Μ-opioid Receptor Gene Research Articles

µ-Opioid Receptor Gene (OPRM1) Polymorphism A118G: Lack of Association in Finnish Populations with Alcohol Dependence or Alcohol Consumption

Aims: The molecular epidemiological studies on the association of the opioid receptor µ-1 (OPRM1) polymorphism A118G (Asn40Asp, rs1799971) and alcohol use disorders have given conflicting results. The aim of this study was to test the possible association of A118G polymorphism and alcohol use disorders and alcohol consumption in three large cohort-based study samples. Methods: The association between the OPRM1 A118G (Asn40Asp, rs1799971) polymorphism and alcohol use disorders and alcohol consumption was analyzed using three different population-based samples: (a) a Finnish cohort study, Health 2000, with 503 participants having a DSM-IV diagnosis for alcohol dependence and/or alcohol abuse and 506 age- and sex-matched controls; (b) a Finnish cohort study, FINRISK (n = 2360) and (c) the Helsinki Birth Cohort Study (n = 1384). The latter two populations lacked diagnosis-based phenotypes, but included detailed information on alcohol consumption. Results: We found no statistically significant differences in genotypic or allelic distribution between controls and subjects with alcohol dependence or abuse diagnoses. Likewise no significant effects were observed between the A118G genotype and alcohol consumption. Conclusion: These results suggest that A118G (Asn40Asp) polymorphism may not have a major effect on the development of alcohol use disorders at least in the Finnish population.

Association study of OPRM1 polymorphisms with Schizophrenia in Han Chinese population

BackgroundThe expression of μ-opioid receptor has important role in cognitive dysfunction in Schizophrenia (SZ). The results of studies about the association of polymorphisms of μ-opioid receptor gene (OPRM1) with SZ were inconsistent.MethodsWe conducted a case–control study to investigate the genetic association between OPRM1 polymorphisms and SZ among the Han chinese population. 264 SZ patients and 264 age-matched control subjects were recruited. Four SNPs of OPRM1 were successfully genotyped by using PCR-RFLP.ResultsOf four polymorphisms, rs1799971 and rs2075572 were shown to associate with SZ. Compared with the A allele of rs1799971 and C allele of rs2075572, the G allele of rs1799971 and rs2075572 was associated with an almost 0.46-fold risk (OR = 0.46, 95% CI: 0.357-0.59, P < 0.01) and 0.7-fold risk (OR = 0.707, 95% CI: 0.534-0.937, P = 0.015) of the occurrence of SZ,. When subjects were divided by gender, rs1799971 remained significant difference only in males (OR = 0.309, 95% CI: 0.218-0.439 for G allele, P < 0.01), and rs2075572 only in females (OR = 0.399, 95% CI: 0.246-0.648 for G allele, P < 0.01). In secondary analysis with subsets of patients, the G allele of rs1799971 (compared to the A allele) was associated with a decreased risk of all patients and male patients with apathy symptoms (OR = 0.086, 95% CI: 0.048-0.151, P = 0.01; OR = 0.083, 95% CI: 0.045-0.153, P < 0.01), and the G allele of rs2075572 (compared to the C allele) was associated with a decreased risk of all patients and female patients with positive family history (OR = 0.468, 95% CI: 0.309-0.71, P < 0.01; OR = 0.34, 95% CI: 0.195-0.593, P < 0.01). In addition, haplotype analysis revealed that two SNP haplotypes (A-C-C-G and G-C-C-A) were associated with decreased risks of SZ (P < 0.01). The other two (G-C-C-G and G-G-C-G) with increased risks of SZ (P < 0.01).ConclusionsThe present study demonstrated for the first time that the OPRM1 polymorphism may be a risk factor for schizophrenia in the Han Chinese. Further studies are needed to give a global view of this polymorphism in pathogenesis of schizophrenia in a large-scale sample, family-based association design or well-defined subgroups of schizophrenia.

