Mediation of opioid analgesia by a truncated 6-transmembrane GPCR.
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ABSTRACT:
SUBMITTER: Lu Z
PROVIDER: S-EPMC4563690 | biostudies-literature | 2015 Jul
REPOSITORIES: biostudies-literature
Publications
Mediation of opioid analgesia by a truncated 6-transmembrane GPCR.
Lu Zhigang Z Xu Jin J Rossi Grace C GC Majumdar Susruta S Pasternak Gavril W GW Pan Ying-Xian YX
The Journal of clinical investigation 20150526 7
The generation of potent opioid analgesics that lack the side effects of traditional opioids may be possible by targeting truncated splice variants of the μ-opioid receptor. μ-Opioids act through GPCRs that are generated from the Oprm1 gene, which undergoes extensive alternative splicing. The most abundant set of Oprm1 variants encode classical full-length 7 transmembrane domain (7TM) μ-opioid receptors that mediate the actions of the traditional μ-opioid drugs morphine and methadone. In contras ...[more]
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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.
| S-EPMC5820199 | biostudies-literature
Project description:The clinical management of severe pain depends heavily on opioids acting through mu opioid receptors encoded by the Oprm1 gene, which undergoes extensive alternative splicing. In addition to generating a series of prototypic seven transmembrane domain (7TM) G protein-coupled receptors (GPCRs), Oprm1 also produces a set of truncated splice variants containing only six transmembrane domains (6TM) through which selected opioids such as IBNtxA (3'-iodobenzoyl-6?-naltrexamide) mediate a potent analgesia without many undesirable effects. Although morphine analgesia is independent of these 6TM mu receptor isoforms, we now show that the selective loss of the 6TM variants in a knockout model eliminates the analgesic actions of delta and kappa opioids and of ?2-adrenergic compounds, but not cannabinoid, neurotensin, or muscarinic drugs. These observations were confirmed by using antisense paradigms. Despite their role in analgesia, loss of the 6TM variants were not involved with delta opioid-induced seizure activity, aversion to the kappa drug U50, 488H, or ?2-mediated hypolocomotion. These observations support the existence of parallel opioid and nonopioid pain modulatory systems and highlight the ability to dissociate unwanted delta, kappa1, and ?2 actions from analgesia.
| S-EPMC4822618 | biostudies-literature
Project description:The ?-opioid receptor gene, OPRM1, undergoes extensive alternative pre-mRNA splicing, as illustrated by the identification of an array of splice variants generated by both 5' and 3' alternative splicing. The current study reports the identification of another set of splice variants conserved across species that are generated through exon skipping or insertion that encodes proteins containing only a single transmembrane (TM) domain. Using a Tet-Off system, we demonstrated that the truncated single TM variants can dimerize with the full-length 7-TM ?-opioid receptor (MOR-1) in the endoplasmic reticulum, leading to increased expression of MOR-1 at the protein level by a chaperone-like function that minimizes endoplasmic reticulum-associated degradation. In vivo antisense studies suggested that the single TM variants play an important role in morphine analgesia, presumably through modulation of receptor expression levels. Our studies suggest the functional roles of truncated receptors in other G protein-coupled receptor families.
