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。

BACKGROUND & AIMS: :Methadone is a synthetic opioid that binds to the κ-opioid receptor with a low affinity. This study tested the hypotheses that the genetic polymorphisms in the κ-opioid receptor 1 (OPRK1) gene region are associated with methadone treatment responses in a Taiwan methadone maintenance treatment (MMT) cohort. Seventeen single nucleotide polymorphisms (SNPs) in OPRK1 were selected and genotyped on DNA of 366 MMT patients. Six SNPs from rs7843965 to rs1051660 (intron 2 to exon 2) were significantly associated with body weight (P < 0.007). A haplotype of 4 SNPs rs7832417-rs16918853-rs702764-rs7817710 (exon 4 to intron 3) was associated with bone or joint aches (P ≤ 0.004) and with the amount of alcohol use (standard drinks per day; global P < 0.0001). The haplotype rs10958350-rs7016778-rs12675595 was associated with gooseflesh skin (global P < 0.0001), yawning (global P = 0.0001), and restlessness (global P < 0.0001) withdrawal symptoms. The findings suggest that genetic polymorphisms in OPRK1 were associated with the body weight, alcohol use, and opioid withdrawal symptoms in MMT patients.

背景与目标： ：美沙酮是一种合成的阿片类药物，它以低亲和力与κ阿片受体结合。这项研究检验了以下假设：在台湾美沙酮维持治疗（MMT）队列中，κ阿片受体1（OPRK1）基因区域的遗传多态性与美沙酮治疗反应相关。选择了OPRK1中的17个单核苷酸多态性（SNP），并在366名MMT患者的DNA上进行了基因分型。从rs7843965至rs1051660（内含子2至外显子2）的6个SNP与体重显着相关（P <0.007）。 4个SNP rs7832417-rs16918853-rs702764-rs7817710（内含子3的外显子4）的单倍型与骨骼或关节疼痛（P≤0.004）以及饮酒量（每天标准饮料；总体P <0.0001）相关。单体型rs10958350-rs7016778-rs12675595与鹅肉皮肤（整体P <0.0001），打哈欠（整体P = 0.0001）和躁动不安（整体P <0.0001）有关。研究结果表明，OPRK1基因多态性与MMT患者的体重，饮酒和阿片类药物戒断症状有关。

BACKGROUND & AIMS: :A variety of studies were addressed to differentiate responders and non-responders to substitution treatment among heroin dependent patients, without conclusive findings. In particular, preliminary pharmacogenetic findings have been reported to predict treatment effectiveness in mental health and substance use disorders. Aim of the present study was to investigate the possible association of buprenorphine (BUP) treatment outcome with gene variants that may affect kappa-opioid receptors and dopamine system function. One hundred and seven heroin addicts (West European, Caucasians) who underwent buprenorphine maintenance treatment were genotyped and classified into two groups (A and B) on the basis of treatment outcome. Non-responders to buprenorphine (group B) have been identified taking into account early drop out, continuous use of heroin, severe behavioral or psychiatric problems, misbehavior and diversion during the 6 months treatment period. No difference was evidenced between responders and non-responders to BUP in the frequency of kappa opioid receptor (OPRK1) 36G>T SNP. The frequency of dopamine transporter (DAT) gene polymorphism (SLC6A3/DAT1), allele 10, was evidently much higher in "non-responder" than in "responder" individuals (64.9% vs. 55.93%) whereas the frequency of the category of other alleles (6, 7 and 11) was higher in responder than in non-responder individuals (11.02% vs. 2.13% respectively). On one hand, the hypothesis that possible gene-related changes in kappa-opioid receptor could consistently affect buprenorphine pharmacological action and clinical effectiveness was not confirmed in our study, at least in relation to the single nucleotide polymorphism 36G>T. On the other hand, the possibility that gene-related dopamine changes could have reduced BUP effectiveness and impaired maintenance treatment outcome was cautiously supported by our findings. DAT1 gene variants such as allele 10, previously reported in association with personality and behavioral problems, would have influenced the effects of BUP-induced dopamine release, modulated through mu and kappa opioid receptors, and probably the related reinforcing capacity of the drug.

