Opioid Receptor Gene Research Articles

Opioid receptor and dopaminergic gene expression increase in the brains of dominant medaka Oryzias latipes males after repeated fights.

The central opioid system and dopaminergic activity in mammals play key roles in mediating social reward, impulsivity, cognition, decision making, and motivation for learning and social interactions. Repeated positive fighting experiences enhance the gene expression levels of μ-type opioid receptor (Mor), tyrosine hydroxylase (Th), an enzyme involved in dopamine synthesis, and dopamine receptor type 2 (D2r) in the reward-related brain regions of aggressive mice. However, it remains unclear whether the opioid system and dopaminergic activity are associated with repeated winning in fish. In this study, we investigated changes in the expression levels of Mor, Th1, and D2r in different regions of the brain of adult medaka Oryzias latipes males after intermittent and continuous fight for 3 days. When a pair of males was provided a fighting opportunity for 20 min per day, we noted that within the 3-day observation period, aggressive winning males showed significantly higher expression levels of Mor in telencephalon and diencephalon, Th1 in diencephalon, and D2r in telencephalon than subordinate losing males. However, no such differences in gene expression level were observed between winning and losing males in the 3-day continuous fight. Further, no differences were detected in the total number of aggressive actions among the winners from each fighting test. However, the total number of "chase" actions, with a stronger aggressiveness index, was higher for the repeated winning male in the three-time intermittent fight than for the winner in the 3-day continuous fight. These findings suggest that repeated intermittent winning experiences with strong aggressiveness could be perceived as a reward by O. latipes males.

Epigenetic and sex differences in opioid use disorder in chronic pain: A real-world study linked with OPRM1 DNA methylation.

Opioid use disorder (OUD) is a multifaceted condition influenced by sex, genetic and environmental factors that could be linked with epigenetic changes. Understanding how these factors interact is crucial to understand and address the development and progression of this disorder. Our aim was to elucidate different potential epigenetic and genetic mechanisms between women and men that correlate with OUD under real-world pain unit conditions. Associations between analgesic response and the DNA methylation level of the opioid mu receptor (OPRM1) gene (CpG sites 1-5 selected in the promoter region) were evaluated in 345 long opioid-treated chronic non cancer pain: cases with OUD (n = 67) and controls (without OUD, n = 278). Cases showed younger ages, low employment status and quality of life, but higher morphine equivalent daily dose and psychotropic use, compared to the controls. The patients with OUD showed a significant decrease in OPRM1 DNA methylation, which correlated with clinical outcomes like pain relief, depression and different adverse events. Significant differences were found at the five CpG sites studied for men, and exclusively in women for CpG site 3, in relation to OUD diagnosis. These findings support the importance of epigenetics and sex as biological variables to be considered toward efficient OUD understanding and therapy development.

Alterations in methylation and SNPs of OPRM1 gene show lack of association with heroin (nyaope) consumption in South African males of African ancestry

Nyaope is a highly addictive heroin derivative that elicits its effects via the -opioid receptor. Gene mutations and (cytosine-phospho-guanosine) CpG methylation, alter the function of the -opioid receptor gene (OPRM1) and protein. The single nucleotide polymorphisms (SNPs) rs1799971 (118 A>G) and intronic rs3778150 (T>C) in the OPRM1 have previously been associated with heroin use. The SNP rs1799971 can influence methylation levels of OPRM1 and alter mRNA and protein expression. This study compared the degree of OPRM1 methylation and allele frequency of SNPs rs1799971 and rs3778150 in black South African male nyaope users (n=200) to age-and gender-matched controls (n=55).DNA was extracted from whole blood samples, and analysed by methylation-specific PCR and sequencing to determine methylation frequencies across 29 CpGs within the OPRM1promoter gene region. SNPsrs1799971 (118 A>G) and rs3778150 (T>C) were assessed using SNP genotyping Taqman assays.Using a positive methylation assignment method, most CpGs were significantly more unmethylated in nyaope users than in controls. Using a partial methylation assignment method, most CpGs displayed significantly higher percentages of partial methylation in nyaope users than in controls. The AG genotype frequency for SNP (118 A>G), was higher in controls than in nyaope users while other genotypes (AA & GG) for SNP rs1799971 and (TT, CT, CC) SNP rs3778150 were broadly similar in both groups. There was no correlation observed between nyaope consumption and the presence of SNP rs1799971 and/or rs3778150 in the study populations.This study provided evidence that methylation may not be associated with the intake of nyaope and that SNPs rs1799971 and rs3778150 did not alter the methylation status of the OPRM1 promoter gene or contribute to nyaope addiction in a black South African male population.