| S-EPMC3774389 | biostudies-literature
Project description:BACKGROUND:This is an updated version of the original Cochrane review published in Issue 4, 2006. Patients may control postoperative pain by self administration of intravenous opioids using devices designed for this purpose (patient controlled analgesia or PCA). A 1992 meta-analysis by Ballantyne et al found a strong patient preference for PCA over non-patient controlled analgesia, but disclosed no differences in analgesic consumption or length of postoperative hospital stay. Although Ballantyne's meta-analysis found that PCA did have a small but statistically significant benefit upon pain intensity, a 2001 review by Walder et al did not find statistically significant differences in pain intensity or pain relief between PCA and groups treated with non-patient controlled analgesia. OBJECTIVES:To evaluate the efficacy and safety of patient controlled intravenous opioid analgesia (termed PCA in this review) versus non-patient controlled opioid analgesia of as-needed opioid analgesia for postoperative pain relief. SEARCH METHODS:We ran the search for the previous review in November 2004. For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 12), MEDLINE (1966 to 28 January 2015), and EMBASE (1980 to 28 January 2015) for randomized controlled trials (RCTs) in any language, and reference lists of reviews and retrieved articles. SELECTION CRITERIA:We selected RCTs that assessed pain intensity as a primary or secondary outcome. These studies compared PCA without a continuous background infusion with non-patient controlled opioid analgesic regimens. We excluded studies that explicitly stated they involved patients with chronic pain. DATA COLLECTION AND ANALYSIS:Two review authors independently extracted data, which included demographic variables, type of surgery, interventions, efficacy, and adverse events. We graded each included study for methodological quality by assessing risk of bias and employed the GRADE approach to assess the overall quality of the evidence. We performed meta-analysis of outcomes that included pain intensity assessed by a 0 to 100 visual analog scale (VAS), opioid consumption, patient satisfaction, length of stay, and adverse events. MAIN RESULTS:Forty-nine studies with 1725 participants receiving PCA and 1687 participants assigned to a control group met the inclusion criteria. The original review included 55 studies with 2023 patients receiving PCA and 1838 patients assigned to a control group. There were fewer included studies in our updated review due to the revised exclusion criteria. For the primary outcome, participants receiving PCA had lower VAS pain intensity scores versus non-patient controlled analgesia over most time intervals, e.g., scores over 0 to 24 hours were nine points lower (95% confidence interval (CI) -13 to -5, moderate quality evidence) and over 0 to 48 hours were 10 points lower (95% CI -12 to -7, low quality evidence). Among the secondary outcomes, participants were more satisfied with PCA (81% versus 61%, P value = 0.002) and consumed higher amounts of opioids than controls (0 to 24 hours, 7 mg more of intravenous morphine equivalents, 95% CI 1 mg to 13 mg). Those receiving PCA had a higher incidence of pruritus (15% versus 8%, P value = 0.01) but had a similar incidence of other adverse events. There was no difference in the length of hospital stay. AUTHORS' CONCLUSIONS:Since the last version of this review, we have found new studies providing additional information. We reanalyzed the data but the results did not substantially alter any of our previously published conclusions. This review provides moderate to low quality evidence that PCA is an efficacious alternative to non-patient controlled systemic analgesia for postoperative pain control.
| S-EPMC7387354 | biostudies-literature
Project description:The mu opioid receptor gene undergoes extensive alternative splicing. Mu opioids can be divided into three classes based on the role of different groups of splice variants. Morphine and methadone require only full length seven transmembrane (7TM) variants for analgesia, whereas IBNtxA (3'-iodobenzyol-6?-naltrexamide) needs only truncated 6TM variants. A set of endomorphin analogs fall into a third group that requires both 6TM and 7TM splice variants. Unlike morphine, endomorphin 1 and 2, DAPP (Dmt,d-Ala-Phe-Phe-NH2), and IDAPP (3'-iodo-Dmt-d-Ala-Phe-Phe-NH2) analgesia was lost in an exon 11 knockout mouse lacking 6TM variants. Restoring 6TM variant expression in a knockout mouse lacking both 6TM and 7TM variants failed to rescue DAPP or IDAPP analgesia. However, re-establishing 6TM expression in an exon 11 knockout mouse that still expressed 7TM variants did rescue the response, consistent with the need for both 6TM and 7TM variants. In receptor binding assays, 125I-IDAPP labeled more sites (Bmax) than 3H-DAMGO ([d-Ala2,N-MePhe4,Gly(ol)5]-enkephalin) in wild-type mice. In exon 11 knockout mice, 125I-IDAPP binding was lowered to levels similar to 3H-DAMGO, which remained relatively unchanged compared to wild-type mice. 125I-IDAPP binding was totally lost in an exon 1/exon 11 knockout model lacking all Oprm1 variant expression, confirming that the drug was not cross labeling non-mu opioid receptors. These findings suggested that 125I-IDAPP labeled two populations of mu binding sites in wild-type mice, one corresponding to 7TM variants and the second dependent upon 6TM variants. Together, these data indicate that endomorphin analogs represent a unique, genetically defined, and distinct class of mu opioid analgesic.
