Opioid Receptor Gene Research Articles

Regulation and Functional Implications of Opioid Receptor Splicing in Opioid Pharmacology and HIV Pathogenesis.

Despite the identification and characterization of four opioid receptor subtypes and the genes from which they are encoded, pharmacological data does not conform to the predications of a four opioid receptor model. Instead, current studies of opioid pharmacology suggest the existence of additional receptor subtypes; however, no additional opioid receptor subtype has been identified to date. It is now understood that this discrepancy is due to the generation of multiple isoforms of opioid receptor subtypes. While several mechanisms are utilized to generate these isoforms, the primary mechanism involves alternative splicing of the pre-mRNA transcript. Extensive alternative splicing patterns for opioid receptors have since been identified and discrepancies in opioid pharmacology are now partially attributed to variable expression of these isoforms. Recent studies have been successful in characterizing the localization of these isoforms as well as their specificity in ligand binding; however, the regulation of opioid receptor splicing specificity is poorly characterized. Furthermore, the functional significance of individual receptor isoforms and the extent to which opioid- and/or HIV-mediated changes in the opioid receptor isoform profile contributes to altered opioid pharmacology or the well-known physiological role of opioids in the exacerbation of HIV neurocognitive dysfunction is unknown. As such, the current review details constitutive splicing mechanisms as well as the specific architecture of opioid receptor genes, transcripts, and receptors in order to highlight the current understanding of opioid receptor isoforms, potential mechanisms of their regulation and signaling, and their functional significance in both opioid pharmacology and HIV-associated neuropathology.

Simian Immunodeficiency Virus Impacts MicroRNA-16 Mediated Post-Transcriptional Regulation of mu Opioid Receptor in CEM ×174 Cells.

Although the mechanism which regulates transcription in the 5'-UTR of the mu opioid receptor gene (OPRM1) in lymphocytes has been well-studied, a question remains as to whether there is post-transcriptional regulation of OPRM1 gene in lymphocytes. In this study, the authors describe both the role played by miRNAs and the impact of SIVmac239 infection on post-transcriptional regulation of OPRM1 gene in CEM ×174 cells. Our results show that miR-16 is able to bind the target site in the range of 8699-8719 nt from the stop codon in MOR-1 mRNA 3'-UTR and suppress the expression of OPRM1 gene. Mutation of this target site reduces the effect of miR-16. Morphine (1 µM) inhibits the expression of miR-16, and this effect is reversed by the antagonist naloxone. Thus, morphine may up-regulate receptor level by both stimulating OPRM1 gene transcription and stabilizing its mRNA. SIVmac239 infection results in an apparent elevation of miR-16 and gradual reduction of OPRM1 gene expression. The inverse correlation of elevated miR-16 and reduced OPRM1 gene expression under viral loading confirmed the effect of SIVmac239 on post-transcriptional regulation of OPRM1 gene in lymphocytes. The authors conclude that miR-16 is a primary factor in post-transcriptional regulation of OPRM1 gene. SIVmac239 upregulates miR-16 levels and consequently suppresses OPRM1 gene expression. This finding will be helpful for full understanding of the regulatory mechanism of OPRM1 gene in lymphocytes, as well as the synergistic mechanism of HIV infection and morphine addiction in the pathogenesis of AIDS.

Opioid neuroscience for addiction medicine: From animal models to FDA approval for alcohol addiction.

Alcohol addiction is one of the most common and devastating diseases in the world. Given the tremendous heterogeneity of alcohol-addicted individuals, it is unlikely that one medication will help nearly all patients. Thus, there is a clear need to develop predictors of response to existing medications. Naltrexone is a mu opioid receptor antagonist which has been approved in the United States for treatment of alcohol addiction since 1994. It has limited efficacy, in part due to noncompliance, but many patients do not respond despite high levels of compliance. There are reports that a mis-sense single-nucleotide polymorphism (rs179919 or A118G) in the mu opioid receptor gene predicts a favorable response to naltrexone if an individual carries a "G" allele. This chapter will review the evidence for this hypothesis. The data suggest that the "G" allele has a complex role in alcohol addiction, increasing the rewarding valence of alcohol. Whether the G allele increases risk for alcoholism and whether it predisposes to a beneficial naltrexone response among alcohol-addicted persons must await additional research with large sample sizes of multiple ethnicities in prospective clinical trials.

