OPRM1 Research Articles

A118G polymorphism of OPRM1 gene caused different morphine consumption in female patients after total knee replacement

BackgroundWe intended to clarify the effect of gender and A118G polymorphism of Opioid Receptor μ1 (OPRM1) on the required morphine for patients to maintain Visual Analogue Scale ≦ 3 for post-operative pain control after total knee replacement (TKR). MethodsWith approval from Institutional Review Board (IRB) and obtainment of informed consents, 111 patients undergoing primary TKR were enrolled without violating the exclusion criteria, including previous history of allergy to morphine, alcohol or substance abuse, use of psychotropic medications, morbid obesity of body mass index (BMI) > 40 kg/m2, chronic pain with evidence of central sensitization, and uncooperative use of patient controlled analgesia (PCA) device. The amount of PCA-delivered morphine for pain control and the ‘demand’ (the count of button pushing for requiring pain medication from PCA) were recorded at 3, 6, 12, 24, 36, 48 and 72 h after the operation. One-way ANOVA with post-hoc test by Scheffe's method was adopted for statistical analysis of each variant (AA, AG, GG). The side-effects (nausea, vomiting and sedation) from morphine were recorded. P < 0.05 was considered to be statistically significant. ResultsWith sequencing by ABI PRISM 310 Genetic Analyser, we disclosed that the allele frequency was 75.5% for the A allele (female: 77.5%, male: 69.6%) and 24.5% for the G allele (female: 22.5%, male: 30.4%). The frequency of genotype occurrence was 61.3% for AA, 24.3% for AG and 14.4% for GG. Female patients of homozygous G118G of OPRMI required more morphine from PCA device for post-operative pain control than patients of AA and AG genotypes. No significant difference in morphine consumption for post-operative pain control was disclosed among three genotypes for male patients. ConclusionsThe impact caused by G118G polymorphism of OPRM1 on requirement of morphine consumption for post-operative pain control is potentially gender-linked.

Common Biological Modulators of Acute Pain: An Overview Within the AAAPT Project (ACTTION-APS-AAPM Acute Pain Taxonomy).

The ACTTION-APS-AAPM Acute Pain Taxonomy (AAAPT) project relies on the identification of modulators to improve characterization and classification of acute pain conditions. In the frame of the AAAPT effort, this paper presents an overview of common biological modulators of acute pain. Nonsystematic overview. Females may experience more acute pain than males, but the clinical significance may be modest. Increasing age is associated with decreasing analgesic requirement and decreasing pain intensity after surgery and with higher risk of acute low back pain. Racial and ethnic minorities have worse pain, function, and perceived well-being. Patients with preexisting chronic pain and opioid use are at higher risk of severe acute pain and high opioid consumption. The OPRM1 gene A118G polymorphism is associated with pain severity and opioid consumption, with modest quantitative impact. Most studies have found positive associations between pain sensitivity and intensity of acute clinical pain. However, the strength of the association is unclear. Surgical techniques, approaches, and complications influence postoperative pain. Sex, age, race, ethnicity, preexisting chronic pain and opioid use, surgical approaches, genetic factors, and pain sensitivity are biological modulators of acute pain. Large studies with multisite replication will quantify accurately the association between modulators and acute pain and establish the value of modulators for characterization and classification of acute pain conditions, as well as their ability to identify patients at risk of uncontrolled pain. The development and validation of quick, bed-side pain sensitivity tests would allow their implementation as clinical screening tools. Acute nonsurgical pain requires more investigation.

Significant association of mu-opioid receptor 1 haplotype with tobacco smoking in healthy control subjects but not in patients with schizophrenia and alcohol dependence

Tobacco smoking is highly prevalent in patients with schizophrenia and alcohol dependence. The underlying neurobiology of nicotine addiction is complex. Rewarding effects of nicotine from cigarettes are associated, among others, with mu-opioid receptors encoded by the OPRM1 gene. The aim of the study was to evaluate the association between two OPRM1 gene polymorphisms, rs1799971 and rs510769, and tobacco smoking in Caucasian patients with schizophrenia, alcohol dependence, and healthy control subjects. The study included 1058 Caucasians (277 patients with schizophrenia, 359 patients with alcohol dependence, and 422 healthy control subjects), subdivided according to the nicotine dependence into smokers (i.e. current smokers) and non-smokers. A significant association was found between the GC haplotype (OPRM1 rs1799971 and rs510769) and smoking in healthy controls, but not in patients with schizophrenia and alcohol dependence. A nominal association was detected in all cases/controls, but this significance did not survive the correction for the multiple testing. This is the first study to reveal that nicotine dependence is associated with the GC haplotype of the OPRM1 rs1799971 and rs510769 in all subjects or specifically in healthy controls. These results did not confirm the strong connection between OPRM1 polymorphisms and nicotine dependence in schizophrenia or alcohol dependence.