The Impact of Opioid Receptor Gene Polymorphism on Fentanyl and Alfentanil's Analgesic Effects in the Pediatric Perioperative Period.

The polymorphism of the gene coding mu-opioid receptor (OPRM1) is one of the factors contributing to the variability in the response to opioid analgesics in children. The goal of this study is to investigate its role in association with postoperative acute pain in children of various ages. This prospective study analyzed 110 pediatric patients, after plastic or orthopedic surgery, who were genotyped and randomly assigned to receive fentanyl or alfentanil. Postoperative pain was rated using Numerical Rating Scale (0-10). All the patients were genotyped forOPRM1 118A>G (rs1799971) gene polymorphism. School children under the age of 11 with the OPRM1 AA genotype were shown to have a higher BMI (p<0.05). Children over the age of 12 carrying G allele OPRM1, had increased postoperative pain sensitivity and intensity (3.28±1.95 vs 4.91±2.17; p<0.05), as compared to AA allele carriers. OPRM1 118A>G polymorphism may explain the variation in the perception of postoperative pain in children over the age of 12 and may be a useful predictor for adjusting the dose of analgesics, but the dose is relative to the patient's needs regardless of his genetic characteristics. In younger children, carriers of polymorphic OPRM1 118G allele may be protected from obesity, due to diminished MOP expression.

Chronic intermittent ethanol exposure-induced m6A modifications around mRNA stop codons of opioid receptor genes

ABSTRACT Chronic alcohol consumption may alter mRNA methylation and expression levels of genes related to addiction and reward in the brain, potentially contributing to alcohol tolerance and dependence. Neuron-like (SH-SY5Y) and non-neuronal (SW620) cells were utilized as models to examine chronic intermittent ethanol (CIE) exposure-induced global m6A RNA methylation changes, as well as m6A mRNA methylation changes around the stop codon of three opioid receptor genes (OPRM1, OPRD1, and OPRK1), which are known to regulate pain, reward, and addiction behaviours. CIE exposure for three weeks significantly increased global RNA methylation levels in both SH-SY5Y (t = 3.98, P = 0.007) and SW620 (t = 2.24, P = 0.067) cells. However, a 3-week CIE exposure resulted in hypomethylation around mRNA stop codon regions of OPRM1 and OPRD1 in both cell lines [OPRM1 (SH-SY5Y): t = -5.05, P = 0.0005; OPRM1 (SW620): t = -3.19, P = 0.013; OPRD1 (SH-SY5Y): t = -13.43, P < 0.00001; OPRD1 (SW620): t = -4.00, P = 0.003]. Additionally, mRNA expression levels of OPRM1, OPRD1, and OPRK1 were downregulated (corresponding to mRNA hypomethylation) in both SH-SY5Y and SW620 cells after a 3-week CIE exposure. The present study demonstrated that chronic ethanol exposure altered global RNA methylation levels, as well as mRNA methylation and expression levels of opioid receptor genes in both neuron-like and non-neuronal cells. Our findings suggest a potential epitranscriptomic mechanism by which chronic alcohol consumption remodels the expression of reward-related and alcohol responsive genes in the brain, thus increasing the risk of alcohol use disorder development. Abbreviations: OPRM1: the μ-opioid receptor; OPRD1: the δ-opioid receptor; OPRK1: the κ-opioid receptor; CIE: chronic intermittent ethanol exposure; CIE+WD: chronic intermittent ethanol exposure followed by a 24-hr withdrawal; SH-SY5Y: human neuroblastoma cell Line; SW620: human colon carcinoma cell line; RT-qPCR: reverse transcription followed by quantitative polymerase reaction; MazF-RT-qPCR: MazF digestion followed by RT-qPCR