The correlation between post-operative fentanyl requirements and μ-opioid receptor gene A118G polymorphism in patients undergoing radical gastrectomy

The aim of this study was to investigate the effect of the μ-opioid receptor gene (OPRM1) A118G polymorphism on the requirement for post-operative fentanyl analgesia in patients undergoing radical gastrectomy. One hundred and twenty-eight gastric cancer patients scheduled to undergo radical gastrectomy under general anesthesia were enrolled in the study. Post-operative, patient-controlled intravenous analgesia of fentanyl was provided for satisfactory analgesia until 48 h after surgery. OPRM1 A118G was screened by DNA sequence analysis of polymerase chain reaction (PCR)-amplified DNA. Differences in fentanyl consumption and adverse effects were compared among the different genotypes at 24 and 48 h after surgery. The ranges of fentanyl dose in the 128 patients at 24 and 48 h after surgery were 5.4–17.3 μg/kg and 12.4–29.9 μg/kg, respectively. Among these patients, there were 54 wild-type homozygotes (AA), 53 heterozygotes (AG) and 21 mutant homozygotes (GG). The frequency of the G allele was 0.371 in the OPRM1 polymorphism. There were no significant differences in fentanyl dose or adverse effects, including nausea, vomiting and dizziness, for the OPRM1 A118G polymorphism (P>0.05). The OPRM1 A118G polymorphism does not play a significant role in post-operative fentanyl analgesic dose or post-operative nausea, vomiting and dizziness in patients undergoing radical gastrectomy.

Opioid receptor mu 1 gene, fat intake and obesity in adolescence

Dietary preference for fat may increase risk for obesity. It is a complex behavior regulated in part by the amygdala, a brain structure involved in reward processing and food behavior, and modulated by genetic factors. Here, we conducted a genome-wide association study (GWAS) to search for gene loci associated with dietary intake of fat, and we tested whether these loci are also associated with adiposity and amygdala volume. We studied 598 adolescents (12-18 years) recruited from the French-Canadian founder population and genotyped them with 530 011 single-nucleotide polymorphisms. Fat intake was assessed with a 24-hour food recall. Adiposity was examined with anthropometry and bioimpedance. Amygdala volume was measured by magnetic resonance imaging. GWAS identified a locus of fat intake in the μ-opioid receptor gene (OPRM1, rs2281617, P=5.2 × 10(-6)), which encodes a receptor expressed in the brain-reward system and shown previously to modulate fat preference in animals. The minor OPRM1 allele appeared to have a 'protective' effect: it was associated with lower fat intake (by 4%) and lower body-fat mass (by ∼2 kg, P=0.02). Consistent with the possible amygdala-mediated inhibition of fat preference, this allele was additionally associated with higher amygdala volume (by 69 mm(3), P=0.02) and, in the carriers of this allele, amygdala volume correlated inversely with fat intake (P=0.02). Finally, OPRM1 was associated with fat intake in an independent sample of 490 young adults. In summary, OPRM1 may modulate dietary intake of fat and hence risk for obesity, and this effect may be modulated by subtle variations in the amygdala volume.

The Effect of OPRM1 and COMT Genotypes on the Analgesic Response to Intravenous Fentanyl Labor Analgesia