Differential sensitivity of human neurons carrying μ opioid receptor (MOR) N40D variants in response to ethanol.

The acute and chronic effects of alcohol on the brain and behavior are linked to alterations in inhibitory synaptic transmission. Alcohol's most consistent effect at the synaptic level is probably a facilitation of γ-aminobutyric acid (GABA) release, as seen from several rodent studies. The impact of alcohol on GABAergic neurotransmission in human neurons is unknown, due to a lack of a suitable experimental model. Human neurons can also be used to model effects of genetic variants linked with alcohol use disorders (AUDs). The A118G single nucleotide polymorphism (SNP rs1799971) of the OPRM1 gene encoding the N40D (D40 minor allele) mu-opioid receptor (MOR) variant has been linked with individuals who have an AUD. However, while N40D is clearly associated with other drugs of abuse, involvement with AUDs is controversial. In this study, we employed Ascl1-and Dlx2-induced inhibitory neuronal cells (AD-iNs) generated from human iPS cell lines carrying N40D variants, and investigated the impact of ethanol acutely and chronically on GABAergic synaptic transmission. We found that N40 AD-iNs display a stronger facilitation (versus D40) of spontaneous and miniature inhibitory postsynaptic current frequency in response to acute ethanol application. Quantitative immunocytochemistry of Synapsin 1+ synaptic puncta revealed a similar synapse number between N40 and D40 iNs, suggesting an ethanol modulation of presynaptic GABA release without affecting synapse density. Interestingly, D40 iNs exposed to chronic intermittent ethanol application caused a significant increase in mIPSC frequency, with only a modest enhancement observed in N40 iNs. These data suggest that the MOR genotype may confer differential sensitivity to synaptic output, which depends on ethanol exposure time and concentration for AD-iNs and may help explain alcohol dependence in individuals who carry the MOR D40 SNPs. Furthermore, this study supports the use of human neuronal cells carrying risk-associated genetic variants linked to disease, as invitro models to assay the synaptic actions of alcohol on human neuronal cells.

Individualized Medication Management in Ontario Long-Term Care Clinical Impact on Management of Depression, Pain, and Dementia

ObjectivesAssess the potential benefits of identifying drug-gene interactions in nursing home (NH) residents on multiple medications. Reduce the use of high-risk medications for residents with reduced drug metabolism. DesignOpen-label, nonrandomized, mixed methods study. SettingFour NHs in Ontario. MeasurementsPotential drug therapy problems (DTPs) for study cohort were identified during a medication review by a pharmacist using pharmacogenetic (PGx) clinical decision support to identify medication change opportunities. The number of DTPs identified during a standard medication review was compared with the number of DTPs identified with a PGx clinical decision support. Analysis of medication dispensing data at enrollment compared with dispensing in a 60-day window following medication review were compared for the PGx-tested study cohort with controls. ResultsPrescription patterns of 90 study participants were compared with 895 controls for the same time period. Study participants were on 7 to 47 drugs, of which drugs with PGx indications ranged from 1 to 17 medications. The average medication load was 4.6 medications with PGx indications per person, whereas the controls were on 3.5 PGx drugs. Furthermore, 94% of cases and 84% of controls were on 2 or more drugs with PGx indication during the study period. Pharmacogenetic analysis identified 114 distinct DTPs in the 90 study participants, of which 29 were classified as serious. In this study, over 35% of residents were treated with antidepressants; of these, 64% have altered CYP2C19 or CYP2D6 metabolism and could benefit from drug dose adjustment or from a switch to alternative antidepressants. Twenty percent of residents were treated with hydromorphone, of which 30% have reduced response to opioids because of variations in the OPRM1 gene. Conclusions and ImplicationsThis study demonstrated the clinical potential of PGx-based medication optimization for NH residents, impacting the management of depression, chronic pain, heart disease, and gastrointestinal symptoms.

