Abstract
Here we have studied regulatory changes of µ-opioid receptors accompanying in vivo 14-methoxymetopon treatments of rats. Previously, this ligand has been shown to be an extremely potent, centrally acting µ-opioid specific analgesic with low physical dependence, tolerance, respiratory depression, constipation and other side effects. Our work shows that it is a highly potent full agonist of µ-opioid receptor coupled G-protein signaling in vitro, alike the well-known opioid agonist, etorphine. However, unlike etorphine, which desensitized and down-regulated the endogenous µ-opioid receptors, 14-methoxymetopon, given to rats intraperitoneally (i.p.) either acutely or chronically, did not change the binding or G-protein signaling of µ-opioid receptors in rat brain subcellular membranes. Thereby, these data provide further evidence that there is no direct relationship between the efficacy of the ligand in signaling and its ability to internalize or desensitize the receptor. Viewed collectively with published work, it is discussed that µ-opioid receptors display functional selectivity, also called ‘biased agonism’. This concept implies that each ligand may induce unique, ligand-specific receptor conformation that can result in distinct agonist- directed trafficking and/or signal transduction pathways associated with the receptor. Ligand-specific signaling may open up new directions for designing potent analgesics that do not interact with unwanted signaling pathways, which mediate undesired side-effects, such as tolerance and dependence.
Keywords: Opioid, alkaloid, µ-opioid receptor, receptor binding, G-protein signaling, tolerance, dependence, regulation.
Current Pharmaceutical Design
Title:Lack of Regulatory Changes of µ-Opioid Receptors by 14-Methoxymetopon Treatment in Rat Brain. Further Evidence for Functional Selectivity
Volume: 19 Issue: 42
Author(s): Resat Cinar, Orsolya Kekesi, Erika Birkas, Gabriella Fabian, Helmut Schmidhammer and Maria Szucs
Affiliation:
Keywords: Opioid, alkaloid, µ-opioid receptor, receptor binding, G-protein signaling, tolerance, dependence, regulation.
Abstract: Here we have studied regulatory changes of µ-opioid receptors accompanying in vivo 14-methoxymetopon treatments of rats. Previously, this ligand has been shown to be an extremely potent, centrally acting µ-opioid specific analgesic with low physical dependence, tolerance, respiratory depression, constipation and other side effects. Our work shows that it is a highly potent full agonist of µ-opioid receptor coupled G-protein signaling in vitro, alike the well-known opioid agonist, etorphine. However, unlike etorphine, which desensitized and down-regulated the endogenous µ-opioid receptors, 14-methoxymetopon, given to rats intraperitoneally (i.p.) either acutely or chronically, did not change the binding or G-protein signaling of µ-opioid receptors in rat brain subcellular membranes. Thereby, these data provide further evidence that there is no direct relationship between the efficacy of the ligand in signaling and its ability to internalize or desensitize the receptor. Viewed collectively with published work, it is discussed that µ-opioid receptors display functional selectivity, also called ‘biased agonism’. This concept implies that each ligand may induce unique, ligand-specific receptor conformation that can result in distinct agonist- directed trafficking and/or signal transduction pathways associated with the receptor. Ligand-specific signaling may open up new directions for designing potent analgesics that do not interact with unwanted signaling pathways, which mediate undesired side-effects, such as tolerance and dependence.
Export Options
About this article
Cite this article as:
Cinar Resat, Kekesi Orsolya, Birkas Erika, Fabian Gabriella, Schmidhammer Helmut and Szucs Maria, Lack of Regulatory Changes of µ-Opioid Receptors by 14-Methoxymetopon Treatment in Rat Brain. Further Evidence for Functional Selectivity, Current Pharmaceutical Design 2013; 19 (42) . https://dx.doi.org/10.2174/138161281942140105161245
DOI https://dx.doi.org/10.2174/138161281942140105161245 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Retromer's Role in Endosomal Trafficking and Impaired Function in Neurodegenerative Diseases
Current Protein & Peptide Science Patients with Increased Non-Ceruloplasmin Copper Appear a Distinct Sub-Group of Alzheimer's Disease: A Neuroimaging Study
Current Alzheimer Research Addiction Liability of Pharmacotherapeutic Interventions in Obesity
Current Pharmaceutical Design 2-Amino/Azido/Hydrazino-5-alkoxy-5H-[1]benzopyrano[4,3-d]pyrimidines:Synthesis and Pharmacological Evaluation
Medicinal Chemistry Aqueous Humor Pharmacokinetics of Dorzolamide Loaded PLGAChitosan Nanoparticles by Ultra Performance Liquid Chromatography
Current Pharmaceutical Analysis Editorial [Hot Topic: Innate Immune Responses in CNS Neurodegenerative Diseases (Guest Editors: Hans van Noort and Sandra Amor)]
CNS & Neurological Disorders - Drug Targets A Review of Biomarkers in Mood and Psychotic Disorders: A Dissection of Clinical vs. Preclinical Correlates
Current Neuropharmacology Asymptomatic Alzheimers Disease: A Prodrome or a State of Resilience?
Current Alzheimer Research Metabotropic Glutamate Receptors: A Review on Prospectives and Therapeutic Aspects
Mini-Reviews in Medicinal Chemistry Integrated Biomarkers for Depression in Alzheimer’s Disease: A Critical Review
Current Alzheimer Research A Guide to Treatment of Sarcoidosis
Current Drug Therapy Identifying a Higher Throughput Assay for Metabolism Dependent Inhibition (MDI)
Drug Metabolism Letters Computational Approaches for Translational Oncology: Concepts and Patents
Recent Patents on Anti-Cancer Drug Discovery Applications of the Combination of Microwave and Parallel Synthesis in Medicinal Chemistry
Combinatorial Chemistry & High Throughput Screening Application of Agents Against Interferon-Gamma-Dependent Chemokines in Immunotherapy
Letters in Drug Design & Discovery Antiviral Herbs - Present and Future
Infectious Disorders - Drug Targets Medical Complications in Anorexia and Bulimia Nervosa
Endocrine, Metabolic & Immune Disorders - Drug Targets Methamphetamine and HIV Infection, Role in Neurocognitive Dysfunction
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Testosterone and Cardioprotection Against Myocardial Ischemia
Cardiovascular & Hematological Disorders-Drug Targets Susceptibility Genes for the Side Effect of Antipsychotics on Body Weight and Obesity
Current Drug Targets