的影响和植入前的胚胎发育。我们验证了小鼠成熟精子中OPRD1和OPRK1的存在，不仅在mRNA水平而且在蛋白质水平。此外，在体外受精前用DPDPE孵育精子，对精子的受精率有影响，并减少了到达的胚泡数目，而纳达尔酮可逆转胚泡。取而代之的是，使用κ激动剂U-50488和拮抗剂去甲倍萘啶对获得的胚泡的数量和质量没有任何影响。尽管如今，纯三角洲或κ阿片类药物配体尚未用于临床，但正在进行临床试验以在不久的将来使用，因此，了解这些受体在精子中的调节是否会产生任何相关的结果将是很有趣的。到受精能力。

BACKGROUND & AIMS: :Opioids are the gold standard for pharmacological treatment of neuropathic pain, but their analgesic effects are unsatisfactory in part due to nerve injury-induced downregulation of opioid receptors in dorsal root ganglia (DRG) neurons. How nerve injury drives such downregulation remains elusive. DNA methyltransferase (DNMT)-triggered DNA methylation represses gene expression. We show here that blocking the nerve injury-induced increase in DRG DNMT3a (a de novo DNMT) rescued the expression of Oprm1 and Oprk1 mRNAs and their respective encoding mu-opioid receptor (MOR) and kappa-opioid receptor (KOR) proteins in the injured DRG. Blocking this increase also prevented the nerve injury-induced increase in DNA methylation in the promoter and 5'-untranslated region of the Oprm1 gene in the injured DRG, restored morphine or loperamide (a peripheral acting MOR preferring agonist) analgesic effects, and attenuated the development of their analgesic tolerance under neuropathic pain conditions. Mimicking this increase reduced the expression of Oprm1 and Oprk1 mRNAs and their coding MOR and KOR in DRG and augmented MOR-gated neurotransmitter release from the primary afferents. Mechanistically, DNMT3a regulation of Oprm1 gene expression required the methyl-CpG-binding protein 1, MBD1, as MBD1 knockout resulted in the decreased binding of DNMT3a to the Oprm1 gene promoter and blocked the DNMT3a-triggered repression of Oprm1 gene expression in DRG neurons. These data suggest that DNMT3a is required for nerve injury-induced and MBD1-mediated epigenetic silencing of the MOR and KOR in the injured DRG. DNMT3a inhibition may serve as a promising adjuvant therapy for opioid use in neuropathic pain management.

背景与目标： 阿片类药物是药物治疗神经性疼痛的金标准，但其镇痛效果并不理想，部分原因是神经损伤导致背根神经节（DRG）神经元中阿片受体的下调。神经损伤如何驱动这种下调仍然难以捉摸。 DNA甲基转移酶（DNMT）触发的DNA甲基化抑制基因表达。我们在这里显示，阻止神经损伤引起的DRG DNMT3a（从头DNMT）的增加挽救了Oprm1和Oprk1 mRNA的表达及其各自编码的mu阿片受体（MOR）和κ阿片受体（KOR）蛋白。受伤的DRG。阻止这种增加还可以防止神经损伤引起的受损DRG中Oprm1基因的启动子和5'-非翻译区DNA甲基化的增加，恢复吗啡或洛哌丁胺（外围作用的MOR更倾向于激动剂）的镇痛作用，并减弱在神经性疼痛情况下其镇痛耐受性的发展。模仿这种增加，减少了DRG中Oprm1和Oprk1 mRNA的表达及其编码MOR和KOR，并增加了原发传入受体的MOR门控神经递质的释放。从机理上讲，DNMT3a调节Oprm1基因表达需要甲基CpG结合蛋白1 MBD1，因为敲除MBD1导致DNMT3a与Oprm1基因启动子的结合减少，并阻止DNMT3a触发的DRG神经元中Oprm1基因表达的抑制。这些数据表明，DNMT3a是神经损伤诱导的和MBD1介导的受损DRG中MOR和KOR的表观遗传沉默所必需的。 DNMT3a抑制作用可作为有希望的阿片类药物用于神经性疼痛管理的辅助疗法。

BACKGROUND & AIMS: :Synthetic κ-opioid receptor (KOR) agonists induce dysphoric and pro-depressive effects and variations in the KOR (OPRK1) and prodynorphin (PDYN) genes have been shown to be associated with alcohol dependence. We genotyped 23 single nucleotide polymorphisms (SNPs) in the PDYN and OPRK1 genes in 816 alcohol-dependent subjects and investigated their association with: (1) negative craving measured by a subscale of the Inventory of Drug Taking Situations; (2) a self-reported history of depression; (3) the intensity of depressive symptoms measured by the Beck Depression Inventory-II. In addition, 13 of the 23 PDYN and OPRK1 SNPs, which were previously genotyped in a set of 1248 controls, were used to evaluate association with alcohol dependence. SNP and haplotype tests of association were performed. Analysis of a haplotype spanning the PDYN gene (rs6045784, rs910080, rs2235751, rs2281285) revealed significant association with alcohol dependence (p = 0.00079) and with negative craving (p = 0.0499). A candidate haplotype containing the PDYN rs2281285-rs1997794 SNPs that was previously associated with alcohol dependence was also associated with negative craving (p = 0.024) and alcohol dependence (p = 0.0008) in this study. A trend for association between depression severity and PDYN variation was detected. No associations of OPRK1 gene variation with alcohol dependence or other studied phenotypes were found. These findings support the hypothesis that sequence variation in the PDYN gene contributes to both alcohol dependence and the induction of negative craving in alcohol-dependent subjects.

背景与目标： ：合成的κ阿片受体（KOR）激动剂可引起烦躁不安和促抑郁作用，并且已证明KOR（OPRK1）和强啡肽原（PDYN）基因的变异与酒精依赖有关。我们对816名酒精依赖者的PDYN和OPRK1基因中的23个单核苷酸多态性（SNP）进行了基因分型，并调查了它们与以下因素的关联： （2）自我报告的抑郁史； （3）通过贝克抑郁量表-II测量抑郁症状的强度。另外，先前在一组1248个对照中进行基因分型的23种PDYN和OPRK1 SNP中的13种被用来评估与酒精依赖的相关性。进行了SNP和单倍型关联测试。分析跨越PDYN基因的单倍型（rs6045784，rs910080，rs2235751，rs2281285）发现与酒精依赖（p = 0.00079）和消极渴望（p = 0.0499）显着相关。在这项研究中，以前与酒精依赖相关的包含PDYN rs2281285-rs1997794 SNP的候选单倍型也与消极渴望（p = 0.024）和酒精依赖（p = 0.0008）相关。检测到抑郁症严重程度与PDYN变化之间存在关联趋势。没有发现OPRK1基因变异与酒精依赖或其他研究表型的关联。这些发现支持以下假设：PDYN基因中的序列变异有助于酒精依赖性和诱导酒精依赖性受试者产生负性渴望。