Using pharmacogenetics to structure individual pain management protocols in total knee arthroplasty

The purpose of this study was to use pharmacogenetics to determine the frequency of genetic variants in our total knee arthroplasty (TKA) patients that could affect postoperative pain medications. Pharmacogenetic testing evaluates patient DNA to determine if a drug is expected to have a normal clinical effect, heightened effect, or no effect at all on the patient. It also predicts whether patients are likely to experience side effects from medicine. We further sought to determine if changing the multimodal programme based on these results would improve pain control or reduce side effects. In this pilot study, buccal samples were collected from 31 primary TKA patients. Pharmacogenetics testing examined genetic variants in genes OPRM1, CYP1A2, CYP2B6, CYP2C19, CYP3A4, CYP2C9, and CYP2D6. These genes affect the pharmacodynamics and pharmacokinetics of non-steroidal anti-inflammatory drugs and opioids. We examined the frequency of genetic variants to any of the medications we prescribed including celecoxib, hydrocodone, and tramadol. Patients were randomized to one of two groups: the control group received the standard postoperative pain regimen, and the study group received a customized regimen based on the pharmacogenetic results. For the first ten postoperative days, patients recorded pain scores, medication, and side effects. Genetic variants involving one or more medications in the multimodal pain protocol occurred in 13 of the 31 patients (42%). In total, eight patients (26%) had variants affecting more than one of the medications. For the 25 patients who recorded pain and medication logs, the mean pain levels and morphine equivalents (MEQs) consumed in the first ten days were higher in the control group than in the custom-guided group (p = 0.019 for pain and p = 0.655 for MEQ). Overall, 42% of patients had a variant involving one of the pain medications prescribed in our perioperative pain program for TKA. Ongoing research will help determine if using these data to modify a patient's medication will improve outcomes. Cite this article: Bone Joint J 2020;102-B(6 Supple A):73-78.

Role of OPRM1, clinical and anthropometric variants in neonatal pain reduction

An increased awareness on neonatal pain-associated complications has led to the development of pain scales adequate to assess the level of pain experienced by newborns such as the ABC score. A commonly used analgesic procedure is to administer a 33% oral dextrose solution to newborns prior to the painful intervention. Although this procedure is very successful, not in all subjects it reaches complete efficacy. A possible explanation for the different response to the treatment could be genetic variability. We have investigated the genetic variability of the OPRM1 gene in 1077 newborns in relation to non-pharmacologic pain relief treatment. We observed that the procedure was successful in 966 individuals and there was no association between the genotypes and the analgesic efficacy when comparing individuals that had an ABC score = 0 and ABC score >0. However, considering only the individuals with ABC score>0, we found that the homozygous carriers of the G allele of the missense variant SNP rs1799971 (A118G) showed an interesting association with higher ABC score. We also observed that individuals fed with formula milk were more likely to not respond to the analgesic treatment compared to those that had been breastfed.

Pharmacological studies of morphine in a novel humanized mu opioid receptor mouse model

Full‐length 7‐transmembrane (TM) variants of mu opioid receptor (MOR) share similar amino acid sequences of TM domains in rodents and humans; however, interspecies differences in N‐ and C‐terminal amino acid sequences of MOR splice variants dramatically affect the downstream signaling. Thus, it is essential to develop a mouse model that expresses human MOR for opioid pharmacological studies. We generated two lines of fully humanized MOR mice, line #1 and #2. The novel murine model having human OPRM1 genes and human‐specific variants was examined by RT‐PCR. Humanized MOR mice were characterized in vivo using a tail‐flick, charcoal meal, open field, tail suspension, naloxone precipitation tests, and rectal temperature measurement. The data indicated that wild‐type (WT) and humanized MOR mice exhibited different pharmacology of morphine, including antinociception, tolerance, sedation, and withdrawal syndromes, suggesting the presence of species difference between mouse and human MORs. Therefore, humanized MOR mice could serve as a novel mouse model for pharmacogenetic studies of opioids.

Mapping of Morphine-Induced OPRM1 Gene Expression Pattern in the Adult Zebrafish Brain.