The use of L-asparaginase for the treatment of solid tumors: data from experimental studies and clinical trials

Drug therapy is one of the main strategies of cancer treatment. L-asparaginase, the enzyme that hydrolyzes asparagine, has been included in the treatment regimens for acute lymphoblastic leukemia and other hematological malignancies since more than 50 years ago, but its use for the treatment of solid tumors is still extremely limited. This review analyzes experimental data on the sensitivity of cell lines and xenografts of solid tumors to L-asparaginase, examines the results of clinical trials. Among the mechanisms of the cytotoxic effect of L-asparaginase on tumor cells, such processes as depletion of aspartic and glutamic acids, influence on the internal and external pathways of apoptosis, inhibition of cellular processes through a decrease in the activity of the mTOR protein, and weakening of the expression of the telomerase gene are discussed. Separately, molecular markers are considered, which can be used to suggest the effectiveness of future therapy with L-asparaginase in solid tumors. These markers include expression levels of asparagine synthetase and glutamine synthetase genes, degree of methylation of the ASNS gene promoter region, PTEN protein activity and autophagy, bone marrow environment of tumor cells, as well as expression of genes associated with asparaginase resistance (such as the μ1 opioid receptor gene and the huntingtin-associated protein 1 gene).

Methylation and expression quantitative trait loci rs1799971 in the OPRM1 gene and rs4654327 in the OPRD1 gene are associated with opioid use disorder

Opioid use disorder (OUD) is a chronic and relapsing brain disease that results in significant mortality worldwide. Genetic factors are estimated to contribute to 40%-60% of the liability, with polymorphisms of opioid receptor genes implicated in this disorder. However, the mechanisms underlying these associations are not yet fully understood. In the present study, we first examined the methylation levels in the promoter region of the OPRM1, OPRD1, and OPRK1 genes in 111 healthy controls (HCs) and 120 patients with OUD, and genotyped three tag SNPs in these genes. Correlations between these SNPs and the methylation levels of the CpG sites and expression levels of the genes were analyzed. After identifying the mQTLs and eQTLs, we determined the associations between the mQTLs/eQTLs and susceptibility to and characteristics of OUD in 930 HCs and 801 patients with OUD. Our results demonstrated that SNPs rs1799971 in the OPRM1 gene and rs4654327 in the OPRD1 gene were both mQTLs and eQTLs. We observed unique correlations between mQTLs and methylation levels of several CpG sites in the OUD group compared to the HC group. Interestingly, both the two mQTLs and eQTLs were associated with the susceptibility to OUD. In conclusion, we suppose that mQTLs and eQTLs in genes may underlie the associations between certain risk genetic polymorphisms and OUD. These mQTLs and eQTLs could potentially serve as promising biomarkers for better management of opioid misuse.

Morphine Analgesia, Cannabinoid Receptor 2, and Opioid Growth Factor Receptor Cancer Tissue Expression Improve Survival after Pancreatic Cancer Surgery.