IV fentanyl is used as a labor analgesic; however, few studies have reported the effects of IV fentanyl for early labor analgesia. We evaluated the analgesic response to IV fentanyl according to the combined effect of the single-nucleotide polymorphisms rs1799971 (c.118A/G, p. 40Asn/Asp) of the µ-opioid receptor gene (OPRM1) and rs4680 (c.472G/A, p.158Val/Met) of the catechol-O-methyltransferase (COMT) gene in women requesting labor analgesia. Labor analgesia was initiated with IV fentanyl 1.5 μg/kg. The primary outcome was analgesic success, defined as Numerical Verbal Pain Scale score≤10/100 15 minutes after the dose of fentanyl. Analgesic and side effect outcomes were compared according to OPRM1 and COMT genotypes. One hundred six women were enrolled and received IV fentanyl. IV analgesic success was 6% in women with the combination Asn/Asn-Met/Met (n=17) versus 20% in all other women combined (not Asn/Asn-Met/Met; P=0.30; difference=14%; 95% confidence interval [CI], -10% to 26%). IV analgesic success was 20% in women 118A/A (Asn/Asn) versus 21% for A/G and G/G of OPRM1 (P=0.82; difference=2%; 95% CI, -17% to 19%), and 10% in women 472A (Met/Met) versus 22% for A/G (Met/Val) and G/G (Val/Val) of COMT (P=0.24; difference=12%; 95% CI, -6% to 26%). Met/Met158 (n=31) versus Met/Val or Val/Val of COMT was associated with a smaller decrease in Numerical Verbal Pain Scale (24±18 vs 37±23; P=0.005; mean difference=-13; 99% CI, -25 to -1). This study was underpowered to draw firm conclusions on the influence of OPRM1 and COMT genotypes on labor analgesia with IV fentanyl. Further larger studies are needed to evaluate whether genotyping COMT alone or in combination with OPRM1 may have potentially useful clinical implications, such as not offering IV fentanyl in early labor to women who will most likely not benefit from it.

Fronto‐striatal functional connectivity during response inhibition in alcohol dependence

Poor response inhibition has been implicated in the development of alcohol dependence, yet little is known about how neural pathways underlying cognitive control are affected in this disorder. Moreover, endogenous opioid levels may impact the functionality of inhibitory control pathways. This study investigated the relationship between alcohol dependence severity and functional connectivity of fronto-striatal networks during response inhibition in an alcohol-dependent sample. A secondary aim of this study was to test the moderating effect of a functional polymorphism (A118G) of the μ-opioid receptor (OPRM1) gene. Twenty individuals with alcohol dependence (six females; 90% Caucasian; mean age = 29.4) who were prospectively genotyped on the OPRM1 gene underwent blood oxygen level-dependent functional magnetic resonance imaging while performing a Stop-Signal Task. The relationship between alcohol dependence severity and functional connectivity within fronto-striatal networks important for response inhibition was assessed using psychophysiological interaction analyses. Analyses revealed greater alcohol dependence severity was associated with weaker functional connectivity between the putamen and prefrontal regions (e.g. the anterior insula, anterior cingulate and medial prefrontal cortex) during response inhibition. Furthermore, the OPRM1 genotype was associated with differential response inhibition-related functional connectivity. This study demonstrates that individuals with more severe alcohol dependence exhibit less frontal connectivity with the striatum, a component of cognitive control networks important for response inhibition. These findings suggest that the fronto-striatal pathway underlying response inhibition is weakened as alcoholism progresses.

Preliminary evidence for a gene-environment interaction in predicting alcohol use disorders in adolescents.

Emerging research suggests that genetic influences on adolescent drinking are moderated by environmental factors. The present study builds on molecular-genetic findings by conducting the first analysis of gene-environment interactions in the association between a functional single nucleotide polymorphism (SNP) of the μ-opioid receptor (OPRM1) gene (A118G) and risk of developing an alcohol use disorder (AUD) during adolescence. Specifically, we tested whether variation in parenting practices or affiliation with deviant peers moderated the link between the OPRM1 gene and risk of an AUD. Adolescents reporting European ancestry (N=104), ages 12 to 19years (M=15.60, SD=1.77), were interviewed to ascertain AUD diagnoses, provided a DNA sample for genetic analyses, and completed measures of parental monitoring and deviant peer affiliation. Logistic regression was used to test the effects of environmental variables and their interactions with OPRM1 genotype as predictors of AUD diagnosis while controlling for age and sex. Case-control comparisons showed that the proportion of youth with an AUD (n=18) significantly differed by genotype such that 33.3% of G allele carriers met criteria for an AUD compared to 10.8% of youth who were homozygous for the A allele (p=0.006). The OPRM1 × parental monitoring (odds ratio=0.16) and OPRM1 × deviant peer affiliation (odds ratio=7.64) interactions were significant predictors of AUD risk, such that G allele carriers with high levels of deviant peer affiliation or lower levels of parental monitoring had the greatest likelihood of developing an AUD (p-values <0.01). This study provides initial evidence that the association between the A118G SNP of the OPRM1 gene and risk of AUDs is moderated by modifiable factors. These results are limited, however, by the small sample size and require replication.