| S-EPMC5177531 | biostudies-literature
Project description:Opiates such as morphine and fentanyl, a major class of analgesics used in the clinical management of pain, exert their effects through the activation of opioid receptors. Opioids are among the most commonly prescribed and frequently abused drugs in the USA; however, the prolonged use of opiates often leads to the development of tolerance and addiction. Although blockade of opioid receptors with antagonists such as naltrexone and naloxone can lessen addictive impulses and facilitate recovery from overdose, systemic disruption of endogenous opioid receptor signalling through the use of these antagonistic drugs can have severe side effects. In the light of these challenges, current efforts have focused on identifying new therapeutic targets that selectively and specifically modulate opioid receptor signalling and function so as to achieve analgesia without the adverse effects associated with chronic opiate use. We have previously reported that opioid receptors interact with each other to form heteromeric complexes and that these interactions affect morphine signalling. Since chronic morphine administration leads to an enhanced level of these heteromers, these opioid receptor heteromeric complexes represent novel therapeutic targets for the treatment of pain and opiate addiction. In this review, we discuss the role of heteromeric opioid receptor complexes with a focus on mu opioid receptor (MOR) and delta opioid receptor (DOR) heteromers. We also highlight the evidence for altered pharmacological properties of opioid ligands and changes in ligand function resulting from the heteromer formation.
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Project description:Translating pharmacogenetics to clinical practice has been particularly challenging in the context of pain, due to the complexity of this multifaceted phenotype and the overall subjective nature of pain perception and response to analgesia. Overall, numerous genes involved with the pharmacokinetics and dynamics of opioids response are candidate genes in the context of opioid analgesia. The clinical relevance of CYP2D6 genotyping to predict analgesic outcomes is still relatively unknown; the two extremes in CYP2D6 genotype (ultrarapid and poor metabolism) seem to predict pain response and/or adverse effects. Overall, the level of evidence linking genetic variability (CYP2D6 and CYP3A4) to oxycodone response and phenotype (altered biotransformation of oxycodone into oxymorphone and overall clearance of oxycodone and oxymorphone) is strong; however, there has been no randomized clinical trial on the benefits of genetic testing prior to oxycodone therapy. On the other hand, predicting the analgesic response to morphine based on pharmacogenetic testing is more complex; though there was hope that simple genetic testing would allow tailoring morphine doses to provide optimal analgesia, this is unlikely to occur. A variety of polymorphisms clearly influence pain perception and behavior in response to pain. However, the response to analgesics also differs depending on the pain modality and the potential for repeated noxious stimuli, the opioid prescribed, and even its route of administration.
| S-EPMC3513230 | biostudies-literature
Project description:ImportanceThe overprescription of opioids to surgical patients is recognized as an important factor contributing to the opioid crisis. However, the value of prescribing opioid analgesia (OA) vs opioid-free analgesia (OFA) after postoperative discharge remains uncertain.ObjectiveTo investigate the feasibility of conducting a full-scale randomized clinical trial (RCT) to assess the comparative effectiveness of OA vs OFA after outpatient general surgery.Design, setting, and participantsThis parallel, 2-group, assessor-blind, pragmatic pilot RCT was conducted from January 29 to September 3, 2020 (last follow-up on October 2, 2020). at 2 university-affiliated hospitals in Montreal, Quebec, Canada. Participants were adult patients (aged ≥18 years) undergoing outpatient abdominal (ie, cholecystectomy, appendectomy, or hernia repair) or breast (ie, partial or total mastectomy) general surgical procedures. Exclusion criteria were contraindications to drugs used in the trial, preoperative opioid use, conditions that could affect assessment of outcomes, and intraoperative or early complications requiring hospitalization.InterventionsPatients were randomized 1:1 to receive OA (around-the-clock nonopioids and opioids for breakthrough pain) or OFA (around-the-clock nonopioids with increasing doses and/or addition of nonopioid medications for breakthrough pain) after postoperative