Morphine is a potent analgesic opiate commonly used in treating pain, and it is also a substance of abuse and highly addictive. Hence, it is vital to discover the action sites of morphine in the brain to increase its efficacy of treatment. In the present study, we aimed at identifying comprehensive neuroanatomical locations that are sensitive to morphine in the adult zebrafish (Danio rerio). We performed in situ hybridization to localize the mu opioid receptor (oprm1) gene and to map the morphine sensitive brain areas using neuronal PAS domain-containing protein 4a (npas4a), an early gene marker. Real-time PCR was used to detect changes in mRNA levels of oprm1 and npas4a in control and acute morphine treated fish (2 mg/L; 20 min). Intense positive oprm1 signals were seen in the telencephalon, preoptic area, habenula, hypothalamic area and periventricular gray zone of the optic tectum. Acute morphine exposure significantly increased oprm1 and npas4a mRNA levels in the medial zone of dorsal telencephalon (Dm), ventral region of the ventral telencephalon (Vv), preoptic area, and in the hypothalamus but a decrease in oprm1 and npas4a signals in the dorsal habenula. This study provides a detailed map of oprm1 localization in the brain, which includes previously unreported oprm1 in the habenula of teleost. Presence of oprm1 in multiple brain sites implies multiple action targets of morphine and potential brain functions which could include reward, cognitive and negative emotions.

Morphine produces potent antinociception, sedation, and hypothermia in humanized mice expressing human mu-opioid receptor splice variants.

Morphine is a strong painkiller acting through mu-opioid receptor (MOR). Full-length 7-transmembrane (TM) variants of MOR share similar amino acid sequences of TM domains in rodents and humans; however, interspecies differences in N- and C-terminal amino acid sequences of MOR splice variants dramatically affect the downstream signaling. Thus, it is essential to develop a mouse model that expresses human MOR splice variants for opioid pharmacological studies. We generated 2 lines of fully humanized MOR mice (hMOR; mMOR mice), line #1 and #2. The novel murine model having human OPRM1 genes and human-specific variants was examined by reverse-transcription polymerase chain reaction and the MinION nanopore sequencing. The differences in the regional distribution of MOR between wild-type and humanized MOR mice brains were detected by RNAscope and radioligand binding assay. hMOR; mMOR mice were characterized in vivo using a tail-flick, charcoal meal, open field, tail suspension, naloxone precipitation tests, and rectal temperature measurement. The data indicated that wild-type and humanized MOR mice exhibited different pharmacology of morphine, including antinociception, tolerance, sedation, and withdrawal syndromes, suggesting the presence of species difference between mouse and human MORs. Therefore, hMOR; mMOR mice could serve as a novel mouse model for pharmacogenetic studies of opioids.

Differential genetic risk for methamphetamine intake confers differential sensitivity to the temperature-altering effects of other addictive drugs.

Mice selectively bred for high methamphetamine (MA) drinking (MAHDR), compared with mice bred for low MA drinking (MALDR), exhibit greater sensitivity to MA reward and insensitivity to aversive and hypothermic effects of MA. Previous work identified the trace amine-associated receptor 1 gene (Taar1) as a quantitative trait gene for MA intake that also impacts thermal response to MA. All MAHDR mice are homozygous for the mutant Taar1 m1J allele, whereas all MALDR mice possess at least one copy of the reference Taar1 + allele. To determine if their differential sensitivity to MA-induced hypothermia extends to drugs of similar and different classes, we examined sensitivity to the hypothermic effect of the stimulant cocaine, the amphetamine-like substance 3,4-methylenedioxymethamphetamine (MDMA), and the opioid morphine in these lines. The lines did not differ in thermal response to cocaine, only MALDR mice exhibited a hypothermic response to MDMA, and MAHDR mice were more sensitive to the hypothermic effect of morphine than MALDR mice. We speculated that the μ-opioid receptor gene (Oprm1) impacts morphine response, and genotyped the mice tested for morphine-induced hypothermia. We report genetic linkage between Taar1 and Oprm1; MAHDR mice more often inherit the Oprm1 D2 allele and MALDR mice more often inherit the Oprm1 B6 allele. Data from a family of recombinant inbred mouse strains support the influence of Oprm1 genotype, but not Taar1 genotype, on thermal response to morphine. These results nominate Oprm1 as a genetic risk factor for morphine-induced hypothermia, and provide additional evidence for a connection between drug preference and drug thermal response.

κ Opioid Receptor 1 Single Nucleotide Polymorphisms were Associated with the Methadone Dosage.