Proteasome subunit and opioid receptor gene expression down-regulation induced by paraquat and maneb in human neuroblastoma SH-SY5Y cells.

Paraquat (PQ) and maneb (MB) are able to induce neurotoxic effects by promoting α-synuclein (α-syn) aggregates and altering tyrosine hydroxylase (TH), thus increasing the risk of Parkinson's disease (PD). These pesticides promote neurotoxic effects also by affecting proteasome function that normally regulate protein turnover. We investigated the effects of the two pesticides exposure on multiple targets involved in PD, using SH-SY5Y cells. First, we evaluated TH and α-syn protein levels following PQ and MB cell exposure and a significant increase of these protein levels was observed. Subsequently, since a relationship between ubiquitin/proteasome and opioid receptors has been proposed, the effects of pesticides on their gene expression have been investigated. A decrease of β1 and Rpt3 proteasome subunit mRNA levels, together with the μ and δ opioid receptor down-regulation, was detected. The reported alterations, here simultaneously observed, help to clarify the involvement of multiple biological markers implicated in PD, often separately evaluated.

An animal model of differential genetic risk for methamphetamine intake.

The question of whether genetic factors contribute to risk for methamphetamine (MA) use and dependence has not been intensively investigated. Compared to human populations, genetic animal models offer the advantages of control over genetic family history and drug exposure. Using selective breeding, we created lines of mice that differ in genetic risk for voluntary MA intake and identified the chromosomal addresses of contributory genes. A quantitative trait locus was identified on chromosome 10 that accounts for more than 50% of the genetic variance in MA intake in the selected mouse lines. In addition, behavioral and physiological screening identified differences corresponding with risk for MA intake that have generated hypotheses that are testable in humans. Heightened sensitivity to aversive and certain physiological effects of MA, such as MA-induced reduction in body temperature, are hallmarks of mice bred for low MA intake. Furthermore, unlike MA-avoiding mice, MA-preferring mice are sensitive to rewarding and reinforcing MA effects, and to MA-induced increases in brain extracellular dopamine levels. Gene expression analyses implicate the importance of a network enriched in transcription factor genes, some of which regulate the mu opioid receptor gene, Oprm1, in risk for MA use. Neuroimmune factors appear to play a role in differential response to MA between the mice bred for high and low intake. In addition, chromosome 10 candidate gene studies provide strong support for a trace amine-associated receptor 1 gene, Taar1, polymorphism in risk for MA intake. MA is a trace amine-associated receptor 1 (TAAR1) agonist, and a non-functional Taar1 allele segregates with high MA consumption. Thus, reduced TAAR1 function has the potential to increase risk for MA use. Overall, existing findings support the MA drinking lines as a powerful model for identifying genetic factors involved in determining risk for harmful MA use. Future directions include the development of a binge model of MA intake, examining the effect of withdrawal from chronic MA on MA intake, and studying potential Taar1 gene × gene and gene × environment interactions. These and other studies are intended to improve our genetic model with regard to its translational value to human addiction.

Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts.

