Mu Receptors Research Articles

Delta opioid receptor antagonism/inverse agonism and its effect on mu opioid receptor signaling in SH‐SY5Y cells

Opioid analgesics are prescribed with success to combat chronic and severe pain, yet there are many clinical and public health problems associated with the use of these medications that include constipation, respiratory depression and physical dependence. Academic scientists to pharmaceutical companies are developing opioid drugs, G‐protein biased agonists and allosteric modulators to name a few, in an effort to identify safer and more effective analgesics. Previous studies have reported that the co‐administration of naltrindole (a delta opioid receptor antagonist) with morphine (mu opioid receptor agonist) in vivo maintains analgesia yet reduces the development of morphine tolerance and dependence. Following this observation, in collaboration with the Mosberg lab we have discovered and characterized several mu agonist/delta antagonist “bifunctional compounds” that lack tolerance and dependence liabilities in vivo. The goal of my studies is to use these bifunctional compounds, as well as selective mu and delta opioid receptor ligands, in an attempt to explain this phenomenon on a molecular level. The SH‐SY5Y human neuroblastoma cell line is an ideal system in which to assess mu and delta receptor cross‐talk because it endogenously expresses both receptor types. My first objective was to demonstrate mu opioid receptor tolerance at the level of the G protein (a decrease in GTPγ35S binding) using the selective agonist DAMGO. Compared to untreated cells, DAMGO (1μM, 6 hours) treated cells showed a 50% reduction in DAMGO‐mediated GTPγ35S binding and a slight decrease in basal GTPγ35S binding. I then found that the addition of the delta inverse agonist ICI 174,864 (1μM, 6 hours) prevented DAMGO‐mediated tolerance. To further study this response I used another delta antagonist TIPPΨ and three bifunctional compounds. Overall the results suggest that delta opioid receptor inhibition is advantageous for sustained mu opioid receptor function in a cellular model of opioid tolerance. Experiments are ongoing to decipher how delta blockade alters mu‐opioid receptor signaling.Support or Funding InformationDA‐03910 and NIGMS‐GM007767

Genetic dissociation of morphine analgesia from hyperalgesia in mice.

Morphine is the prototypic mu opioid, producing its analgesic actions through traditional 7 transmembrane domain (7TM) G-protein-coupled receptors generated by the mu opioid receptor gene (Oprm1). However, the Oprm1 gene undergoes extensive alternative splicing to yield three structurally distinct sets of splice variants. In addition to the full-length 7TM receptors, it produces a set of truncated variants comprised of only 6 transmembrane domains (6TM). This study explored the relative contributions of 7TM and 6TM variants in a range of morphine actions. Groups of male and mixed-gender wild-type and exon 11 Oprm1 knockout mice were examined in a series of behavioral assays measuring analgesia, hyperalgesia, respiration, and reward in conditioned place preference assays. Loss of the 6TM variants in an exon 11 knockout (E11 KO) mouse did not affect morphine analgesia, reward, or respiratory depression. However, E11 KO mice lacking 6TM variants failed to show morphine-induced hyperalgesia, developed tolerance more slowly than wild-type mice, and did not display hyperlocomotion. Together, our findings confirm the established role of 7TM mu receptor variants in morphine analgesia, reward, and respiratory depression, but reveal an unexpected obligatory role for 6TM variants in morphine-induced hyperalgesia and a modulatory role in morphine tolerance and dependence.

Perioperative Management of the Surgical Patient on Suboxone (Buprenorphine and Naloxone)

Over the past two decades, the incidence of legal and illegal drug abuse and dependency has increased at alarming levels, resulting in a rise in the number of associated deaths. Multiple resources are available to manage addiction, including the use of buprenorphine with or without naloxone. Consequently, more and more patients are requiring this treatment and are presenting for elective and emergent surgery where treatment of acute postoperative pain in the setting of buprenorphine use becomes challenging due to its unique properties. Buprenorphine has unique properties in which it binds to the opioid (mu) receptor with a higher affinity than other opioids. Buprenorphine is bound for a long period of time (32 hours), but its opioid effects have a ceiling. Since the receptors are occupied, when illegal or prescribed opioids are abused, they cannot activate the occupied receptors, and, in parallel, the effects that lead to addiction, tolerance, and craving are limited. However, in the surgical setting, increased opioid use may be appropriately needed to manage pain, which is hindered and limited by buprenorphine. Using current studies and strategies, we propose an algorithm to effectively manage buprenorphine in the perioperative setting.