Background: Heroin use disorder (HUD) is a complex brain disease that includes multiple phenotypes. Heroin acts primarily as a mu-opioid receptor (OPRM1) agonist. The κ opioid receptor 1 (OPRK1) is critically involved in abstinence and remission. Multiple studies confirm that the OPRM1 and OPRK1 genes are associated with HUD. However, their relationship with the addictive phenotype is still unclear. This study was designed to identify the genetic polymorphisms within OPRM1 and OPRK1 with six HUD phenotypes. Methods: A total of 801 patients with HUD were recruited from the Methadone Maintenance Treatment Program in Xi'an. We identified eight potential functional single nucleotide polymorphisms (SNPs) in the two genes that were genotyped using SNaPshot SNP technology. We then performed a case-control association analysis, investigated particular disease phenotypes, and assessed the extent of epistasis among the variants of the two genes. Results: The OPRK1 rs3802279, rs3802281, and rs963549 genotypes were significantly associated with methadone dosage analyzed by Pearson's chi-square test or binary logistic regression to correct for covariates. The rs3802279 CC, rs3802281 TT, and rs963549 CC genotype carriers required a lower methadone maintenance dose per day. Multifactor dimensionality reduction analysis indicated strong interactions between sex and OPRK1 rs963549. The results of the OPRM1 genotyping did not reveal any associations with the various HUD phenotypes. Conclusion: These findings support an important role of the OPRK1 polymorphism in determining the daily methadone dose and may guide future studies in identifying additional genetic risk factors for HUD.

Effect of short-term intake of high- and low-concentrations of sucrose solution on the neurochemistry of male and female mice.

The effect of short-term intake of high- and low-concentrations of sucrose solution on the neurochemistry of male and female mice was studied. The body weight, feed intake, sucrose solution consumption and brain monoamine neurotransmitters were determined after 34 days' intake of 1% and 8% sucrose solutions. The gene expression and protein levels related to dopamine and opioids were also determined. The results showed that the intake of 1% and 8% sucrose solution for 34 days did not cause significant changes in the weight development of both male and female mice. The preference for sucrose varies with sex. Both males and females had greater preference for the high concentration sucrose solution than the low concentration sucrose solution. The continuous intake of sucrose stimulated the release of monoamine neurotransmitters (DA, 5-HT, NE) in the brains of mice, and the reward effect of 8% sucrose solution is significantly higher than that of 1% sucrose solution. The sex of mice did not affect the release of neurotransmitters. The gene expressions of D1 and D2 were up-regulated in the 1% sucrose group of male mice, while the OPRM1 gene expression was down-regulated. The expression of these three genes in the 8% sucrose group of male mice was all down-regulated, while the gene expressions of D1 and D2 in the 1% and 8% sucrose group (p < 0.05) of female mice were both up-regulated.

The role of opioids in cancer progression.

The role of opioids in cancer progression.

350: Epigenetic changes in neonates of mothers with opioid use disorder

Chronic opioid use is associated with an increase in reactive oxygen species. These reactive oxygen species can affect DNA methylation. Little is known regarding the association of chronic opioid use disorder (OUD) in pregnancy and DNA methylation alterations related to this fetal exposure. We performed a prospective pilot study of 19 women with OUD who were enrolled in our multispecialty antepartum program (PATHways) and were prescribed buprenorphine for medication-assisted treatment. In addition, 13 controls without OUD were also enrolled. Demographic characteristics and the Perceived Stress Scale were recorded. We assessed DNA methylation patterns of key CpG sites of the FKBP5, NR3C1, and OPRM1 genes in cord blood specimens obtained from the two groups. 7 CpG sites were selected for the FKBP5 gene, 5 for the NR3C1 gene, and 13 for the OPRM1 gene. These genes were chosen because of their association with opioid metabolism and their relationship to glucocorticoid activity to interrogate differences related to stress. DNA methylation modification was also evaluated considering potential effect modifiers of buprenorphine dose and maternal age. Student t-test was used to compare groups and multiple linear regression was used for predicting the amount of methylation modified by age and buprenorphine dose. The OUD group was significantly different from the control group in that they were more likely to be tobacco users, have greater parity, and increased perceived stress. Neonates of women treated for OUD did not demonstrate a difference in the methylation of composite or individual CpG sites in the FKBP5, NR3C1, and OPRM1 genes. However, DNA methylation of the FKBP5 gene was modified by the buprenorphine dose as related to age. For older patients, as buprenorphine dose increased DNA methylation decreased, but for younger patients, as buprenorphine dose increased DNA methylation increased (p=0.03). DNA methylation of the FKBP5 gene may be altered in utero related to dose and modified by maternal age. Further testing of developmental changes in this population is needed.