The mu1 opioid receptor gene, OPRM1, has long been a high-priority candidate for human genetic studies of addiction. Because of its potential functional significance, the non-synonymous variant rs1799971 (A118G, Asn40Asp) in OPRM1 has been extensively studied, yet its role in addiction has remained unclear, with conflicting association findings. To resolve the question of what effect, if any, rs1799971 has on substance dependence risk, we conducted collaborative meta-analyses of 25 datasets with over 28,000 European-ancestry subjects. We investigated non-specific risk for "general" substance dependence, comparing cases dependent on any substance to controls who were non-dependent on all assessed substances. We also examined five specific substance dependence diagnoses: DSM-IV alcohol, opioid, cannabis, and cocaine dependence, and nicotine dependence defined by the proxy of heavy/light smoking (cigarettes-per-day >20 vs. ≤ 10). The G allele showed a modest protective effect on general substance dependence (OR = 0.90, 95% C.I. [0.83-0.97], p value = 0.0095, N = 16,908). We observed similar effects for each individual substance, although these were not statistically significant, likely because of reduced sample sizes. We conclude that rs1799971 contributes to mechanisms of addiction liability that are shared across different addictive substances. This project highlights the benefits of examining addictive behaviors collectively and the power of collaborative data sharing and meta-analyses.

Canine opioid receptor gene polymorphism and behaviour associations

Canine opioid receptor gene polymorphism and behaviour associations

Histone deacetylase inhibitors relieve morphine resistance in neuropathic pain after peripheral nerve injury

Neuropathic pain is often insensitive to morphine. Our previous study has demonstrated that neuron-restrictive silencer factor represses mu opioid receptor (MOP) gene expression in the dorsal root ganglion (DRG) via histone hypoacetylation-mediated mechanisms after peripheral nerve injury, thereby causing loss of peripheral morphine analgesia. Here, we showed that histone deacetylase (HDAC) inhibitors, such as trichostatin A and valproic acid, restored peripheral and systemic morphine analgesia in neuropathic pain. Also, these agents blocked nerve injury-induced MOP down-regulation in the DRG. These results suggest that HDAC inhibitors could serve as adjuvant analgesics to morphine for the management of neuropathic pain.

A new potent analgesic agent with reduced liability to produce morphine tolerance

The therapeutic use of opioids is limited by the development of tolerance to the analgesic effect and the cellular and molecular mechanisms underlying this phenomenon are still not completely understood. For this reason the search for new analgesic derivatives, endowed with lower tolerance, is always an active field. The newly synthesized 14-O-Methylmorphine-6-sulfate (14-O-MeM6SU) shows high efficacy in in vitro assays and a strong analgesic action in the rat tail flick test. The aim of present work was to investigate: the analgesic effect of 14-O-MeM6SU in mouse tail-flick test; the tolerance to analgesic effect of 14-O-MeM6SU compared to morphine in mice, the effects of test compounds on glutamatergic neurotransmission by measuring spontaneous excitatory postsynaptic currents (sEPSCs) of layer V pyramidal cells from rat prefrontal cortices; and the effect of acute and chronic 14-O-MeM6SU treatments on opioid receptor gene expression in SH-SY5Y neuroblastoma cells expressing μ-opioid (MOP) and nociceptin/opioid receptor-like 1 (NOP) receptors. 14-O-MeM6SU was 17 times more potent than morphine in analgesia and had long duration of action in analgesic dose equipotent to morphine. Mice were treated subcutaneously (s.c.) either with 200 μmol/kg morphine or with 14-O-MeM6SU (12 μmol/kg) twice daily for three days. The magnitude of tolerance or cross-tolerance indicated by the shift in antinociceptive ED50 measured was greater for morphine compared to 14-O-MeM6SU. Subsequent to behavioral testing, patch-clamp experiments in layer V pyramidal neurons of rat prefrontal cortical slices in the presence of bicuculline were performed. Both 14-O-MeM6SU (0.1 μM) and morphine (1 μM) decreased the frequency of sEPSCs, indicating reduction of glutamate release. The effect of the novel compound was reversed by the opioid receptor antagonist naloxone, indicating an opioid mediated action. In contrast, the amplitude was not affected. Finally, gene expression data showed a dose dependent down-regulation of MOP receptor after 24h and 48 h exposure to 14-O-MeM6SU. Interestingly, no changes were detected for NOP receptor gene expression. The specific lack of this effect could be related to the lower tolerance development to analgesic effect of 14-O-MeM6SU. Furthermore, 14-O-MeM6SU displayed high intrinsic efficacy possibly an important factor in the observed effects. Further, the observed inhibition of glutamatergic signaling might be attributed also to the reduction of opioid tolerance. Based on our results the development of a new clinically important, safe analgesic agent might be possible.