Neuromimunnological mechanisms of pain syndrome development

The purpose of this review is to generalize and analyze the results of studies of the mechanism of pain syndrome development, to evaluate the role of molecular receptors common for nervous and immunocompetent cells in the combined regulation of pain control systems and immune responses. The opiate nociception system refers to the basic structures of pain signal suppression. It includes opioids, usually short peptides, which are ligands of interaction with mu, kappa and delta receptors. Endogenous opioids provide a biochemical link between the brain, neuroendocrine and immune systems. Anti-opiate system maintains homeostatic control of antinociceptive effects of opiates. The questions of possible mechanisms of regulation of pain sensitivity and immunocompetence of the organism are considered.

Granulocyte colony stimulating factor (GCSF) treatment in neuropathic pain

<p>Granulocyte colony stimulating factor (GCSF) is an endogenous growth factor that can stimulate granulocyte formation and is used widely in hematogenous disease without significant clinical side effects. Several clinical and animal studies had showed that both a single high-dose and repeated low-dose systemic GCSF treatment can attenuate neuropathic pain after central or peripheral nerve injury. GCSF treatment can recruit more opioid containing neutrophils to injured tissue, up-regulate opioid receptors (mu opioid receptor) on the injured nerve, which decreased nociceptive signals from injured nerve to the spinal dorsal horn. Thereafter, activated microglia, increased phosphorylated-p38 (p-p38) and pro-inflammatory cytokines on the spinal dorsal horn are suppressed, which further attenuated neuropathic pain. The systemic GCSF administration may avoid the addiction side effect induced by repeated exogenous opioid exposure and provide a new therapeutic strategy to treat neuropathic pain.</p>

OPRM1 and COMT Gene-Gene Interaction Is Associated With Postoperative Pain and Opioid Consumption After Orthopedic Trauma.

mu-opioid receptor ( OPRM1) and catechol-O-methyltransferase ( COMT) contribute to the neurotransmission pathway of pain. COMT affects mu receptor expression and density in the brain. The aim of this study was to explore the OPRM1 and COMT interaction effects on postoperative pain and opioid consumption. This cross-sectional exploratory study used genotype and clinical data from 153 postoperative patients. Using multiple regression analyses, four single-nucleotide polymorphisms of COMT (rs6269, rs4633, rs4818, and rs4680), their haplotypes, and diplotypes were considered for their interactions with A118G of OPRM1 regarding postoperative pain and opioid consumption. For opioid consumption, significant interactions were found between OPRM1 A118G and COMT rs4680 ( p = .037) and between OPRM1 and COMT rs4633 ( p = .037). Patients having Met158Met of COMT rs4680 and AG/GG of OPRM1 or TT of COMT rs4633 and AG/GG of OPRM1 consumed the largest amount of opioid compared to those having other combinations. For postoperative pain, a significant interaction was found between OPRM1 and the low pain sensitivity (LPS; GCGG) haplotype of COMT ( p = .017). For patients with no copies of the LPS haplotype, AA of OPRM1 A118G was significantly associated with higher pain scores compared to the variant AG/GG. However, the opposite direction was observed for patients with at least one copy of the LPS haplotype. The interaction of OPRM1 with COMT may contribute to variability in postoperative pain and opioid consumption. Additional larger studies are needed to confirm findings.

Opioid-Induced Constipation: A Comprehensive Overview

In the United States, 4.3 million adults are regularly taking opioid medications. Opioid-induced constipation (OIC) is underdiagnosed considering the prevalence of opioid use among Americans. This review is intended to clarify issues related to OIC. OIC is caused by opioids binding to specific receptors in the gastrointestinal system, resulting in various anatomic effects, including decreased gastric motility, increased sphincter tone, reduced intestinal secretions, and increased water absorption in the bowel. Various treatments include water and fiber consumption, laxatives, enemas, cessation of opioids, and central and peripheral opioid antagonists. OIC is treatable, but timely diagnosis and patient education are paramount for successful resolution. Key words: chronic pain; constipation; mu, delta, and kappa receptors; myenteric plexus; opioid; opioid-induced constipation; opioid receptor antagonists; submucosal plexus

Mu and delta opioid receptor knockout mice show increased colonic sensitivity.