Interacting Effects of Naltrexone and OPRM1 and DAT1 Variation on the Neural Response to Alcohol Cues

Variation at a single nucleotide polymorphism in the μ-opioid receptor gene (OPRM1), A118G (Asn40Asp), may moderate naltrexone (NTX) effects in alcohol dependence. Both NTX and A118G variation have also been reported to affect alcohol cue-elicited brain activation. This study investigated whether sub-acute NTX treatment and A118G genotype interacted in their effects on cue-elicited activation of the ventral striatum (VS), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC). Secondarily, variation at a variable number tandem repeat polymorphism in the dopamine transporter gene (DAT1/SLC6A3), which has been associated with increased reward-related activation in VS, was analyzed as a moderator of medication and A118G effects. Seventy-four non-treatment-seeking alcohol-dependent individuals, half preselected to carry at least one copy of the A118G G (Asp) allele, were randomized to NTX (50 mg) or placebo for 7 days, and performed an fMRI alcohol cue reactivity task on day 6. Region-of-interest analyses indicated no main effects of medication or A118G genotype. However, these factors interacted in their effects on OFC activation, such that, among NTX-treated individuals, G-allele carriers had less activation than A-allele homozygotes. DAT1 variation also moderated medication/A118G effects. There was a three-way interaction between medication and A118G and DAT1 genotypes on VS activation, such that, among G-allele carriers who received NTX, DAT1 10-repeat-allele (10R) homozygotes had less activation than 9-repeat-allele (9R) carriers. Further, 10R homozygotes who received NTX had less mPFC activation than 9R carriers. Polymorphic variation in OPRM1 and DAT1 should be considered in future studies of NTX, particularly regarding its effects on reward processing.

Regulation of mammalian MOR-1 gene expression after chronic treatment with morphine

Morphine is an effective analgesic that acts by binding to the μ-opioid receptor (MOR) coded in the human by the OPRM1 gene. In the present study, we investigated the regulation of μ-opioid receptor (MOR-1) mRNA levels in all-trans-retinoic acid-differentiated SH-SY5Y human neuroblastoma cells under in vitro conditions with 10 μM morphine treatment for 24 h. In addition, we measured the MOR-1 levels in recombinant Chinese hamster ovary (CHO) cells, transfected with human μ-opioid receptor gene (hMOR) with 10 μM morphine treatment for 24 h. The isolated mRNA from these cells was subjected to real-time quantitative RT-PCR analysis to determine the regulation of μ-opioid receptor gene expression. It was observed that morphine treatment did not alter MOR-1 levels in undifferentiated SH-SY5Y cells compared to undifferentiated control cells. However, the MOR-1 levels in all-trans-retinoic acid-differentiated cells were significantly higher compared to the undifferentiated cells. Morphine treatment in differentiated SH-SY5Y cells caused significant downregulation of MOR-1 expression compared to the control cells. In the morphine-treated CHO cells, the hMOR-1 mRNA levels remained the same as the untreated control. Finally, pretreatment of SH-SY5Y cells with 10 μM naloxone, the antagonist of μ-opioid receptor, for 1 h significantly blocked the downregulation of MOR-1 mRNA levels with morphine treatment. These findings suggest that regulation of MOR-1 gene expression is cell-type specific after chronic morphine treatment and provide some evidence in the understanding of morphine tolerance.

