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Importance: With the current opioid crisis, it is important to improve understanding of the biological mechanisms of opioid use disorder (OUD)., Objectives: To detect genetic risk variants for OUD and determine genetic correlations and causal association with OUD and other traits., Design, Setting, and Participants: A genome-wide association study of electronic health record-defined OUD in the Million Veteran Program sample was conducted, comprising 8529 affected European American individuals and 71 200 opioid-exposed European American controls (defined by electronic health record trajectory analysis) and 4032 affected African American individuals and 26 029 opioid-exposed African American controls. Participants were enrolled from January 10, 2011, to May 21, 2018, with electronic health record data for OUD diagnosis from October 1, 1999, to February 7, 2018. Million Veteran Program results and additional OUD case-control genome-wide association study results from the Yale-Penn and Study of Addiction: Genetics and Environment samples were meta-analyzed (total numbers: European American individuals, 10 544 OUD cases and 72 163 opioid-exposed controls; African American individuals, 5212 cases and 26 876 controls). Data on Yale-Penn participants were collected from February 14, 1999, to April 1, 2017, and data on Study of Addiction: Genetics and Environment participants were collected from 1990 to 2007. The key result was replicated in 2 independent cohorts: proxy-phenotype buprenorphine treatment in the UK Biobank and newly genotyped Yale-Penn participants. Genetic correlations between OUD and other traits were tested, and mendelian randomization analysis was conducted to identify potential causal associations., Main Outcomes and Measures: Main outcomes were International Classification of Diseases, Ninth Revision-diagnosed OUD or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision-diagnosed OUD (Million Veteran Program), and DSM-IV-defined opioid dependence (Yale-Penn and Study of Addiction: Genetics and Environment)., Results: A total of 114 759 individuals (101 016 men [88%]; mean [SD] age, 60.1 [12.8] years) were included. In 82 707 European American individuals, a functional coding variant (rs1799971, encoding Asn40Asp) in OPRM1 (μ-opioid receptor gene, the main biological target for opioid drugs; OMIM 600018) reached genome-wide significance (G allele: β = -0.066 [SE = 0.012]; P = 1.51 × 10-8). The finding was replicated in 2 independent samples. Single-nucleotide polymorphism-based heritability of OUD was 11.3% (SE = 1.8%). Opioid use disorder was genetically correlated with 83 traits, including multiple substance use traits, psychiatric illnesses, cognitive performance, and others. Mendelian randomization analysis revealed the following associations with OUD: risk of tobacco smoking, depression, neuroticism, worry neuroticism subcluster, and cognitive performance. No genome-wide significant association was detected for African American individuals or in transpopulation meta-analysis., Conclusions and Relevance: This genome-wide meta-analysis identified a significant association of OUD with an OPRM1 variant, which was replicated in 2 independent samples. Post-genome-wide association study analysis revealed associated pleiotropic characteristics. Recruitment of additional individuals with OUD for future studies-especially those of non-European ancestry-is a crucial next step in identifying additional significant risk loci.

Background: In this study, the μ-Opioid receptor activity was assessed pre-operatively for its association with postoperative pain level and second analgesic requirement in patients undergoing septoplasty., Methods: In our prospective study, 120 adult patients underwent septoplasty from June 2015 to January 2019 were randomly divided into 2 pre-operative groups. The first group (n = 60) was patients given tramadol (1-2 mg/kg) for post-operative analgesia, and the second group (control group) (n = 60) was initially prescribed only fentanyl (1 μg/ kg-i.v.) in the induction. Acetaminophen with codeine analgesic 325/30 mg (p.o.) was used as an rescue painkiller in the post-operative period. The μ-Opioid receptor activity was investigated in pre-operative blood samples and compared to post-operative pain level and time required for second round of analgesic administration. The visual analogue score (VAS) was used to evaluate the post-operative pain degree (0 no pain; 10 worst pain). The patients' post-operative VAS scores were evaluated upon arrival to recovery room, and at the 1st, 3rd, 7th, 10th, and 24th hour post-operative period., Results: Demographic data and peri-operative variables were similar in both study group (p < 0.05).There was no significant difference between the receptor levels in both groups and the mean receptor level was 200.94 ± 15.34 pg/mL (max:489.92 ± 22.36 pg/mL, min: 94.56 ± 11.23 pg/mL).In patients who used tramadol as the levels of μ-Opioid receptors increased, VAS scores of patients and second analgesic use decreased in post-operative period.The VAS scores in patients with higher receptor levels were lower in the recovery room (p < 0.05), 1st (p < 0.05) and 3rd hours (p < 0.05).The VAS scores were lower in the tramadol group compared to the control group (p < 0.05).Number of secondary analgesic requirement was significantly lower in patients of the tramadol group with higher receptor levels compared to the ones with lower receptor (p < 0.05) for arrival at the recovery room and 1st hour. Patients in the tramadol group needed a second pain killer much later than patients in the control group., Conclusions: Our study demonstrates that patients with higher μOR levels have a higher efficacy of opioid analgesic agents and an lesser need for additional analgesic agents., Trial Registration: This trial was registered retrospectively (The ACTRN: ACTRN12619001652167 , registration date: 26/11/2019).