Pancreatic cancer (PDAC) has a poor prognosis despite surgical removal and adjuvant therapy. Additionally, the effects of postoperative analgesia with morphine and piritramide on survival among PDAC patients are unknown, as are their interactions with opioid/cannabinoid receptor gene expressions in PDAC tissue. Cancer-specific survival data for 71 PDAC patients who underwent radical surgery followed by postoperative analgesia with morphine (n = 48) or piritramide (n = 23) were therefore analyzed in conjunction with opioid/cannabinoid receptor gene expressions in the patients' tumors. Receptor gene expressions were determined using the quantitative real-time polymerase chain reaction. Patients receiving morphine had significantly longer cancer-specific survival (CSS) than those receiving piritramide postoperative analgesia (median 22.4 vs. 15 months; p = 0.038). This finding was supported by multivariate modelling (p < 0.001). The morphine and piritramide groups had similar morphine equipotent doses, receptor expression, and baseline characteristics. The opioid/cannabinoid receptor gene expression was analyzed in a group of 130 pancreatic cancer patients. Of the studied receptors, high cannabinoid receptor 2 (CB2) and opioid growth factor receptor (OGFR) gene expressions have a positive influence on the length of overall survival (OS; p = 0.029, resp. p = 0.01). Conversely, high delta opioid receptor gene expression shortened OS (p = 0.043). Multivariate modelling indicated that high CB2 and OGFR expression improved OS (HR = 0.538, p = 0.011, resp. HR = 0.435, p = 0.001), while high OPRD receptor expression shortened OS (HR = 2.264, p = 0.002). Morphine analgesia, CB2, and OGFR cancer tissue gene expression thus improved CSS resp. OS after radical PDAC surgery, whereas delta opioid receptor expression shortened OS.

Predictors of treatment retention and survival among methadone-maintained patients: A possible role for a functional delta opioid receptor gene variant

BackgroundVariants in the delta opioid receptor gene, OPRD1, were associated with opioid use disorder and response to treatment. The study goal was to assess whether OPRD1 variants predict survival and retention in methadone maintenance treatment (MMT). MethodsRetention and survival time since admission (June 1993 - June 2022) until leaving treatment (for retention), or at the end of follow-up (Dec 2022) (for retention and survival) were analyzed in 488 patients. Vital data was taken from a national registry. Predictors were estimated using Kaplan-Meier and Cox regression models. ResultsLonger retention and survival were found for carriers of the T allele of SNP rs204076. This SNP is associated with OPRD1 expression in cortex (GTEx). Carriers of the T allele (n = 251) survived longer compared to non-carriers (24.7 vs. 20.2 years, p = 0.005) and had longer retention (11.2 vs. 8.8 years, p = 0.04). Multivariate analysis identified the T allele as an independent predictor of longer survival time (p = 0.003) and retention (p = 0.009). Additional predictors for survival were no benzodiazepine use after one year in MMT, no hepatitis C, <20 years of opioid usage, and admission at age < 30. Additional predictors for longer retention were no use of other drugs except opioids on admission, and no drugs at one year, as well as methadone dose ≥ 100mg/d at one year and axis I & II DSM-5 psychiatric diagnosis. ConclusionsThe OPRD1 SNP rs204076 and non-genetic predictors contribute to survival time and retention in MMT patients.

Association between opioid and dopamine receptor gene polymorphisms OPRM1rs1799971, DAT VNTR9-10 repeat allele, DRD1 rs4532 and DRD2 rs1799732 and alcohol dependence: an ethnicity oriented meta-analysis.

We carried out a meta-analysis of four opioid and dopamine candidate gene polymorphisms having conflicting results in prior literature, namely OPRM1 rs1799971, DAT VNTR9-10 repeat, DRD1 rs4532 and DRD2 rs1799732, to clarify their association with alcohol dependence and further stratified results by ethnicity to analyze possible ethnicity-mediated effects. Inclusion criteria: case-control studies assessing the association between OPRM1 rs1799971, DAT VNTR9/10 repeat allele, DRD1 rs4532 and DRD2 rs1799732 with alcohol dependence, with sufficient data available to calculate the odds ratio (OR) within a 95% confidence interval. Exclusion criteria: studies of quantitative measures of alcohol consumption, response to medications or analyses of other markers in the candidate genes, studies without controls, animal studies and lack of genotyping data. Information sources were PubMed, Google Scholar and ScienceDirect databases, all of which were searched for articles published till 2021. Heterogeneity between studies and publication bias, subgroup analyses and sensitivity analyses were carried out. A total of 41 published studies were included in the current meta-analysis. For the OPRM1 gene, there was a statistically significant association in the Asian population with a pooled OR of 1.707 (95% CI, 1.32-2.20 P < 0.0001) and 1.618 (95% CI, 1.16-2.26 P = 0.005) in the additive and dominant genetic models. For DAT VNTR 9/10 repeat, a statistically significant association of the risk vs. common allele was observed in AD with a pooled OR of 1.104 (95% CI, 1.00-1.21 P = 0.046) in the allele model and the additive genetic model in the Caucasian population with pooled OR of 1.152 (95% CI, 1.01-1.31 P = 0.034). Results indicate that some of the effects may be ethnicity-specific. The meta-analysis has been registered in the CRD PROSPERO (CRD42023411576).