The Effect of OPRM1 rs648893 Gene Polymorphism on Opioid Addiction in an Iranian population in Zabol: A Case-Control Study

Introduction: Opioid addiction (OA) is a neurologically life-threatening challenge associated with socioeconomic and health concerns for individuals and society. The addictive drugs trigger neuromodulators and neurotransmitters through the opioid receptors and corresponding endogenous peptide ligands. In addition, drug addiction is reportedly related to the mu-opioid receptor (OPRM1) encoding gene and its variants. According to the role of the rs648893 polymorphism of the OPRM1 gene in numerous disorders, it has been suggested as a candidate associated with drug addiction. The present case-control study was conducted to evaluate the role of OPRM1 rs648893 polymorphism in the OA risk. Methods: To this end, the rs648893 polymorphism was genotyped by tetra amplification refractory mutation system-polymerase chain reaction among 160 Iranian subjects consisting of 105 OA cases and 155 controls. Results: According to our findings, there was no significant association between OA and the OPRM1 rs648893 gene polymorphism. Moreover, a marginally insignificant difference was found between OA cases and controls in accordance with the allelic frequencies (P=0.05) Conclusion: In general, our results reported no association between OPRM1 rs648893 gene polymorphism and OA although further research among various ethnicities with larger sample sizes is needed to draw a definite conclusion on the association of rs648893 polymorphism and other OPRM1 intronic variants with opioid and other addictions.

Haplotype-Based Association and In Silico Studies of OPRM1 Gene Variants with Susceptibility to Opioid Dependence Among Addicted Iranians Undergoing Methadone Treatment.

The associations of OPRM1 gene variants with opioid dependence have been demonstrated. This study investigated the association of rs495491, rs1799971 (A118G), rs589046, and rs10457090 variants of OPRM1 gene with opium dependence and their haplotypes among addicted individuals undergoing methadone treatment. Moreover, we investigated whether any of these variants were associated with libido dysfunction or insomnia among addicted people. A total of 404 individuals were genotyped by amplification refractory mutation system (ARMS) PCR. In silico studies were designed through homology modeling of A118G structures (N40 and D40) and docked with 41 FDA-approved drugs of OPRM1 protein by SWISS-MODEL, COACH, MolProbity, ProSA, Errat, Glide XP, and Autodock 4. Results revealed that rs495491, A118G, rs589046, and rs10457090 were significantly associated with opium dependence under recessive (P = 6.66E-10), dominant (P = 0.017), co-dominant (P = 0.001), and recessive (P = 9.28E-6) models of inheritance, respectively. Further analyses indicated three significant haplotypes including A-A-A-C (P-permutation < 1E-9), G-G-A-C (P-permutation = 0.04), and G-A-G-C (P-permutation = 8.69E-4). Genotype-phenotype associations of OPRM1 variants with insomnia and libido dysfunction showed no significant association. Docking showed the higher binding affinity of N40 rather than D40 model; however, methadone and morphine were bonded with D40 structure more powerful. Consequently, rs495491, A118G, rs589046, and rs10457090 were associated with opioid dependence among Iranians; also, A118G might be the most remarkable marker of OPRM1 owing to its vital structural roles.

Machine-learned analysis of global and glial/opioid intersection\u2013related DNA methylation in patients with persistent pain after breast cancer surgery