Role of steroid hormones and morphine treatment in the modulation of opioid receptor gene expression in brain structures in the female rat.

This study determined the effects of acute treatment with morphine on the expression of the Oprm1, Oprk1, and Oprd1 genes (which encode μ, κ, and δ receptors, respectively) in the striatum, hypothalamus, and periaqueductal gray (PAG) in ovariectomized female rats treated with estrogen. Ovariectomized female rats were divided into five equal groups. Two groups received estrogen (50 µg/kg, 54 h before testing) and saline (ES group) or 3.5 mg/kg morphine (EM group) 2 h before euthanasia. The SS group received saline solution 54 and 2 h before the experiments. The SM group received saline 54 h and 3.5 mg/kg morphine 2 h before the experiments. The W group remained undisturbed. The genes expression were evaluated. Oprm1 and Oprk1 expression were activated, respectively, in the hypothalamus and PAG and in the striatum and PAG by morphine only in estrogen-treated animals. Oprd1 expression in the hypothalamus and PAG was activated by morphine in both estrogen-treated and -nontreated animals. The Oprm1 and Oprk1 gene response to morphine might depend on estrogen, whereas the Oprd1 gene response to morphine might not depend on estrogen, supporting the hypothesis of a functional role for ovarian hormones in opioid receptor-mediated functional adaptations in the female brain.

Variations in opioid receptor genes in neonatal abstinence syndrome

BackgroundThere is significant variability in the severity of neonatal abstinence syndrome (NAS) due to in-utero opioid exposure. We wanted to determine if single nucleotide polymorphisms (SNPs) in key candidate genes contribute to this variability. MethodsFull-term opioid-exposed newborns and their mothers (n=86 pairs) were studied. DNA was genotyped for 80 SNPs from 14 genes utilizing a custom designed microarray. The association of each SNP with NAS outcomes was evaluated. ResultsSNPs in two opioid receptor genes in the infants were associated with worse NAS severity: (1) The PNOC rs732636 A allele (OR=3.8, p=0.004) for treatment with 2 medications and a longer hospital stay (LOS) of 5.8 days (p=0.01), and (2) The OPRK1 rs702764 C allele (OR=4.1, p=0.003) for treatment with 2 medications. The OPRM1 rs1799971 G allele (β=−6.9 days, p=0.02) and COMT rs740603 A allele (β=−5.3 days, p=0.01) were associated with shorter LOS. The OPRD1 rs204076 A allele in the mothers was associated with a longer LOS by 6.6 days (p=0.008). Results were significant point-wise but did not meet the experiment-wide significance level. ConclusionsThese findings suggest that SNPs in opioid receptor and the PNOC genes are associated with NAS severity. However, further testing in a large sample is warranted. This has important implications for prenatal prediction and personalized treatment regimens for infants at highest risk for severe NAS.

The genetic influences on oxycodone response characteristics in human experimental pain.

Human experimental pain studies are of value to study basic pain mechanisms under controlled conditions. The aim of this study was to investigate whether genetic variation across selected mu-, kappa- and delta-opioid receptor genes (OPRM1, OPRK1and OPRD1, respectively) influenced analgesic response to oxycodone in healthy volunteers. Experimental multimodal, multitissue pain data from previously published studies carried out in Caucasian volunteers were used. Data on thermal skin pain tolerance threshold (PTT) (n=37), muscle pressure PTT (n=31), mechanical visceral PTT (n=43) and thermal visceral PTT (n=41) were included. Genetic associations with pain outcomes were explored. Nineteen opioid receptor genetic polymorphisms were included in this study. Variability in oxycodone response to skin heat was associated with OPRM1 single-nucleotide polymorphisms (SNPs) rs589046 (P<0.0001) and rs563649 (P<0.0001). Variability in oxycodone response to visceral pressure was associated with four OPRM1 SNPs: rs589046 (P=0.015), rs1799971 (P=0.045), rs9479757 (P=0.009) and rs533586 (P=0.046). OPRM1 SNPs were not associated with oxycodone visceral heat threshold, however, one OPRD1 rs419335 reached significance (P=0.015). Another OPRD1 SNP rs2234918 (P=0.041) was associated with muscle pressure. There were no associations with OPRK1 SNPs and oxycodone response for any of the pain modalities. Associations were found between analgesic effects of oxycodone and OPRM1 and OPRD1 SNPs; therefore, variation in opioid receptor genes may partly explain responder characteristics to oxycodone.