Objective: This study was carried out to delineate differences between major depressive disorder (MDD) and healthy controls in dynorphin and kappa opioid receptor (KOR) levels in association with changes in the β-endorphin - mu opioid receptor (MOR) and immune-inflammatory system., Methods: The present study examines dynorphin, KOR, β-endorphin, MOR, interleukin (IL)-6 and IL-10 in 60 drug-free male participants with MDD and 30 age-matched healthy males., Results: Serum dynorphin, KOR, β-endorphin and MOR are significantly higher in MDD as compared to controls. The increases in the dynorphin/KOR system and β-endorphin/MOR system are significantly intercorrelated and are both strongly associated with increased IL-6 and IL-10 levels. Dynorphin, β-endorphin, KOR and both cytokines showed a good diagnostic performance for MDD versus controls with a bootstrapped (n = 2000) area under the receiver operating curve of 0.972. The dynorphin/KOR system is significantly decreased in depression with comorbid nicotine dependence., Conclusion: Our findings suggest that, in MDD, immune activation is associated with a simultaneous activation of dynorphin/KOR and β-endorphin/MOR signaling and that these opioid systems may participate in the pathophysiology of depression by (a) exerting immune-regulatory activities attenuating the primary immune response and (b) modulating reward responses and mood as well as emotional and behavioural responses to stress.

Large number of studies consider gonadal hormones as factors influencing pain perception by changing the activity of nociceptive and antinociceptive systems. Recent studies indicate that testosterone, along with some other gonadal hormones, plays a key role in the regulation of TRPV1 and MOR expression. In addition, some works focus on the relationship between pain sensation and hostility indices, as well as their interaction with gonadal hormones. The purpose of this study is to elucidate the relationship of thermal sensation and pain threshold with free testosterone, transient receptor potential cation channel subfamily V member 1(TRPV1) and µ-opioid receptor (MOR) protein levels as well as various degrees of hostility in young healthy males. Significant positive correlation is found between heat pain threshold, free testosterone and MOR levels. Each of these parameters significantly correlates positively with various degrees of assault and insignificantly with that of verbal and indirect hostility. They also significantly correlate negatively with various degrees of irritability, resentment, suspicion and guilt. Significant negative correlation is detected between heat pain threshold and TRPV1 level as well as free testosterone and TRPV1 level. The relationship among cold pain threshold, free testosterone, TRPV1, MOR levels and hostility indices is insignificant. Consequently, we consider it to the purpose to further studies in this direction including interaction among other forms of pain sensation and psychological indices.

Background: Persistent postoperative pain (PPP) is common after total knee arthroplasty (TKA). The primary aim of this prospective cohort study was to identify important predictors of moderate to severe PPP 6 and 12 months after TKA., Methods: Consenting patients (n=300) undergoing primary unilateral TKA attended a preoperative session to collect clinical information (age, gender, BMI, preoperative knee pain, comorbid pain, likely neuropathic pain) and psychological variables (depression, anxiety, catastrophising, expected pain). Quantitative sensory testing (pressure pain thresholds, temporal summation, conditioned pain modulation) was performed, and blood samples were obtained for subsequent genotyping of OPRM1 and COMT. Acute postoperative pain was measured at rest and during movement. Surgical factors (surgery time, patella resurfacing, anaesthetic type) were collected after operation. Follow-up questionnaires were sent 6 and 12 months after surgery. Multivariate logistic regression was used to identify predictors of PPP., Results: The prevalence of moderate to severe PPP was 21% (n=60) and 16% (n=45) 6 and 12 months after surgery, with 55% (n=33) and 60% (n=31) of PPP likely neuropathic in nature. At 6 months, a combination of preoperative pain intensity, expected pain, trait anxiety, and temporal summation (Akaike information criterion, 309.9; area under receiver operating characteristic (ROC) curve, 0.70) was able to correctly classify 66% of patients into moderate to severe PPP and no to mild PPP groups. At 12 months, preoperative pain intensity, expected pain, and trait anxiety (Akaike information criterion, 286.8; area under ROC curve, 0.66) correctly classified 66% of patients., Conclusions: Findings from this study highlight several factors that may be targeted in future intervention studies to reduce the development of PPP., Trial Registry Number: ACTRN12612001089820., (Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