A Cre Driver Line for Genetic Targeting of Kappa Opioid Receptor Expressing Cells.

Here we describe the generation and characterization of a Cre knock-in mouse line that harbors a Cre insertion in the 3'UTR of the κ opioid receptor gene (Oprk1) locus and provides genetic access to populations of κ opioid receptor (KOR)-expressing neurons throughout the brain. Using a combination of techniques including RNA in situ hybridization and immunohistochemistry, we report that Cre is expressed with high fidelity in KOR-expressing cells throughout the brain in this mouse line. We also provide evidence that Cre insertion does not alter basal KOR function. Baseline anxiety-like behaviors and nociceptive thresholds are unaltered in Oprk1-Cre mice. Chemogenetic activation of KOR-expressing cells in the basolateral amygdala (BLAKOR cells) resulted in several sex-specific effects on anxiety-like and aversive behaviors. Activation led to decreased anxiety-like behavior on the elevated plus maze and increased sociability in female but not in male Oprk1-Cre mice. Activation of BLAKOR cells also attenuated KOR agonist-induced conditioned place aversion (CPA) in male Oprk1-Cre mice. Overall, these results suggest a potential role for BLAKOR cells in regulating anxiety-like behaviors and KOR-agonist mediated CPA. In summary, these results provide evidence for the utility of the newly generated Oprk1-Cre mice in assessing localization, anatomy, and function of KOR circuits throughout the brain.

222. Acute Stress Increases Striatal Connectivity With Cortical Regions That Preferentially Express μ and κ Opioid Receptor Genes

222. Acute Stress Increases Striatal Connectivity With Cortical Regions That Preferentially Express μ and κ Opioid Receptor Genes

Abstract 2201: Effect of opioid and cannabinoid receptors gene expression on survival of patients with colorectal cancer

Abstract Introduction: Colorectal cancer (CRC) is one of the leading causes of cancer death in the world. CRC patients are often treated with opioid (e.g., morphine, or synthetic opioid piritramide) analgesia for pain, nausea, and side effects of chemotherapy. These analgesics act through opioid and cannabinoid receptors, which pathways are involved in tumor progression and metastases and thus can negatively affect the survival of patients. In our previous studies, we analyzed the presence of circulating tumor cells (CTCs) in two groups of CRC patients. One group received morphine analgesia (MA) and second piritramide analgesia (PA). We found that MA associated with increased CTCs levels and significantly shorter cancer-specific survival (CSS). These findings lead to further analysis of the opioid and cannabinoid receptors tumor gene expressions. We expected that the different expression of specific receptors in tumor tissue makes a difference between the effects of MA and PA on patients´ survival. Methods: Gene expression of opioid receptors µ (OPRM), κ (OPRK), δ (OPRD), nociceptin (OPRL) and cannabinoid receptors 1 and 2 (CB1, CB2) was analyzed in RNA purified from tumor tissues in 131 patients with CRC. Expression of markers was detected using real-time RT-PCR on LightCycler 1536 from Roche. Β-actin gene expression was used for gene expression normalization. Specific cut-off values were calculated for each marker using maxstat R software, ver. 3.3.1. Relationship between expression of receptors in tumor tissue and patients’ survival was analyzed using COX regression, Kruskal-Wallis/ANOVA test, and Kaplan-Meier method. Results: In total, 118 patients (45 females and 73 males, average age 68 years), of clinical stage-III were analyzed. It was found that MA in CRC patients was associated with significantly shorter cancer-specific survival (CSS; p=0,027). The univariate survival analysis revealed that CRC patients with high OPRM tumor tissue gene expression had significantly longer overall survival (OS; p=0.017) and patients with CB2 gene expression had significantly longer disease-free survival (DFS; p=0,029). All other tested opioid receptors expressions had no statistically significant effect on patients’ survival. Conclusion: The diverse opioid receptors’ expressions on tumor and immune cells can affect the survival of cancer patients treated with opioid analgesia. Morphine perioperative analgesia seems to shorten the CCS in CRC patients in our study. However, further research is required to elucidate the effect of opioids on different cell populations. Acknowledgement: This study was supported by Ministry of Health of the Czech Republic [NV18-03-00470]; Palacky University Olomouc [LF 2022_012]; European Regional Development Fund [ENOCHCZ.02.1.01/0.0/0.0/16_019/0000868) and European Union - Next Generation EU (EXCELES LX22NPO5102). Citation Format: Monika Vidlarova, Josef Srovnal, Emil Berta, Sona Gurska, Alona Rehulkova, Pavla Kourilova, Marian Hajduch. Effect of opioid and cannabinoid receptors gene expression on survival of patients with colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2201.

