ArticleProceedings of the National Academy of Sciences of the United States of America2015
Stabilization of morphine tolerance with long-term dosing: association with selective upregulation of mu-opioid receptor splice variant mRNAs.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed.
- Molecular and cellular basis of mu-opioid receptor signaling: mechanisms underlying tolerance and dependence development.Frontiers in neuroscience · 2025Review
- Binding preference at the μ-opioid receptor underlies distinct pharmacology of cyclopropyl versus valeryl analogs of fentanyl.Neuropharmacology · 2023Article
- Changes in Plasma Metabolic Signature upon Acute and Chronic Morphine Administration in Morphine-Tolerant Mice.Metabolites · 2023Article
- Epigenetic Modulation of Opioid Receptors by Drugs of Abuse.International journal of molecular sciences · 2022Review
- δ-Opioid receptors in primary sensory neurons tonically restrain nociceptive input in chronic pain but do not enhance morphine analgesic tolerance.Neuropharmacology · 2022Article
- Exploring Pharmacological Functions of Alternatively Spliced Variants of the Mu Opioid Receptor Gene,International journal of molecular sciences · 2022Review
- Dysregulated expression of the alternatively spliced variant mRNAs of the mu opioid receptor gene, OPRM1, in the medial prefrontal cortex of male human heroin abusers and heroin self-administering male rats.Journal of neuroscience research · 2022Article
- Alternative Pre-mRNA Splicing of the Mu Opioid Receptor Gene,Biomolecules · 2021Review
- Mu Opioids Induce Biased Signaling at the Full-Length Seven Transmembrane C-Terminal Splice Variants of the mu Opioid Receptor Gene, Oprm1.Cellular and molecular neurobiology · 2021Article
- Synthesis of the Mechanisms of Opioid Tolerance: Do We Still Say NO?Cellular and molecular neurobiology · 2021Review
- Interactive Mechanisms of Supraspinal Sites of Opioid Analgesic Action: A Festschrift to Dr. Gavril W. Pasternak.Cellular and molecular neurobiology · 2021Review
- Relevance of Mu-Opioid Receptor Splice Variants and Plasticity of Their Signaling Sequelae to Opioid Analgesic Tolerance.Cellular and molecular neurobiology · 2021Review
- Endogenous Opioid Peptides and Alternatively Spliced Mu Opioid Receptor Seven Transmembrane Carboxyl-Terminal Variants.International journal of molecular sciences · 2021Review
- Increased functional coupling of the mu opioid receptor in the anterior insula of depressed individuals.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2021Article
- Abuse Liability, Anti-Nociceptive, and Discriminative Stimulus Properties of IBNtxA.ACS pharmacology & translational science · 2020Article
- Morphine modulates the expression of mu-opioid receptor exon 5-associated full-length C-terminal splice variants by upregulating miR-378a-3p.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2020Article
- Identification of Abundant and Evolutionarily Conserved Opioid Receptor Circular RNAs in the Nervous System Modulated by Morphine.Molecular pharmacology · 2019Article
- Comprehensive molecular pharmacology screening reveals potential new receptor interactions for clinically relevant opioids.PloS one · 2019Article
- Regulation of an Opioid Receptor Chaperone Protein, RTP4, by Morphine.Molecular pharmacology · 2019Article
- Inhibition of Histone Deacetylases Attenuates Morphine Tolerance and Restores MOR Expression in the DRG of BCP Rats.Frontiers in pharmacology · 2018Article
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Authors and funding
7 authors.
Funding
Abstract
Chronic morphine administration is associated with the development of tolerance, both clinically and in animal models. Many assume that tolerance is a continually progressive response to chronic opioid dosing. However, clinicians have long appreciated the ability to manage cancer pain in patients for months on stable opioid doses, implying that extended dosing may eventually result in a steady state in which the degree of tolerance remains constant despite the continued administration of a fixed morphine dose. Preclinical animal studies have used short-term paradigms, typically a week or less, whereas the clinical experience is based upon months of treatment. Chronic administration of different fixed morphine doses produced a progressive increase in the ED50 that peaked at 3 wk in mice, consistent with prior results at shorter times. Continued morphine dosing beyond 3 wk revealed stabilization of the level of tolerance for up to 6 wk with no further increase in the ED50. The degree of tolerance at all time points was dependent upon the dose of morphine. The mRNA levels for the various mu opioid receptor splice variants were assessed to determine whether stabilization of morphine tolerance was associated with changes in their levels. After 6 wk of treatment, mRNA levels of the variants increased as much as 300-fold for selected variants in specific brain regions. These findings reconcile preclinical and clinical observations regarding the development of morphine tolerance.
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