The A118G Single-Nucleotide Polymorphism of Human µ-Opioid Receptor Gene and Use of Labor Analgesia

The human µ-opioid receptor (MOR) is the major site of action of endogenous opioids and most of the clinically used opioid analgesics. The single-nucleotide polymorphism (SNP), A118G of the MOR 1 gene (OPRM1), has been associated with altered pain perception. The aim of this study was to investigate whether this polymorphism of OPRM1 is associated with a number of pain-related behaviors during labor. In this observational retrospective population-based study, pregnant women (n = 814) were recruited at gestational week 18. A plasma sample was collected from each participant and an SNP genotyping assay was performed. No differences in sociodemographic variables or labor pain-related outcomes, such as stage of cervical dilation on arrival at the delivery unit or use of any type of second-line analgesia during spontaneous labor, were found between noncarriers and G-allele carriers of OPRM1. We conclude that there is no association between the A118G polymorphism of OPRM1 regarding pain-related behavior during labor.

Hypermethylation of OPRM1 promoter region in European Americans with alcohol dependence

The μ-opioid receptor mediates rewarding effects of alcohol and illicit drugs. We hypothesized that altered DNA methylation in the μ-opioid receptor gene (OPRM1) might influence the vulnerability to alcohol dependence (AD). Genomic DNA was extracted from the peripheral blood of 125 European Americans with AD and 69 screened European American controls. Methylation levels of 16 CpGs in the OPRM1 promoter region were examined by bisulfite sequencing analysis. A multivariate analysis of covariance was conducted to analyze AD-associated methylation changes in the OPRM1 promoter region, using days of intoxication in the past 30 days, sex, age, ancestry proportion and childhood adversity (CA) as covariates. Three CpGs (80, 71, and 10 bp upstream of the OPRM1 translation start site) were more highly methylated in AD cases than in controls (CpG-80: P=0.033; CpG-71: P=0.004; CpG-10: P=0.008). Although these sites were not significant after correction for multiple comparisons, the overall methylation level of the 16 CpGs was significantly higher in AD cases (13.6%) than in controls (10.6%) (P=0.049). Sex and CA did not significantly influence OPRM1 promoter methylation levels. Our findings suggest that OPRM1 promoter hypermethylation may increase the risk for AD and other substance dependence disorders.

Regulation of μ‐opioid type 1 receptors by microRNA134 in dorsal root ganglion neurons following peripheral inflammation

MOR1 is the main transcript of μ-opioid receptor (MOR) gene, which represents a mandatory molecule for the analgesic effects of opioids and plays an important role in the pathology of inflammatory pain. MicroRNAs (miR) are non-coding molecules that primarily modulate gene expression at the post-transcriptional level in various pathophysiological conditions. Based on in silico analysis, an exact match to the seed sequence of miR-134 was found in 3'-untranslated region of MOR1. Given the important roles of MOR1 in pain modulation, the purpose of this study is to investigate whether miR-134 can regulate the MOR1 following allodynia. Using Freund's adjuvant (CFA)-induced chronic inflammatory pain model, we investigated the expression profiles of miR-134 and MOR1 in rat dorsal root ganglia (DRG) using quantitative real-time polymerase chain reaction, in situ hybridization and immunohistochemistry, respectively. The relationship of miR-134 and MOR1 expressions was analysed by linear regression. Luciferase assay was used to examine whether MOR1 was the target of miR-134. Our results showed that miR-134 expression level was inversely related to MOR1 expression. Down-regulation of miR-134 and up-regulation of MOR1 in the same tissues after inflammatory pain were observed. Functional experiments showed that MOR1 expression in SH-SY5Y cells was up-regulated after inhibition of miR-134, indicating that MOR1 was a target of miR-134. Our present data suggested a model that miR-134 participated in CFA-induced inflammatory pain by balancing the expression of MOR1 in DRGs, which implied that miR-134 may be a potential therapeutic target for the treatment of neuropathic pain including inflammation.