Opiates act through opioid receptors to diminish pain. Here, we investigated whether mu (MOR) and delta (DOR) receptor endogenous activity assessed in the whole mouse body or in particular at peripheral receptors on primary nociceptive neurons, control colonic pain. We compared global MOR and DOR receptor knockout (KO) mice, mice with a conditional deletion of MOR and DOR in Nav1.8-positive nociceptive primary afferent neurons (cKO), and control floxed mice of both genders for visceral sensitivity. Visceromotor responses to colorectal distension (CRD) and macroscopic colon scores were recorded on naïve mice and mice with acute colitis induced by 3% dextran sodium sulphate (DSS) for 5days. Transcript expression for opioid genes and cytokines was measured by quantitative RT-PCR. Naïve MOR and DOR global KO mice show increased visceral sensitivity that was not observed in cKO mice. MOR and preproenkephalin (Penk) were the most expressed opioid genes in colon. MOR KO mice had augmented kappa opioid receptor and Tumour-Necrosis-Factor-α and diminished Penk transcript levels while DOR, preprodynorphin and Interleukin-1β were unchanged. Global MOR KO females had a thicker colon than floxed females. No alteration was detected in DOR mutant animals. A 5-day DSS treatment led to comparable hypersensitivity in the different mouse lines. Our results suggest that mu and delta opioid receptor global endogenous activity but not activity at the peripheral Nav1.8 neurons contribute to visceral sensitivity in naïve mice, and that endogenous MOR and DOR tones were insufficient to elicit analgesia after 5-day DSS-induced colitis. Knockout mice for mu and delta opioid receptor have augmented colon sensitivity in the CRD assay. It shows endogenous mu and delta opioid analgesia that may be explored as potential targets for alleviating chronic intestinal pain.

Perioperative Management of the Surgical Patient on Suboxone (Buprenorphine and Naloxone)

Over the past two decades, the incidence of legal and illegal drug abuse and dependency has increased at alarming levels, resulting in a rise in the number of associated deaths. Multiple resources are available to manage addiction, including the use of buprenorphine with or without naloxone. Consequently, more and more patients are requiring this treatment and are presenting for elective and emergent surgery where treatment of acute postoperative pain in the setting of buprenorphine use becomes challenging due to its unique properties. Buprenorphine has unique properties in which it binds to the opioid (mu) receptor with a higher affinity than other opioids. Buprenorphine is bound for a long period of time (32 hours), but its opioid effects have a ceiling. Since the receptors are occupied, when illegal or prescribed opioids are abused, they cannot activate the occupied receptors, and, in parallel, the effects that lead to addiction, tolerance, and craving are limited. However, in the surgical setting, increased opioid use may be appropriately needed to manage pain, which is hindered and limited by buprenorphine. Using current studies and strategies, we propose an algorithm to effectively manage buprenorphine in the perioperative setting.

Pharmacological characterization of cebranopadol a novel analgesic acting as mixed nociceptin/orphanin FQ and opioid receptor agonist.

The aim of the study was to investigate the in vitro and in vivo pharmacological profile of cebranopadol, a novel agonist for opioid and nociceptin/orphanin FQ (N/OFQ) receptors (NOP). In vitro cebranopadol was assayed in calcium mobilization studies in cells coexpressing NOP or opioid receptors and chimeric G‐proteins and in a bioluminescence resonance energy transfer (BRET) assay for studying receptor interaction with G‐protein and β‐arrestin 2. The mouse tail withdrawal and formalin tests were used for investigating cebranopadol antinociceptive properties. In calcium mobilization studies cebranopadol showed the following rank order of potency NOP = mu > kappa ≥ delta. In BRET studies, cebranopadol promoted NOP and mu receptors interaction with G‐protein with similar high potency and efficacy. However, cebranopadol did not stimulated NOP–β‐arrestin 2 interactions and displayed reduced potency at mu/β‐arrestin 2. In vivo, cebranopadol exhibits highly potent and extremely long‐lasting antinociceptive effects. The effects of cebranopadol in the tail withdrawal assay were sensitive to both SB‐612111 and naloxone. Collectively the present results confirm and extend previous finding demonstrating that cebranopadol, by acting as mixed NOP/opioid receptor agonist, elicits robust analgesic effects in different pain models.