The Influence of A118G Single Nucleotide Polymorphism of Human Mu Opioid Receptor Gene and the MDR1 Gene in Egyptian Patients With Tramadol-induced Seizure

Objectives: Although seizures have been reported with tramadol use, the exact mechanism is not yet confirmed. An individual genetic susceptibility may have a role in developing seizures. The purpose of this study was to investigate the frequency of mutant allele of the OPRM A118G and MDR1 C3534T in tramadol users with seizures. Methods: After investigators obtained informed consent and when other causes of seizures were excluded, 74 Egyptian tramadol users, with and without seizures, were assessed clinically, radiologically, and by electroencephalogram. Their blood samples were genotyped for the µ-opioid receptor gene and the multidrug resistant (MDR1) genes. Results: Thirty-seven subjects had seizures. A history of head trauma and more opioid use were reported by the group with seizures. Family history of epilepsy was present in 2 subjects with seizures. There was no significant difference between the 2 groups with regard to the frequency of occurrence of the SNP A118G of the mu opioid receptor gene or the SNP C3435T of the MDR1 gene. Conclusions: This study could not illustrate a potential genetic background in the studied point mutations that could explain the development of tramadol-induced seizures.

Human population genetic structure detected by pain-related mu opioid receptor gene polymorphisms.

Several single nucleotide polymorphisms (SNPs) in the Mu Opioid Receptor gene (OPRM1) have been identified and associated with a wide variety of clinical phenotypes related both to pain sensitivity and analgesic requirements. The A118G and other potentially functional OPRM1 SNPs show significant differences in their allele distributions among populations. However, they have not been properly addressed in a population genetic analysis. Population stratification could lead to erroneous conclusions when they are not taken into account in association studies. The aim of our study was to analyze OPRM1 SNP variability by comparing population samples of the International Hap Map database and to analyze a new population sample from the city of Corrientes, Argentina. The results confirm that OPRM1 SNP variability differs among human populations and displays a clear ancestry genetic structure, with three population clusters: Africa, Asia, and Europe-America.

Mediation of Opioid Analgesia by a Truncated Six Transmembrane G‐Protein‐Coupled Receptor

Potent opioid analgesics lacking side‐effects may be possible by targeting truncated mu receptor splice variants. Mu opioids act through G‐protein coupled receptors generated from the mu opioid receptor (Oprm1) gene which undergoes extensive alternative splicing. The most abundant set of variants encode classical full‐length 7 transmembrane domain (TM) mu opioid receptors that mediate the actions of the traditional mu drugs morphine and methadone. In contrast, IBNtxA (3‐iodobenzoyl‐6β‐naltrexamide) is a potent analgesic against thermal, inflammatory and neuropathic pain whose actions are independent of the 7TM mu opioid receptors and lost in a knockout mouse lacking a set of 6TM truncated mu receptor splice variants. Unlike traditional opioids, IBNtxA has no respiratory depression, physical dependence or reward behavior, suggesting it acts through a novel mu opioid receptor target. Here we demonstrate that a truncated 6TM splice variant, mMOR‐1G, can rescue IBNtxA analgesia in a mu opioid receptor knockout mouse lacking all Oprm1 splice variants due to disruptions of both exons 1 and 11. No mu opioids were active in these mice. A lentivirus containing the 6TM variant mMOR‐1G administered intrathecally restored IBNtxA, but not morphine, analgesia, confirming that a truncated 6TM GPCR is both necessary and sufficient for IBNtxA analgesia.This work was supported by the NIH with grants from NIDA (DA013997 and DA02944) to Y‐X.P. and (DA06241 and DA07242) to G.W.P. and a core grant from the NCI to MSKCC (CA08748).