Brain region‐ and sex‐specific alterations in DAMGO‐stimulated [35S]GTPγS binding in mice with Oprm1A112G

The A118G single nucleotide polymorphism (SNP) of the human μ-opioid receptor (MOPR) gene (OPRM1) was associated with heightened dopamine release by alcohol intake, better treatment outcome for nicotine and alcohol addiction, and reduced analgesic responses to morphine. A mouse model that possesses the equivalent substitution (A112G) in the mouse MOPR gene (OPRM1) was generated to delineate the mechanisms of the impact of the SNP. Mice homozygous for the G112 allele (G/G) displayed lower morphine-induced antinociception than mice homozygous for the A112 allele (A/A), similar to the results in humans. In this study, we examined whether A112G SNP affected MOPR-mediated G protein activation in the mouse model. We compared A/A and G/G mice in the MOPR-selective agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO)-stimulated [(35) S]GTPγS binding in brain regions by autoradiography. When the data of males and females were combined, G/G mice exhibited lower DAMGO-stimulated [(35) S]GTPγS binding in the ventral tegmental area than A/A mice, in accord with the previously reported reduced morphine-induced hyperactivity and locomotor sensitization in G/G mice. In the nucleus accumbens (NAc) core, female G/G mice displayed lower DAMGO-stimulated [(35) S]GTPγS binding than female A/A mice, which is consistent with the previously reported deficiency in morphine-induced conditioned place preference in female G/G mice. In G/G mice, males showed higher DAMGO-stimulated [(35) S]GTPγS binding than females in the cingulate cortex, caudate putamen, NAc core, thalamus and amygdala. Thus, A112G SNP affects DAMGO-stimulated [(35) S]GTPγS binding in region- and sex-specific manners.

Polymorphism of A118G in μ-opioid receptor gene is associated with risk of esophageal squamous cell carcinoma in a Chinese population

Previous studies have indicated a direct effect of μ-opioid receptors on tumor progression or recurrence. An A118G polymorphism in the μ-opioid receptor gene was believed to play an important role in this carcinogenic process. The aim of the present study was to investigate the association between the A118G polymorphism and the risk of esophageal squamous cell carcinoma (ESCC) in a Chinese population. The case-control study included 260 cancer patients and 291 controls from a Chinese Han and Chinese TuJia population in Enshi region, China. Genotypes were determined by TaqMan platform. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated using multivariate unconditional logistic regression. Compared with the G/G genotype, the A/A genotype exhibited a significantly elevated risk for ESCC (OR = 3.12, 95 % CI [1], 1.11-6.01). A significant interaction between the A118G polymorphism and age, smoking status, and family history of cancer was also found (OR = 2.25, 95 % CI 1.36-4.12; OR = 1.75, 95 % CI 1.23-2.32; OR = 3.14, 95 % CI 1.31-7.28, respectively). The A118G polymorphism in the μ-opioid receptor gene might be associated with the risk of ESCC in Chinese population.

Influence of the OPRM1 A118G Polymorphism on Alcohol-Induced Euphoria, Risk for Alcoholism and the Clinical Efficacy of Naltrexone

Alcohol-use disorders are thought to be heterogeneous in etiology, pathophysiology and response to treatment. One hypothesized contributor to this variability is the common A118G polymorphism of the µ-opioid receptor gene, OPRM1. This article critically evaluates the evidence that the A118G substitution affects subjective, behavioral and neurobiological responses to alcohol and the opioid receptor antagonist, naltrexone. Although screening of patients in a clinical setting remains premature, results suggest the A118G substitution may influence one etiological pathway to alcoholism, for which naltrexone pharmacotherapy is more effective.