Mediation of buprenorphine analgesia by a combination of traditional and truncated mu opioid receptor splice variants.

Buprenorphine has long been classified as a mu analgesic, although its high affinity for other opioid receptor classes and the orphanin FQ/nociceptin ORL1 receptor may contribute to its other actions. The current studies confirmed a mu mechanism for buprenorphine analgesia, implicating several subsets of mu receptor splice variants. Buprenorphine analgesia depended on the expression of both exon 1-associated traditional full length 7 transmembrane (7TM) and exon 11-associated truncated 6 transmembrane (6TM) MOR-1 variants. In genetic models, disruption of delta, kappa1 or ORL1 receptors had no impact on buprenorphine analgesia, while loss of the traditional 7TM MOR-1 variants in an exon 1 knockout (KO) mouse markedly lowered buprenorphine analgesia. Loss of the truncated 6TM variants in an exon 11 KO mouse totally eliminated buprenorphine analgesia. In distinction to analgesia, the inhibition of gastrointestinal transit and stimulation of locomotor activity were independent of truncated 6TM variants. Restoring expression of a 6TM variant with a lentivirus rescued buprenorphine analgesia in an exon 11 KO mouse that still expressed the 7TM variants. Despite a potent and robust stimulation of (35) S-GTPγS binding in MOR-1 expressing CHO cells, buprenorphine failed to recruit β-arrestin-2 binding at doses as high as 10 µM. Buprenorphine was an antagonist in DOR-1 expressing cells and an inverse agonist in KOR-1 cells. Buprenorphine analgesia is complex and requires multiple mu receptor splice variant classes but other actions may involve alternative receptors.

Role of buprenorphine in acute postoperative pain

Nowadays acute postoperative pain persists as a high prevalence symptom. The incidence, intensity and duration of postoperative pain vary considerably from one patient to another, from one surgery to another, from one hospital to another, and even from one country to another. It is important to learn about recent developments in central sensitisation, as it plays an important role in postoperative pain. Postoperative pain is mainly nociceptive somatic, in response to surgical damage. The surgical trauma and pain cause an endocrine response that increases the secretion of cortisol, catecholamines, and other stress hormones. Tachycardia, hypertension, decreased regional blood flow, impaired immune response, hyperglycaemia, lipolysis, and negative nitrogen balance also occur. All this plays an important role in morbidity and mortality in the postoperative period. Buprenorphine is a semi-synthetic opioid derived from thebaine. It has a binding affinity for the mu, kappa and delta receptors, and has a slow dissociation from these receptors. Because of its action on the mu and kappa receptors it can be used as an analgesic, as well as for maintenance therapy in patients with a history of drug abuse. This article will describe the characteristics of acute postoperative pain, the pharmacology of buprenorphine, and its interference in the management of postoperative pain.

Interactions between cannabinoid receptor agonists and mu opioid receptor agonists in rhesus monkeys discriminating fentanyl

Cannabinoid receptor agonists such as delta-9-tetrahydrocannabinol (Δ9-THC) enhance some (antinociceptive) but not other (positive reinforcing) effects of mu opioid receptor agonists, suggesting that cannabinoids might be combined with opioids to treat pain without increasing, and possibly decreasing, abuse. The degree to which cannabinoids enhance antinociceptive effects of opioids varies across drugs insofar as Δ9-THC and the synthetic cannabinoid receptor agonist CP55940 increase the potency of some mu opioid receptor agonists (e.g., fentanyl) more than others (e.g., nalbuphine). It is not known whether interactions between cannabinoids and opioids vary similarly for other (abuse-related) effects. This study examined whether Δ9-THC and CP55940 differentially impact the discriminative stimulus effects of fentanyl and nalbuphine in monkeys (n=4) discriminating 0.01mg/kg of fentanyl (s.c.) from saline. Fentanyl (0.00178–0.0178mg/kg) and nalbuphine (0.01–0.32mg/kg) dose-dependently increased drug-lever responding. Neither Δ9-THC (0.032–1.0mg/kg) nor CP55940 (0.0032–0.032mg/kg) enhanced the discriminative stimulus effects of fentanyl or nalbuphine; however, doses of Δ9-THC and CP55940 that shifted the nalbuphine dose-effect curve markedly to the right and/or down were less effective or ineffective in shifting the fentanyl dose-effect curve. The mu opioid receptor antagonist naltrexone (0.032mg/kg) attenuated the discriminative stimulus effects of fentanyl and nalbuphine similarly. These data indicate that the discriminative stimulus effects of nalbuphine are more sensitive to attenuation by cannabinoids than those of fentanyl. That the discriminative stimulus effects of some opioids are more susceptible to modification by drugs from other classes has implications for developing maximally effective therapeutic drug mixtures with reduced abuse liability.

