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Genetic variability of the mu-opioid receptor influences intrathecal fentanyl analgesia requirements in laboring women.

ABSTRACT: Labor initiates one of the most intensely painful episodes in a woman's life. Opioids are used to provide analgesia with substantial interindividual variability in efficacy. mu-Opioid receptor (muOR, OPRM1) genetic variants may explain differences in response to opioid analgesia. We hypothesized that OPRM1 304A/G polymorphism influences the median effective dose (ED(50)) of intrathecal fentanyl via combined spinal-epidural for labor analgesia. Nulliparous women were prospectively recruited around 35 weeks gestation (n=224), and genotyped for 304A/G polymorphism. Those requesting neuraxial labor analgesia were enrolled in one of the two double-blinded trials: up-down sequential allocation (SA, n=50) and a separate confirmatory random-dose allocation trial (RA, n=97). Effective analgesia from intrathecal fentanyl was defined by >or=60 min analgesia with verbal rating score

SUBMITTER: Landau R

PROVIDER: S-EPMC2669083 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Genetic variability of the mu-opioid receptor influences intrathecal fentanyl analgesia requirements in laboring women.

Landau Ruth R Kern Christian C Columb Malachy O MO Smiley Richard M RM Blouin Jean-Louis JL

Pain 20080409 1

Labor initiates one of the most intensely painful episodes in a woman's life. Opioids are used to provide analgesia with substantial interindividual variability in efficacy. mu-Opioid receptor (muOR, OPRM1) genetic variants may explain differences in response to opioid analgesia. We hypothesized that OPRM1 304A/G polymorphism influences the median effective dose (ED(50)) of intrathecal fentanyl via combined spinal-epidural for labor analgesia. Nulliparous women were prospectively recruited aroun ...[more]

PMID: 18403122

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Project description:BackgroundMost clinical opioids act through μ-opioid receptors. They effectively relieve pain but are limited by side effects, such as constipation, respiratory depression, dependence, and addiction. Many efforts have been made toward developing potent analgesics that lack side effects. Three-iodobenzoyl-6β-naltrexamide (IBNtxA) is a novel class of opioid active against thermal, inflammatory, and neuropathic pain, without respiratory depression, physical dependence, and reward behavior. The μ-opioid receptor (OPRM1) gene undergoes extensive alternative precursor messenger ribonucleic acid splicing, generating multiple splice variants that are conserved from rodents to humans. One type of variant is the exon 11 (E11)-associated truncated variant containing 6 transmembrane domains (6TM variant). There are 5 6TM variants in the mouse OPRM1 gene, including mMOR-1G, mMOR-1M, mMOR-1N, mMOR-1K, and mMOR-1L. Gene-targeting mouse models selectively removing 6TM variants in E11 knockout (KO) mice eliminated IBNtxA analgesia without affecting morphine analgesia. Conversely, morphine analgesia is lost in an exon 1 (E1) KO mouse that lacks all 7 transmembrane (7TM) variants but retains 6TM variant expression, while IBNtxA analgesia remains intact. Elimination of both E1 and E11 in an E1/E11 double KO mice abolishes both morphine and IBNtxA analgesia. Reconstituting expression of the 6TM variant mMOR-1G in E1/E11 KO mice through lentiviral expression rescued IBNtxA but not morphine analgesia. The aim of this study was to investigate the effect of lentiviral expression of the other 6TM variants in E1/E11 KO mice on IBNtxA analgesia.MethodsLentiviruses expressing 6TM variants were packaged in HEK293T cells, concentrated by ultracentrifugation, and intrathecally administered 3 times. Opioid analgesia was determined using a radiant-heat tail-flick assay. Expression of lentiviral 6TM variant messenger ribonucleic acids was examined by polymerase chain reaction (PCR) or quantitative PCR.ResultsAll the 6TM variants restored IBNtxA analgesia in the E1/E11 KO mouse, while morphine remained inactive. Expression of lentiviral 6TM variants was confirmed by PCR or quantitative PCR. IBNtxA median effective dose values determined from cumulative dose-response studies in the rescued mice were indistinguishable from wild-type animals. IBNtxA analgesia was maintained for up to 33 weeks in the rescue mice and was readily antagonized by the opioid antagonist levallorphan.ConclusionsOur study demonstrated the pharmacological relevance of mouse 6TM variants in IBNtxA analgesia and established that a common functional core of the receptors corresponding to the transmembrane domains encoded by exons 2 and 3 is sufficient for activity. Thus, 6TM variants offer potential therapeutic targets for a distinct class of analgesics that are effective against broad-spectrum pain models without many side effects associated with traditional opioids.