The human μ-opioid receptor gene polymorphism (A118G) is associated with head pain severity in a clinical cohort of female migraine with aura patients

Migraine is a painful and debilitating, neurovascular disease. Current migraine head pain treatments work with differing efficacies in migraineurs. The opioid system plays an important role in diverse biological functions including analgesia, drug response and pain reduction. The A118G single nucleotide polymorphism (SNP) in exon 1 of the μ-opioid receptor gene (OPRM1) has been associated with elevated pain responses and decreased pain threshold in a variety of populations. The aim of the current preliminary study was to test whether genotypes of the OPRM1 A118G SNP are associated with head pain severity in a clinical cohort of female migraineurs. This was a preliminary study to determine whether genotypes of the OPRM1 A118G SNP are associated with head pain severity in a clinical cohort of female migraineurs. A total of 153 chronic migraine with aura sufferers were assessed for migraine head pain using the Migraine Disability Assessment Score instrument and classified into high and low pain severity groups. DNA was extracted and genotypes obtained for the A118G SNP. Logistic regression analysis adjusting for age effects showed the A118G SNP of the OPRM1 gene to be significantly associated with migraine pain severity in the test population (P = 0.0037). In particular, G118 allele carriers were more likely to be high pain sufferers compared to homozygous carriers of the A118 allele (OR = 3.125, 95 % CI = 1.41, 6.93, P = 0.0037). These findings suggest that A118G genotypes of the OPRM1 gene may influence migraine-associated head pain in females. Further investigations are required to fully understand the effect of this gene variant on migraine head pain including studies in males and in different migraine subtypes, as well as in response to head pain medication.

Association of µ‐opioid receptor (OPRM1) gene polymorphism with response to naltrexone in alcohol dependence: a systematic review and meta‐analysis

Previous studies have suggested that the effect of naltrexone in patients with alcohol dependence may be moderated by genetic factors. In particular, the possession of the G allele of the A118G polymorphism of the µ-opioid receptor gene (OPRM1) has been associated with a better response to naltrexone, although controversial results have been reported. The aim of this paper is to combine previous findings by means of a systematic review and a meta-analysis. We retrieved studies on the relationship between A118G polymorphism in OPRM1 gene and response to treatment with naltrexone in patients with alcohol dependence by means of electronic database search. A meta-analysis was conducted using a random-effects model. Calculations of odds ratio (OR) and their confidence intervals (CI) and tests for heterogeneity of the results have been performed. Six previous studies have analyzed the role of A118G polymorphism in response to naltrexone for alcohol dependence. After meta-analysis, we found that naltrexone-treated patients carrying the G allele had lower relapse rates than those who were homozygous for the A allele (OR: 2.02, 95% CI 1.26-3.22; P = 0.003). There were no differences in abstinence rates. Our results support the fact that the G allele of A118G polymorphism of OPRM1 moderates the effect of naltrexone in patients with alcohol dependence. This genetic marker may therefore identify a subgroup of individuals more likely to respond to this treatment.

μ-Opioid Receptor Gene A118G Polymorphism Predicts Survival in Patients with Breast Cancer

Preclinical studies suggest that opioids may promote tumor growth. Genetic polymorphisms have been shown to affect opioid receptor function and to modify the clinical effects of morphine. In this study we assessed the association between six common polymorphisms in the μ-opioid receptor gene, including the well known A118G polymorphism, and breast cancer survival. A total of 2,039 women ages 23-74 yr (38% African-American, 62% European-American, 55% postmenopausal) diagnosed with breast cancer between 1993-2001 were followed through 2006. Genotyping was performed using the TaqMan platform (Applied Biosystems Inc., Foster City, CA). Kaplan-Meier curves, log-rank tests, and Cox proportional hazard models were used to examine the association between each genotype and survival. After Bonferroni correction for multiple testing, patient genotype at A118G was associated with breast cancer-specific mortality at 10 yr. Women with one or more copies of the G allele had decreased breast cancer-specific mortality (P < 0.001). This association was limited to invasive cases only; effect size appeared to increase with clinical stage. Cox regression model adjusted for age and ethnicity also showed decreased mortality in A/G and G/G genotypes compared with A/A genotype (hazard ratio = 0.57 [0.38, 0.85] and 0.32 [0.22, 0.49], respectively; P = 0.006). These results suggest that opioid pathways may be involved in tumor growth. Further studies examining the association between genetic variants influencing opioid system function and cancer survival are warranted.