Lack of Association between a Functional Polymorphism in Dopamine and Opioid Receptor Genes with Alcoholism in South Indian Tamilian Population.

Background: Single nucleotide polymorphism (SNP) of dopamine receptor (DRD2) and μ opioid receptor (OPRM1) genes are associated with susceptibility towards alcoholism. Hence, our study aimed to investigate the association of rs1799732 (DRD2) and rs1799971(OPRM1) with the risk of alcohol dependence in the south Indian Tamilian population and to compare the frequencies of these SNPs with major global populations. Methods: A total of 150 alcohol-dependent cases aged between 18 and 65 years who satisfied DSM-V were recruited from a de-addiction center (TTK hospital, Chennai). For the control group, 150 unrelated male blood donors with an AUDIT score of less than 8 were included. Genomic DNA was extracted and the alleles were genotyped using Taqman SNP genotyping assays by quantitative PCR. Results: Minor allele frequency (MAF) of rs1799732 and rs1799971 among controls were 16.7% and 50.3% respectively. Fisher’s exact test showed a highly significant difference in MAF of DRD2 and OPRM1 between south Indian controls and European as well as African populations. All the five genetic models of SNPs were evaluated using the Chi-square test revealed no statistically significant association between the SNPs and alcohol dependence. Conclusions: The present study did not find any association between DRD2 −141C Ins/Del and A118G OPRM1 polymorphism with alcoholism in the Tamilian population of south India.

The frequency of OPRK1 G36T and OPRM1 A118G opioid receptor gene polymorphisms in heroin-dependent individuals and non-dependent healthy subjects in Turkey

The frequency of OPRK1 G36T and OPRM1 A118G opioid receptor gene polymorphisms in heroin-dependent individuals and non-dependent healthy subjects in Turkey

Effect of Analgesic Opioid Drugs on Opioid Receptor Genes Expression in HL-1 Mouse Cardiac Myocytes

BACKGROUND: The opioid system was mainly involved three types of opioid receptors (ORs): μ (MOR), δ (DOR) and κ (KOR). These ORs are activated by its agonist, a family of endogenous peptides: Endorphins, enkephalins, and dynorphins, respectively. AIM: This study determined the OR mRNA on effects of agonists exogenous morphine, fentanyl, D-penicillamine (2,5) enkephalin, and ketazocine in HL-1 mouse cardiac myocytes. MATERIALS AND METHODS: HL-1 mouse cardiac myocytes were treated with 10 μM morphine sulfate, 1 μM fentanyl,1 μM D-penicillamine (2,5) enkephalin, and 1 μM ketazocine. Total mRNAs were extracted and cDNA was synthesized and quantitative real-time polymerase chain reaction was used to analyze gene expression. RESULTS: The data analysis of MOR, DOR and KOR mRNA expression on effect of morphine was shown less level than control (0.61-fold, 0.67-fold, and 0.65-fold), respectively. The morphine-induced ORs down-regulation, whereas enkephalin treatment demonstrated highly significantly increased in mRNA of DOR (6.3-fold, p = 0.002). As well as, KOR mRNA expression was found highly significant increased under effect of Ketazocine (7.16-fold, p = 0.004). CONCLUSION: This study found DOR and KOR, but not MOR expressed in HL-1 mouse cardiac myocytes under activation of exogenous opioid analogists. These findings suggested that exogenous analogist’s opioids mimeses the endogenous analogist’s opioids.