Project description:To examine the clinical factors associated with increased opioid dose among mechanically ventilated children in the pediatric intensive care unit.Prospective, observational study with 100% accrual of eligible patients.Seven pediatric intensive care units from tertiary-care children's hospitals in the Collaborative Pediatric Critical Care Research Network.Four hundred nineteen children treated with morphine or fentanyl infusions.None.Data on opioid use, concomitant therapy, demographic and explanatory variables were collected. Significant variability occurred in clinical practices, with up to 100-fold differences in baseline opioid doses, average daily or total doses, or peak infusion rates. Opioid exposure for 7 or 14 days required doubling of the daily opioid dose in 16% patients (95% confidence interval 12%-19%) and 20% patients (95% confidence interval 16%-24%), respectively. Among patients receiving opioids for longer than 3 days (n = 225), this occurred in 28% (95% confidence interval 22%-33%) and 35% (95% confidence interval 29%-41%) by 7 or 14 days, respectively. Doubling of the opioid dose was more likely to occur following opioid infusions for 7 days or longer (odds ratio 7.9, 95% confidence interval 4.3-14.3; p < 0.001) or co-therapy with midazolam (odds ratio 5.6, 95% confidence interval 2.4-12.9; p < 0.001), and it was less likely to occur if morphine was used as the primary opioid (vs. fentanyl) (odds ratio 0.48, 95% confidence interval 0.25-0.92; p = 0.03), for patients receiving higher initial doses (odds ratio 0.96, 95% confidence interval 0.95-0.98; p < 0.001), or if patients had prior pediatric intensive care unit admissions (odds ratio 0.37, 95% confidence interval 0.15-0.89; p = 0.03).Mechanically ventilated children require increasing opioid doses, often associated with prolonged opioid exposure or the need for additional sedation. Efforts to reduce prolonged opioid exposure and clinical practice variation may prevent the complications of opioid therapy.

Project description:Interactions of 21 fentanyl derivatives with ?-opioid receptor (?OR) were studied using experimental and theoretical methods. Their binding to ?OR was assessed with radioligand competitive binding assay. A uniform set of binding affinity data contains values for two novel and one previously uncharacterized derivative. The data confirms trends known so far and thanks to their uniformity, they facilitate further comparisons. In order to provide structural hypotheses explaining the experimental affinities, the complexes of the studied derivatives with ?OR were modeled and subject to molecular dynamics simulations. Five common General Features (GFs) of fentanyls' binding modes stemmed from these simulations. They include: GF1) the ionic interaction between D147 and the ligands' piperidine NH? moiety; GF2) the N-chain orientation towards the ?OR interior; GF3) the other pole of ligands is directed towards the receptor outlet; GF4) the aromatic anilide ring penetrates the subpocket formed by TM3, TM4, ECL1 and ECL2; GF5) the 4-axial substituent (if present) is directed towards W318. Except for the ionic interaction with D147, the majority of fentanyl-?OR contacts is hydrophobic. Interestingly, it was possible to find nonlinear relationships between the binding affinity and the volume of the N-chain and/or anilide's aromatic ring. This kind of relationships is consistent with the apolar character of interactions involved in ligand?receptor binding. The affinity reaches the optimum for medium size while it decreases for both large and small substituents. Additionally, a linear correlation between the volumes and the average dihedral angles of W293 and W133 was revealed by the molecular dynamics study. This seems particularly important, as the W293 residue is involved in the activation processes. Further, the Y326 (OH) and D147 (C?) distance found in the simulations also depends on the ligands' size. In contrast, neither RMSF measures nor D114/Y336 hydrations show significant structure-based correlations. They also do not differentiate studied fentanyl derivatives. Eventually, none of 14 popular scoring functions yielded a significant correlation between the predicted and observed affinity data (R < 0.30, n = 28).

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Genetic variability of the mu-opioid receptor influences intrathecal fentanyl analgesia requirements in laboring women.

Publications

Genetic variability of the mu-opioid receptor influences intrathecal fentanyl analgesia requirements in laboring women.

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