Decreased Cocaine Motor Sensitization and Self-Administration in Mice Overexpressing Cannabinoid CB2 Receptors

The potential involvement of the cannabinoid CB₂ receptors (CB₂r) in the adaptive responses induced by cocaine was studied in transgenic mice overexpressing the CB₂r (CB₂xP) and in wild-type (WT) littermates. For this purpose, the acute and sensitized locomotor responses to cocaine, conditioned place preference, and cocaine intravenous self-administration were evaluated. In addition, we assessed whether CB₂r were localized in neurons and/or astrocytes, and whether they colocalized with dopamine D1 and D2 receptors (D1Dr and D2Dr). Dopamine (DA) extracellular levels in the nucleus accumbens (NAcc), and gene expression of tyrosine hydroxylase (TH) and DA transporter (DAT) in the ventral tegmental area (VTA), and μ-opioid and cannabinoid CB₁ receptors in the NAcc were also studied in both genotypes. CB₂xP mice showed decreased motor response to acute administration of cocaine (10-20 mg/kg) and cocaine-induced motor sensitization compared with WT mice. CB₂xP mice presented cocaine-induced conditioned place aversion and self-administered less cocaine than WT mice. CB₂r were found in neurons and astrocytes and colocalized with D2Dr in the VTA and NAcc. No significant differences in extracellular DA levels in the NAcc were observed between genotypes after cocaine administration. Under baseline conditions, TH and DAT gene expression was higher and μ-opioid receptor gene expression was lower in CB₂xP than in WT mice. However, both genotypes showed similar changes in TH and μ-opioid receptor gene expression after cocaine challenge independently of the pretreatment received. Importantly, the cocaine challenge decreased DAT gene expression to a lesser extent in cocaine-pretreated CB₂xP than in cocaine-pretreated WT mice. These results revealed that CB₂r are involved in cocaine motor responses and cocaine self-administration, suggesting that this receptor could represent a promising target to develop novel treatments for cocaine addiction.

A prospective study of stress and alcohol craving in heavy drinkers

Recent work has examined the relationship between stress and relapse to alcohol use in clinical populations. Few prospective studies, however, have examined stress as a precipitant of alcohol problems. The present study is a longitudinal examination of the role of stress reactivity and alcohol craving in the etiology of alcohol problems in a sample of 41 (mean age=20.8), heavy-drinking, young adults. Participants completed a guided imagery exposure to stressful life events, followed by exposure to a neutral imagery control. Following the exposure, participants completed an alcohol cue exposure paradigm. Measures of negative mood (Profile of Mood States (POMS) depression/dejection scale), tension (POMS tension/anxiety scale) and alcohol craving (measured by the Alcohol Urge Questionnaire (AUQ)) were used as indicators of reactivity to stress and to alcohol cues. Polymorphisms of the corticotropin-releasing hormone binding protein (CRH-BP) gene and of the μ-opioid receptor (OPRM1) gene were examined as moderators of this relationship. Results revealed that stress-induced negative mood predicted negative consequences of drinking (scores on the Drinker's Inventory of Consequences (DrInC-2R)), whereas stress and cue-induced alcohol craving did not predict alcohol use or problems. Additionally, the CRH-BP genotype was found to moderate the relationship between stress-induced negative affect and the negative consequences of drinking. The current study supports and extends laboratory research describing phenotypes of stress-induced alcohol craving.