Redoubling the ring size of an endomorphin-2 analog transforms a centrally acting mu-opioid receptor agonist into a pure peripheral analgesic.

The study reports the synthesis and biological evaluation of two opioid analogs, a monomer and a dimer, obtained as products of the solid-phase, side-chain to side-chain cyclization of the pentapeptide Tyr-d-Lys-Phe-Phe-AspNH2 . The binding affinities to the mu, delta, and kappa opioid receptors, as well as results obtained in a calcium mobilization functional assay are reported. Tyr-[d-Lys-Phe-Phe-Asp]2 -NH2 1 was a potent and selective full agonist of mu with sub-nanomolar affinity, while the dimer (Tyr-[d-Lys-Phe-Phe-Asp]2 -NH2 )2 2 showed a significant mixed mu/kappa affinity, acting as an agonist at the mu. Molecular docking computations were utilized to explain the ability of the dimeric cyclopeptide 2 to interact with the receptor. Interestingly, in spite of the increased ring size, the higher flexibility allowed 2 to fold and fit into the mu receptor binding pocket. Both cyclopeptides were shown to elicit strong antinociceptive activity after intraventricular injection but only cyclomonomer 1 was able to cross the blood-brain barrier. However, the cyclodimer 2 displayed a potent peripheral antinociceptive activity in a mouse model of visceral inflammatory pain. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 309-317, 2016.

Multimodal Analgesia in the Hip Fracture Patient.

Hip fracture is one of the most common injuries among the elderly and, because the population is aging, it is expected to remain a major clinical challenge and public health problem for the foreseeable future. The clinical importance of early mobilization and prompt participation in physical therapy after hip fracture surgery is now widely recognized. Because postoperative pain can impair mobility and delay physical therapy, much attention is now being paid to finding more effective ways of controlling pain after hip fracture. Oversedation with opioid drugs inhibits communication between the patient and the health care team, can delay ambulation and rehabilitation therapy, and may increase the probability of the patient requiring a skilled nursing facility, which adds further cost to the overall health care system. Multiple pain pathways contribute to the perception of postoperative pain, and although opioids are highly effective in blocking nociceptive pain through inhibition of the mu receptors, they do not block other pain pathways. Multimodal analgesia involves the use of several anesthetic and analgesic modalities that are strategically combined to block pain perception at different sites in the peripheral and central nervous systems. This balanced, multifaceted approach provides more effective control of postoperative pain than opioid drugs alone, allows lower doses of opioids to be used as part of the multimodal regimen (thereby reducing the risk of opioid-related adverse events and complications), and may facilitate more rapid recovery and improve certain outcome measures related to recovery time. One prospective randomized study evaluating the clinical value of multimodal pain management in elderly patients undergoing bipolar hip hemiarthroplasty found that a multimodal regimen, including preemptive pain medication and intraoperative periarticular injections, reduced pain on postoperative days 1 and 4, and reduced overall opioid use. This article describes an effective multimodal pain management regimen for hip fracture patients.

Ekspresi HSP 70 dan Ekspresi Reseptor Opioid Mu pada Penurunan Nyeri Terapi Bekam Basah