背景与目标： ：针对不同的研究进行了研究，以区分海洛因依赖患者中替代治疗的反应者和非反应者，但没有结论。特别是，据报道初步的药物遗传学发现可预测心理健康和药物滥用疾病的治疗效果。本研究的目的是研究丁丙诺啡（BUP）治疗结果与可能影响κ阿片受体和多巴胺系统功能的基因变异之间的可能联系。对一百名接受丁丙诺啡维持治疗的海洛因成瘾者（西欧，高加索人）进行基因分型，并根据治疗结果将其分为两组（A和B）。考虑到在6个月的治疗期内早期退出，持续使用海洛因，严重的行为或精神​​病学问题，行为不当和转移，已确定对丁丙诺啡无反应（B组）。 BUP的反应者和非反应者之间的κ阿片受体（OPRK1）36G> T SNP的频率没有差异。多巴胺转运蛋白（DAT）基因多态性（SLC6A3 / DAT1）等位基因10的频率在“无反应者”中明显高于“无反应者”个体（64.9％对55.93％），而应答者中的其他等位基因（6、7和11）高于非应答者（分别为11.02％和2.13％）。一方面，至少在单核苷酸多态性36G> T方面，我们的研究尚未证实这一假设，即阿片受体可能与基因有关的变化会持续影响丁丙诺啡的药理作用和临床有效性。另一方面，我们的发现谨慎地支持了与基因相关的多巴胺变化可能降低BUP有效性并损害维持治疗结果的可能性。 DAT1基因变体（例如等位基因10）先前已与人格和行为问题相关联报道，将影响BUP诱导的多巴胺释放（通过mu和kappa阿片受体调节）的作用，并可能影响药物的相关增强能力。

BACKGROUND & AIMS: BACKGROUND:There is no cure for castration-recurrent prostate cancer (CRPC) and the mechanisms underlying this stage of the disease are unknown. METHODS:We analyzed the transcriptome of human LNCaP prostate cancer cells as they progress to CRPC in vivo using replicate LongSAGE libraries. We refer to these libraries as the LNCaP atlas and compared these gene expression profiles with current suggested models of CRPC. RESULTS:Three million tags were sequenced using in vivo samples at various stages of hormonal progression to reveal 96 novel genes differentially expressed in CRPC. Thirty-one genes encode proteins that are either secreted or are located at the plasma membrane, 21 genes changed levels of expression in response to androgen, and 8 genes have enriched expression in the prostate. Expression of 26, 6, 12, and 15 genes have previously been linked to prostate cancer, Gleason grade, progression, and metastasis, respectively. Expression profiles of genes in CRPC support a role for the transcriptional activity of the androgen receptor (CCNH, CUEDC2, FLNA, PSMA7), steroid synthesis and metabolism (DHCR24, DHRS7, ELOVL5, HSD17B4, OPRK1), neuroendocrine (ENO2, MAOA, OPRK1, S100A10, TRPM8), and proliferation (GAS5, GNB2L1, MT-ND3, NKX3-1, PCGEM1, PTGFR, STEAP1, TMEM30A), but neither supported nor discounted a role for cell survival genes. CONCLUSIONS:The in vivo gene expression atlas for LNCaP was sequenced and support a role for the androgen receptor in CRPC.