The large number of studies occurred in recent decades show the effect of sex hormones on pain sensitivity and response to analgesics. The purpose of current study was to assess the correlation between the mechanical pain sensitivity degree and the dynamics of the μ-opioid receptor protein (MOR) concentration, also to investigate the correlation of sex hormones levels with the degree of mechanical pain sensitivity and the dynamics of MOR concentration. A decreased mechanical pressure threshold, mechanical pain threshold and mechanical pain tolerance have been revealed in the luteal phase of the OMC. The study found the relation of mechanical pain sensitivity decrease degree in the luteal phase of OMC on the dynamics of MOR concentration's variation (increase /decrease). The study also revealed the correlation between the indices of mechanical pain sensitivity and the concentration of follicle-stimulating hormone in the follicular phase of OMC, as well as the correlation between the indices of mechanical pain sensitivity, progesterone and MOR concentrations in the luteal phase of OMC. The relationship between the mechanical pain sensitivity degree, also the MOR concentration andprolactinorluteinizing hormone levels was not found.

Recent studies in psychoneuroimmunology have indicated that proinflammatory cytokines cause several diseases and behaviors that overlap symptomatically with depression. It is known that the endogenous opioid peptide beta-endorphin regulates proinflammatory cytokine secretion from peripheral immune cells via mu-opioid receptor-dependent mechanisms. Therefore, it is possible that the functional polymorphism of the mu-opioid receptor gene (OPRM1, SNP: A118G) influences peripheral circulating proinflammatory cytokine levels and the health-related quality of life (QOL) even in healthy populations. In this study, we compared the serum concentrations of several proinflammatory cytokines (interleukin-2 (IL-2), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma)) and the health-related QOL between OPRM1 genotypes. Interestingly, serum concentrations of IL-6, TNF-alpha, and IFN-gamma were significantly lower and the general health score was significantly higher in carriers of the G allele, who show a strong binding of beta-endorphin to the mu-opioid receptor as compared to individuals without the G allele. Correlation analysis indicated that the general health score was negatively correlated with the IL-6 serum concentration. These results suggest that the sensitive endogenous opioid system in carriers of the G allele may suppress proinflammatory cytokine secretion from peripheral immune cells; consequently, it may influence the health perception.

Objective: Opioid receptor expression and function traditionally have been studied in neuronal cells and recently in mature lymphoid cells; however, little is known about their possible functions in hematopoietic stem cells (CD34(+) cells). We studied the expression of the mu receptor on CD34(+) cells and assessed the signal transduction cascade it induces., Materials and Methods: Mu-receptor expression on cord blood (CB) and peripheral blood (PB) CD34(+) cells was studied by microarrays, immunostaining, and fluorescence-activated cell sorting analysis. Signal transduction by the mu receptor was studied through Western blots and kinase assay of enkephalin-activated CB CD34(+) cells. Apoptotic, differentiation, and proliferation responses following mu-receptor activatioSn were studied by annexin V assay and inverted microscopy., Results: A prominent difference in gene expression, in favor of CB compared to PB CD34(+) cells, was observed in the mu-receptor gene. This receptor was mainly expressed on the CB CD34(+)CD38(-) subpopulation. A MAP kinase signal transduction cascade was shown to be induced through activation of this receptor by enkephalin or morphine., Conclusions: We showed for the first time that the mu receptor is expressed on immature CB stem cells and that its activation by enkephalin or morphine induces a MAP kinase signal transduction cascade. Because the MAP kinase cascade is known to elicit proliferation and differentiation responses, these findings suggest a possible role of endogenous enkephalins in hematopoietic stem cell proliferation and differentiation and may lead to therapeutic applications of opiates in CB stem cell expansion and neuronal differentiation.

Strong evidence for the direct modulation of the immune system by opioids is well documented. Mu-opioids have been shown to alter the release of cytokines important for both host defense and the inflammatory response. Proinflammatory chemokines monocyte chemoattractant protein-1 (MCP-1), RANTES, and IFN-gamma-inducible protein-10 (IP-10) play crucial roles in cell-mediated immune responses, proinflammatory reactions, and viral infections. In this report, we show that [D-Ala(2),N:-Me-Phe(4),Gly-ol(5)]enkephalin (DAMGO), a mu-opioid-selective agonist, augments the expression in human PBMCs of MCP-1, RANTES, and IP-10 at both the mRNA and protein levels. Because of the proposed relationship between opioid abuse and HIV-1 infection, we also examined the impact of DAMGO on chemokine expression in HIV-infected cells. Our results show that DAMGO administration induces a significant increase in RANTES and IP-10 expression, while MCP-1 protein levels remain unaffected in PBMCs infected with the HIV-1 strain. In contrast, we show a dichotomous effect of DAMGO treatment on IP-10 protein levels expressed by T- and M-tropic HIV-infected PBMCs. The differential modulation of chemokine expression in T- and M-tropic HIV-1-infected PBMCs by opioids supports a detrimental role for opioids during HIV-1 infection. Modulation of chemokine expression may enhance trafficking of potential noninfected target cells to the site of active infection, thus directly contributing to HIV-1 replication and disease progression to AIDS.