Introduction: Wet cupping therapy widely used to reduce the pain, but the mechanisms of pain reduction on wet cuppig therapy is unclear. Stretching and punctures on wet cupping therapy cause stress on the cell. Cells that are stressed express HSP 70 and mu opioid receptors. This study aims to prove the correlation increased expression of HSP 70 and an increase in post-mu opioid receptor wet cupping therapy.Methods: The study is an experimental research design with randomized control group post-test only design. Twenty-four rats type Wistar (Rattus norvegicus) were randomly divided into three groups, each consisting of eight mice are negative control group (normal mice), group induction of pain with Complete Freund's Adjuvant (CFA) alone (positive control) and group by induction of pain and bekam basah therapy (10 puncture and negative pressure: - 200 mmHg, 5 minutes). Samples were taken from the skin and immunohistochemical examination with the monoclonal antibody anti mu opioid receptors. The reaction time pain threshold measured using a hot-plate. Data were analyzed by oneway ANOVA and Pearson Correlation using SPSS version 17.Results: This study shows that there is an increased expression of HSP 70 (P <0.05) compared to the positive control group (p <0.05) and increased expression of mu opioid receptors ( p <0.05) compared to the positive control group (p <0.05). There is an increased pain threshold reaction time (p <0.05) compared to the positive controls (11.78 ± 3.56). There is a correlation between an increased expression of HSP 70 and an increase in mu opioid receptor (β = 0893; p = 0.000) and there was a correlation between the increase in mu opioid receptor with a reaction time of pain threshold (β = 0713; p = 0.002).Discussion: Wet cupping therapy increase HSP 70 expression, opioid mu receptor, and decrease pain level.

HUBUNGAN EKSPRESI HSP 70 DAN EKSPRESI RESEPTOR OPIOID MU PADA PENURUNAN NYERI TERAPI BEKAM BASAH

Latar belakang. Terapi bekam basah banyak digunakan untuk mengurangi nyeri, namun mekanisme penurunan nyeri terapi bekam basah belum jelas. Peregangan dan tusukan pada terapi bekam basah menimbulkan stres pada sel. Sel yang mengalami stres mengekspresikan HSP 70 dan reseptor opioid mu.Tujuan penelitian. Penelitian ini bertujuan membuktikan korelasi peningkatan ekspresi HSP 70 dan peningkatan reseptor opioid mu pasca terapi bekam basah.Bahan dan Metode. Jenis penelitian ini adalah penelitian eksperimental dengan rancangan randomized control group post test only design. Dua puluh empat tikus jenis Wistar (Rattus norvegicus) secara random dibagi menjadi tiga kelompok yang masing-masing terdiri dari 8 ekor tikus yaitu kelompok kontrol negatif (tikus normal), kelompok induksi nyeri dengan Complete Freund’s Adjuvant (CFA) saja (kontrol positif) dan kelompok yang diberi induksi nyeri dan terapi bekam basah (10 tusukan dan tekanan negatif: - 200 mmHg, 5 menit). Sampel diambil dari kulit dan dilakukan pemeriksaan imunohistokimia dengan antibodi monoklonal anti reseptor opioid mu. Waktu reaksi ambang nyeri diukur memakai hot-plate. Data dianalisa dengan Anova oneway dan Pearson Correlation dengan menggunakan SPSS versi 17.Hasil. Penelitian ini menunjukkan bahwa terdapat peningkatan ekspresi HSP 70 (20,25 ± 3,53; p< 0.05) dibandingkan kelompok kontrol positif (10,50 ± 2,44; p< 0,05) dan peningkatan ekspresi reseptor opioid mu (21,00 ± 6,34; p< 0.05) dibandingkan kelompok kontrol positif ( 4,25 ± 3,58; p< 0.05). Terdapat peningkatan waktu reaksi ambang nyeri (22,81 ± 6,34; p< 0,05) dibandingkan kontrol positif (11,78 ± 3,56). Terdapat korelasi antara peningkatan ekspresi HSP 70 dan peningkatan reseptor opioid mu (β= 0.893; p= 0.000) dan ada korelasi antara peningkatan reseptor opioid mu dengan waktu reaksi ambang nyeri (β= 0.713; p= 0.002).Kesimpulan. Terjadi peningkatan ekspresi HSP 70 dan reseptor opioid mu pada terapi bekam basah dan terdapat korelasi antara peningkatan ekspresi HSP 70 terhadap ekspresi reseptor opioid mu.Kata kunci : HSP 70, reseptor opioid mu dan bekam basah

Nalmefene and alcohol use disorder. Evaluation of clinical cases at a treatment centre for drug addicts