Endomorphins and DAMGO Utilize Different Mechanisms to Produce Analgesia

There is significant variability among animals in their response to mu opioid receptor (MOR1) analgesics. The mu opioid receptor gene (OPRM1) undergoes extensive alternative splicing, producing several splice variants with 1, 6, and 7 transmembrane (TM) domains. Variants containing 6 TMs lack TM1 and are associated with the exon 11 promoter. We previously showed that mice lacking exon 11 variants respond normally to methadone and morphine, but fentanyl, heroin, and morphine‐6‐glucuronide potency is significantly reduced (Pan et al, 2009). Here, we report that in exon 11 KO mice the DAMGO response is intact both supraspinally and spinally but endomorphin analgesiais significantly reduced. [3H]DAMGO binding in exon 11 KO brain and spinal cord was not significantly altered, but binding of the endomorphin 2 analog 125I‐DAPP (dmt(125I)‐D‐Ala‐Phe‐Phe‐NH2) was reduced.No binding of [3H]DAMGO or 125I‐DAPP was detected in mice lacking both exon 1 7TM MOR variants and exon 11 6TM variants. In [35S]GTPγS studies of brain and spinal cord binding, max stimulation by DAMGO was equal in wild type and exon 11 KO mice whereas IDAPP stimulation was reduced in exon 11 KO mice. Overall, our results indicate that DAMGO does not recruit 6TM exon 11 variants for binding and analgesia, whereas endomorphins require a mechanism including 6TM exon 11 variants for analgesia and a significant portion of binding.

(269) Variations in opioid receptor genes are associated with breast pain in women prior to and with mild and severe persistent breast pain after breast cancer surgery

(269) Variations in opioid receptor genes are associated with breast pain in women prior to and with mild and severe persistent breast pain after breast cancer surgery

The Impact of Genetic Variation on Sensitivity to Opioid Analgesics in Patients with Postoperative Pain: A Systematic Review and Meta-Analysis

Background: Individual response to opioid analgesics varies among patients. Objective: This study sought to clarify the impact of distinct genetic variations on pain, opioid consumption, and opioid side effects in patients with postoperative pain. Study Design: A systematic review and meta-analysis of associations between genetic singlenucleotide polymorphisms (SNPs) and opioids used for acute postoperative pain. Setting: This meta-analysis examined all studies involving an association between genetic polymorphisms and the analgesic efficacy or clinical outcome of opioid analgesics for postoperative pain. Methods: A literature search was performed up to January 31, 2014, using the PubMed, EMBase, ISI Web of Science, and Cochrane Library databases. Results: Fifty-nine studies were included in this systematic review, and 23 studies (a total of 5,902 patients) were included in the final meta-analysis. The results showed that human μ-opioid receptor gene (OPRM1) 118G allele variant carriers consumed more opioids for analgesia (SMD = -0.17, 95% CI = [-0.25, -0.10], P &lt; 0.00001), but reported higher pain scores (MD = -0.11, 95% CI = [-0.17, -0.04], P = 0.002) and less nausea and vomiting (odds ratio = 1.30, 95% CI = [1.08, 1.55], P = 0.005) than the homozygous 118AA patients during the first 24 hour but not the 48 hour postoperative period. Moreover, CYP3A4*1G carriers consumed less opioids than homozygous CYP3A4*1/*1 patients during the first 24 hours postoperative period (MD = 45.12, 95% CI = [36.17, 54.06], P &lt; 0.00001). No significant differences were found in CYP3A5*3, ABCB1 C3435T, and G2477T/A genetic polymorphisms. Limitations: Some potential non-genetic factors can modify the effects of gene SNP on pain and opioid consumption during the postoperative period, such as age, gender, mood, anxiety, and drug-drug interactions. But further analyses could not be performed in the present meta-analysis due to limited information. Conclusion: The results indicate that among the genetic SNPs we studied which include those affecting analgesic drug metabolism, transport of analgesic agents across the blood-brain barrier, and their activity at target receptors and ion channels and in the modulation of neurotransmitter pathways, the A118G allele variant of OPRM1 has the most potent influence on pain management of postoperative patients. Opioid receptor gene information may provide valuable information for clinicians to properly manage the analgesic use of opioids individually for better pain management. Key words: Postoperative pain, meta-analysis, single-nucleotide polymorphism, opioid