discharge.Main outcomes and measuresMain outcomes were a priori RCT feasibility criteria (ie, rates of surgeon agreement, patient eligibility, patient consent, treatment adherence, loss to follow-up, and missing follow-up data). Secondary outcomes included pain intensity and interference, analgesic intake, 30-day unplanned health care use, and adverse events. Between-group comparison of outcomes followed the intention-to-treat principle.ResultsA total of 15 surgeons were approached; all (100%; 95% CI, 78%-100%) agreed to have patients recruited and adhered to the study procedures. Rates of patient eligibility and consent were 73% (95% CI, 66%-78%) and 57% (95% CI, 49%-65%), respectively. Seventy-six patients were randomized (39 [51%] to OA and 37 [49%] to OFA) and included in the intention-to-treat analysis (mean [SD] age, 55.5 [14.5] years; 50 [66%] female); 40 (53%) underwent abdominal surgery, and 36 (47%) underwent breast surgery. Seventy-five patients (99%; 95% CI, 93%-100%) adhered to the allocated treatment; 1 patient randomly assigned to OFA received an opioid prescription. Seventeen patients (44%) randomly assigned to OA consumed opioids after discharge. Seventy-three patients (96%; 95% CI, 89%-99%) completed the 30-day follow-up. The rate of missing questionnaires was 37 of 3724 (1%; 95% CI, 0.7%-1.4%). All the a priori RCT feasibility criteria were fulfilled.Conclusions and relevanceThe findings of this pilot RCT support the feasibility of conducting a robust, full-scale RCT to inform evidence-based prescribing of analgesia after outpatient general surgery.Trial registrationClinicalTrials.gov Identifier: NCT04254679.
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Project description:Cytochrome P450 monooxygenases (P450s), which are well-known drug-metabolizing enzymes, are thought to play a signal transduction role in µ opioid analgesia and may serve as high-affinity (3)H-cimetidine ((3)HCIM) binding sites in the brain. (3)HCIM binding sites may also be related to opioid or nonopioid analgesia. However, of the more than 100 murine P450 enzymes, the specific isoform(s) responsible for either function have not been identified. Presently, three lines of constitutive P450 gene cluster knockout (KO) mice with full-length deletions of 14 Cyp2c, 9 Cyp2d, and 7 Cyp3a genes were studied for deficiencies in (3)HCIM binding and for opioid analgesia. Liver and brain homogenates from all three genotypes showed normal (3)HCIM binding values, indicating that gene products of Cyp2d, Cyp3a, and Cyp2c are not (3)HCIM-binding proteins. Cyp2d KO and Cyp3a KO mice showed normal antinociceptive responses to a moderate systemic dose of morphine (20 mg/kg, s.c.), thereby excluding 16 P450 isoforms as mediators of opioid analgesia. In contrast, Cyp2c KO mice showed a 41% reduction in analgesic responses following systemically (s.c.) administered morphine. However, the significance of brain Cyp2c gene products in opioid analgesia is uncertain because little or no analgesic deficits were noted in Cyp2c KO mice following intracerebroventricular or intrathecalmorphine administration, respectively. These results show that the gene products of Cyp2d and Cyp3a do not contribute to µ opioid analgesia in the central nervous system. A possible role for Cyp2c gene products in opioid analgesia requires further consideration.
| S-EPMC4538858 | biostudies-literature
Project description:Opioids are the most effective drugs for the treatment of severe pain, but they also cause addiction and overdose deaths, which have led to a worldwide opioid crisis. Therefore, the development of safer opioids is urgently needed. In this article, we provide a critical overview of emerging opioid-based strategies aimed at effective pain relief and improved side effect profiles. These approaches comprise biased agonism, the targeting of (i) opioid receptors in peripheral inflamed tissue (by reducing agonist access to the brain, the use of nanocarriers, or low pH-sensitive agonists); (ii) heteromers or multiple receptors (by monovalent, bivalent, and multifunctional ligands); (iii) receptor splice variants; and (iv) endogenous opioid peptides (by preventing their degradation or enhancing their production by gene transfer). Substantial advancements are underscored by pharmaceutical development of new opioids such as peripheral κ-receptor agonists, and by treatments augmenting the action of endogenous opioids, which have entered clinical trials. Additionally, there are several promising novel opioids comprehensively examined in preclinical studies, but also strategies such as biased agonism, which might require careful rethinking.
| S-EPMC6282113 | biostudies-literature