BackgroundGlial cells in the central nervous system play a key role in neuroinflammation and subsequent central sensitization to pain. They are therefore involved in the development of persistent pain. One of the main sites of interaction of the immune system with persistent pain has been identified as neuro-immune crosstalk at the glial-opioid interface. The present study examined a potential association between the DNA methylation of two key players of glial/opioid intersection and persistent postoperative pain.MethodsIn a cohort of 140 women who had undergone breast cancer surgery, and were assigned based on a 3-year follow-up to either a persistent or non-persistent pain phenotype, the role of epigenetic regulation of key players in the glial-opioid interface was assessed. The methylation of genes coding for the Toll-like receptor 4 (TLR4) as a major mediator of glial contributions to persistent pain or for the μ-opioid receptor (OPRM1) was analyzed and its association with the pain phenotype was compared with that conferred by global genome-wide DNA methylation assessed via quantification of the methylation in the retrotransposon LINE1.ResultsTraining of machine learning algorithms indicated that the global DNA methylation provided a similar diagnostic accuracy for persistent pain as previously established non-genetic predictors. However, the diagnosis can be based on a single DNA based marker. By contrast, the methylation of TLR4 or OPRM1 genes could not contribute further to the allocation of the patients to the pain-related phenotype groups.ConclusionsWhile clearly supporting a predictive utility of epigenetic testing, the present analysis cannot provide support for specific epigenetic modulation of persistent postoperative pain via methylation of two key genes of the glial-opioid interface.

Murine model of OPRM1 A118G alters oxycodone self-administration and locomotor activation, but not conditioned place preference

Mu-opioid receptors (MORs) mediate the rewarding properties of oxycodone and other prescription opioid medications, which have played a central role in the current opioid epidemic in the United States. The human mu-opioid receptor gene (OPRM1) contains a functional single nucleotide polymorphism (SNP), A118G, which has been associated with altered opioid addiction risk, however the mechanisms responsible for this are not well understood. To explore this, we examined oxycodone conditioned place preference (CPP) and self-administration behavior (SA) in A112G mice, which possess a functionally analogous SNP in the mouse mu-opioid receptor gene (Oprm1). For CPP, male and female A112G mice homozygous for the A112 (wild-type; AA) or G112 (GG) allele were conditioned with doses of 1 and 3 mg/kg across an 8-day period. For SA, mice were allowed to self administer oxycodone (unit dose 0.25 mg/kg/infusion, FR1) for 4h/day for 10 consecutive days. We observed no effects of genotype or sex on conditioned place preference behavior. Oxycodone 3 mg/kg increased locomotor activity in AA mice but not GG mice, and both male and female GG mice self-administered significantly more oxycodone compared to their wild-type AA littermates. These studies suggest that the G allele promotes greater opioid intake, which may underlie greater opioid addiction morbidity in G-allele carriers.

Correlation between gene polymorphism and opioid efficacy in patients with gastric or intestinal cancer.

To explore the correlation between gene polymorphism and opioid efficacy in patients with gastric or intestinal cancer. Fifty-nine patients who underwent laparoscopic surgery for gastric or intestinal cancer under general anesthesia were included and randomly divided into oxycodone (n=30) and sufentanil groups (n=29) by reproducible random number generation method. Single nucleotide polymorphisms (SNPs) of four alleles: μ-opioid receptor gene OPRM1 A118G, cytochrome P450 (CPY450) enzyme system: CPY3A4*1G, CYP3A5*3, and CYP2D6*10 were detected by PCR-pyrosequencing. Patients in sufentanil group received intravenous sufentanil injection during anesthesia induction, intraoperative maintenance, and postoperative analgesia, while those in oxycodone group received oxycodone. Patients' postoperative VAS score, opioid use, and prevalence of adverse reactions were recorded. The genotype distribution of OPRM1 A118G, CYP3A4*1G, CYP3A5*3, and CYP2D6*10 in Chinese gastric cancer/intestinal cancer patients accorded with the Hardy-Weinberg law (p>0.05). OPRM1 A118G polymorphism correlated with postoperative VAS score and medication dosage, in oxycodone group (p<0.05), while it didn't with those of sufentanil group. The VAS scores in GG group were higher than that in AA group and AG group at T6-T9, (p<0.05); the postoperative pain remedies times in GG group were more than that in the AA and AG groups (p=0.002). CYP3A4*1G polymorphism related to postoperative VAS score, medication dosage and prevalence of adverse reactions in sufentanil group (p<0.05), while it didn't with those of oxycodone group (p>0.05). The total intraoperative medication in AA group was less than that in GG and GA groups (p<0.01), with a higher prevalence of respiratory depression (p=0.01). Nor was there any correlation of CYP3A5*3 and CYP2D6*10 polymorphisms with the efficacy, postoperative VAS score, pain remedies times, postoperative 24 h medication dosage, or prevalence of adverse reactions in oxycodone and sufentanil groups. Gene polymorphism affects the efficacy and adverse reactions of opioids in patients undergoing laparoscopic gastric or intestinal cancer surgery.