IntroductionAlcohol abuse causes dopamine release in the mesolimbic system, which activates the reward circuit. This is linked to an interdependent opioid, serotonergic and endocannabinoid system. Nalmefene is a modulator of the endogenous opioid system, with antagonistic effect on mu and delta receptors, and a partial agonist activity kappa. This means that reduces the reinforcing effects of alcohol consumption through the cortical-mesolimbic system. Therefore, when a patient takes nalmefene, the satisfaction obtained when he drinks is lower, which increases the possibility to have more control over drinking.The efficacy of nalmefene was evaluated in two profiles of patients: 1. No abstinence in alcohol dependence disorder and continuous relapses, 2. Cocaine dependence disorder associated to alcohol abuse.ObjectivesImproving the quality of life and compliance rates due to the difficulties of following a strict treatment to achieve the abstinence. Furthermore, in cases of patients with cocaine dependence disorder and alcohol abuse, the objective is to avoid cocaine use by reducing previous alcohol consumption.Conclusionnalmefene offers the possibility of treating the addiction from a new perspective. Our current clinical experience has been able to treat subjects with conventional treatments failures and those who need to achieve the necessary control to reduce cocaine use.Disclosure of interestThe authors have not supplied their declaration of competing interest.

The AC/AG Diplotype for the 118A>G and IVS2+691G>C Polymorphisms of OPRM1 Gene is Associated with Sleep Quality Among Opioid-Dependent Patients on Methadone Maintenance Therapy.

IntroductionMethadone is a full agonist of the opioid receptor mu 1 which is encoded by the OPRM1 gene. Sleep disorders were frequently reported by opioid-dependent patients during methadone maintenance therapy (MMT). It is possible, therefore, that genetic polymorphisms in OPRM1 influence sleep quality among patients on MMT. This study investigated the association of OPRM1 polymorphisms with sleep quality among opioid-dependent patients on MMT.MethodsThe sleep quality of 165 male opioid-dependent patients receiving MMT was evaluated using the Pittsburgh Sleep Quality Index (PSQI). DNA was extracted from whole blood and subjected to polymerase chain reaction (PCR) genotyping.ResultsPatients with IVS2 + 691 CC genotype had higher PSQI scores [mean (SD) = 5.73 (2.89)] compared to those without the IVS2 + 691 CC genotype (IVS2 + 691 GG/GC genotype) [4.92 (2.31)], but the difference did not reach statistical significance (p = 0.081). Patients with combined 118 AA genotype and IVS2 + 691 GC genotype (AC/AG diplotype) had significantly lower PSQI scores [mean (SD) = 4.25 (2.27)] compared to those without the diplotype [5.68 (2.77)] (p = 0.018).ConclusionOur study indicates that the AC/AG diplotype for the 118A>G and IVS2 + 691G>C polymorphisms of OPRM1 gene is associated with better sleep quality among males with opioid dependence on MMT.

Differential expression of MU [μ] Opioid receptors and N-type calcium channels in the amygdala of morphine tolerant rat: An autoradiographic & immunohistochemistry study

Introduction: Recent studies have shown that amygdala plays a pivotal role in the emotional processing of pain. Opioids like morphine relieve pain by suppressing both the sensory and emotional components of pain. On chronic morphine administration, tolerance develops decreasing its analgesic effect. The underlying changes in the amygdala during morphine tolerance are not definitely known. Mu opioid receptors are binding sites for morphine while N-type voltage-gated calcium channels (VGCCs) directly control the release of neurotransmitters from presynaptic nerve endings. Aims & Objectives: The present study was designed to investigate the status of mu receptors and N-type VGCCs in the amygdala of morphine tolerant rat by autoradiography and immunohistochemistry respectively. Material & Methods: Wistar rats were made morphine tolerant by repeated administration of morphine for 5 days. Later, the rats were euthanized and cryostat sections of the brain were cut at the region of the amygdala. For autoradiographic localization, the sections were incubated with [3H] labeled DAMGO. For immunohistochemistry, the sections were exposed to primary antibody against N-type VGCCs. Results: Using image analysis software, a significant down-regulation of mu receptors and an up-regulation of N-VGCCs were observed after tolerance. This differential change in expression would indicate a less effective antinociceptive action of morphine through / though higher neurotransmitter release after tolerance. Conclusion: In conclusion, the study suggests that morphine tolerance could be associated with altered functional state of the amygdala. Keywords: Amygdala, Mu-opioid receptor, Voltage-gated calcium channel, Autoradiography, Immunohistochemistry