The Influence of the A118G Polymorphism of the μ-Opioid Receptor Gene (OPRM1) on the Course of Total Intravenous Anesthesia in Gynecological Patients

Objective: to investigate the influence of the A118G polymorphism of the μ - opioid receptor gene (OPRM1) on the course of total intravenous anesthesia. Subjects and methods. A sample consisted of 161 gynecological patients who had under - gone elective surgery under conventional total intravenous anesthesia. Heart rate, noninvasive mean blood pressure, peripheral oxygen saturation, bispectral index, and somatosensory evoked potentials were monitored in all the examinees before and after administration of the induction dose of an anesthetic, in the intraoperative and early postoperative period. The polymorphic variants of the gene in question were determined by allele - specific PCR. Results. According to the identified genotype, the patients were divided into 3 groups: 1) 118A/A genotype carriers ( n =101); 2) 118A/G genotype carriers ( n =48); 3) 118G/G genotype carriers ( n =12). It was intraoperatively found that the 118G/G genotype carriers tended to have hypertension and to consume higher quantities of fentanyl and droperidol than the 118A/A and 118A/G carriers. The intergroup difference in the bispectral index was statistically insignificant during surgery. In the early postoperative period, the 118G - allele homozygotes showed a deeper level of sedation, which correlated with the significantly lower values of the bispectral index ( p <0.01) and the higher incidence of adverse reactions ( p <0.01). At the same time, the latency and amplitude of somatosensory evoked potentials in the 118G/G genotype carriers showed the least variations as compared to the A - allele homozygotes and heterozygotes ( p <0.01). Conclusion. The A118G polymorphism of the μ - opioid receptor gene (OPRM1) affects the course of total intravenous anesthesia. The 118G/G genotype patients needed larger doses of narcotic analgesics, requiring a longer follow - up in the early postoperative period.

Bioinformatics and evolution of vertebrate nociceptin and opioid receptors.

G protein-coupled receptors (GPCRs) are ancestrally related membrane proteins on cells that mediate the pharmacological effect of most drugs and neurotransmitters. GPCRs are the largest group of membrane receptor proteins encoded in the human genome. One of the most famous types of GPCRs is the opioid receptors. Opioid family receptors consist of four closely related proteins expressed in all vertebrate brains and spinal cords examined to date. The three classical types of opioid receptors shown unequivocally to mediate analgesia in animal models and in humans are the mu- (MOR), delta- (DOR), and kappa-(KOR) opioid receptor proteins. The fourth and most recent member of the opioid receptor family discovered is the nociceptin or orphanin FQ receptor (ORL). The role of ORL and its ligands in producing analgesia is not as clear, with both analgesic and hyperalgesic effects reported. All four opioid family receptor genes were cloned from expressed mRNA in a number of vertebrate species, and there are enough sequences presently available to carry out bioinformatic analysis. This chapter presents the results of a comparative analysis of vertebrate opioid receptors using pharmacological studies, bioinformatics, and the latest data from human whole-genome studies. Results confirm our initial hypotheses that the four opioid receptor genes most likely arose by whole-genome duplication, that there is an evolutionary vector of opioid receptor type divergence in sequence and function, and that the hMOR gene shows evidence of positive selection or adaptive evolution in Homo sapiens.