背景与目标： 背景：目前尚无治愈去势复发性前列腺癌（CRPC）的方法，而且该疾病这一阶段的潜在机制尚不清楚。
方法：我们使用复制的LongSAGE文库分析了人类LNCaP前列腺癌细胞在体内发展为CRPC时的转录组。我们将这些库称为LNCaP地图集，并将这些基因表达谱与当前建议的CRPC模型进行了比较。
结果：在体内荷尔蒙发展的各个阶段，对体内的300万个标签进行了测序，揭示了96个在CRPC中差异表达的新基因。 31个基因编码分泌的蛋白质或位于质膜的蛋白质，其中21个基因响应雄激素而改变了表达水平，而8个基因在前列腺中富集了表达。 26、6、12和15个基因的表达以前分别与前列腺癌，格里森分级，进展和转移有关。 CRPC中基因的表达谱支持雄激素受体（CCNH，CUEDC2，FLNA，PSMA7），类固醇合成和代谢（DHCR24，DHRS7，ELOVL5，HSD17B4，OPRK1），神经内分泌（ENO2，MAOA，OPRK1）的转录活性，S100A10，TRPM8）和增殖（GAS5，GNB2L1，MT-ND3，NKX3-1，PCGEM1，PTGFR，STEAP1，TMEM30A），但既不支持也不忽视细胞存活基因的作用。
结论：对LNCaP的体内基因表达图谱进行了测序，并支持雄激素受体在CRPC中的作用。

BACKGROUND & AIMS: BACKGROUND:Polymorphisms in the opioid receptor genes may affect the pharmacodynamics (PD) of oxycodone and be part of the reason behind the diversity in clinical response. The aim of the analysis was to model the exposure-response profile of oxycodone for three different pain variables and search for genetic covariates. Model simulations were used to predict how population and effect-size impact the power to detect clinical significant SNPs. METHOD:The population pharmacokinetic-pharmacodynamic (PKPD) model of oral single-dosed oxycodone was based on pooled data from three published studies in healthy volunteers. Pain tolerance data from muscle pressure (n=36), visceral pressure (n=54) and skin pinch (n=34) were included. Genetic associations with 18 opioid-receptor SNPs were explored using a stepwise covariate approach. Model simulations were performed using the estimated model parameters. RESULTS:None of the selected SNPs were associated with analgesic response of oxycodone at P<0.001. Baseline response in muscle cuff pressure was associated with OPRK1 rs7016778 and rs7824175 (P<0.001). Simulations indicated that large differences in drug response between genotypes (>50% for similar population sizes) or large populations (n>200 for a 20% response difference) are necessary to identify clinical significant SNP effects due to high population variability. CONCLUSION:A population PKPD model has been developed for oral oxycodone using three different pain variables to explore impact of genetic covariates and study design. None of the selected polymorphisms were significantly associated with analgesic response of oxycodone, but an association of baseline response in muscle cuff pressure with two OPRK1 SNPs was identified.

背景与目标： 背景：阿片受体基因的多态性可能影响羟考酮的药效学（PD），并且是临床反应多样性背后原因的一部分。该分析的目的是为三种不同的疼痛变量模拟羟考酮的暴露-反应曲线，并寻找遗传协变量。使用模型模拟来预测群体和效应大小如何影响检测临床上显着SNP的能力。
方法：口服羟考酮的口服药代动力学模型（PKPD）基于对健康志愿者的三项已发表研究的汇总数据。包括来自肌肉压力（n = 36），内脏压力（n = 54）和皮肤夹伤（n = 34）的疼痛耐受性数据。使用逐步协变量方法探索了与18个阿片受体SNP的遗传关联。使用估计的模型参数执行模型仿真。
结果：所选SNPs均与羟考酮的镇痛反应无相关性，P <0.001。肌肉袖带压力的基线反应与OPRK1 rs7016778和rs7824175相关（P <0.001）。模拟表明，由于高人群变异性，基因型之间的药物反应差异较大（对于相似的人口规模> 50％）或较大的人群（对于20％的反应差异为n> 200）对于鉴定临床显着的SNP效果是必要的。
结论：使用三种不同的疼痛变量开发了口服羟考酮的人群PKPD模型，以探讨遗传协变量的影响和研究设计。所选的多态性均未与羟考酮的镇痛反应显着相关，但鉴定了袖带压力的基线反应与两个OPRK1 SNP的相关性。