Impaired Expression of Mu- and Kappa-Opioid Receptor mRNA in the Midbrain of Rats with Prenatal Alcohol Intoxication

Disruption of normal epigenetic reprogramming during the prenatal period under the influence of exogenous factors affects fetus development and adult phenotype formation. The mechanisms through which determinants, such as maternal alcohol intake, contribute to the formation of an alcohol-vulnerable phenotype later in life still remain unclear. In this paper, we suggest that alteration in the reinforcing properties of ethanol in prenatally alcohol-exposed subjects may be associated with transcriptional dysregulation of the brain opioid receptor genes. We compared voluntary alcohol intake and levels of mRNA coding for μ- (MOP) and κ-opioid (KOP) receptors in the mesolimbic areas of adult male offspring of the female Wistar rats having received 10% ethanol as the only source of liquid throughout pregnancy or water (control). We found that prenatally alcohol exposed rats had higher alcohol preference on PND60 (free-choice paradigm) and lower mRNA expression for both MOP and KOP in the midbrain compared to the control. This suggests a potential link between prenatal alcohol, dysfunction of the brain opiate system and adult vulnerability for alcohol use disorder.

Association between rs1799971 in the mu opioid receptor gene and methadone maintenance treatment response.

Genetic variations can affect individual response to methadone maintenance treatment (MMT) for heroin addiction. The A118G variant (rs1799971) in the mu opioid receptor gene (OPRM1) is a potential candidate single nucleotide polymorphism (SNP) for personalized MMT. This study determined whether rs1799971 is related to MMT response or dose. We recruited 286 MMT patients from a Han Chinese population. The rs1799971 genotype was determined via TaqMan genotyping assay. The genetic effect of this SNP on MMT response or dose was evaluated using logistic regression. A meta-analysis was performed to merge all available data to evaluate the role of rs1799971 in MMT using RevMan 5.3 software. No statistical significance was observed in the association between the OPRM1 rs1799971 and MMT response or dose in our Chinese cohort. Meta-analysis indicated that the OPRM1 A118G variation was not significantly associated with MMT response or dose requirement. The results suggest that rs1799971 in OPRM1 might not play a critical role alone in influencing MMT response or dose.

Epigenetic Modulation of Opioid Receptors by Drugs of Abuse.

Chronic exposure to drugs of abuse produces profound changes in gene expression and neural activity associated with drug-seeking and taking behavior. Dysregulation of opioid receptor gene expression is commonly observed across a variety of abused substances including opioids, cocaine, and alcohol. Early studies in cultured cells showed that the spatial and temporal gene expression of opioid receptors are regulated by epigenetic mechanisms including DNA and histone modifications and non-coding RNAs. Accumulating evidence indicate that drugs of abuse can modulate opioid receptor gene expression by targeting various epigenetic regulatory networks. Based on current cellular and animal models of substance use disorder and clinical evidence, this review summarizes how chronic drug exposure alters the gene expression of mu, delta, kappa, and nociceptin receptors via DNA and histone modifications. The influence of drugs of abuse on epigenetic modulators, such as non-coding RNAs and transcription factors, is also presented. Finally, the therapeutic potential of manipulating epigenetic processes as an avenue to treat substance use disorder is discussed.

Mu opioid receptor gene (OPRM1) moderates the influence of perceived parental attention on social support seeking

Mu opioid receptor gene (OPRM1) moderates the influence of perceived parental attention on social support seeking