ArticlePharmacological research2016
Antinociceptive effects of the 6-O-sulfate ester of morphine in normal and diabetic rats: Comparative role of mu- and delta-opioid receptors.
Article in Pharmacological research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 21 citations in OpenAlex.
- Peripheralization Strategies Applied to Morphinans and Implications for Improved Treatment of Pain.Molecules (Basel, Switzerland) · 2023Review
- Heroin and its metabolites: relevance to heroin use disorder.Translational psychiatry · 2023Review
- Deuterated buprenorphine retains pharmacodynamic properties of buprenorphine and resists metabolism to the active metabolite norbuprenorphine in rats.Frontiers in pharmacology · 2023Article
- Jinmaitong Alleviates Diabetic Neuropathic Pain Through Modulation of NLRP3 Inflammasome and Gasdermin D in Dorsal Root Ganglia of Diabetic Rats.Frontiers in pharmacology · 2021Article
- Determining 5HTFrontiers in neuroscience · 2021Article
- The Intriguing Effects of Substituents in theMolecules (Basel, Switzerland) · 2020Article
- Ligand-specific recycling profiles determine distinct potential for chronic analgesic tolerance of delta-opioid receptor (DOPr) agonists.Journal of cellular and molecular medicine · 2020Article
- Aromatic-Amine Pendants Produce Highly Potent and Efficacious Mixed Efficacy μ-Opioid Receptor (MOR)/δ-Opioid Receptor (DOR) Peptidomimetics with Enhanced Metabolic Stability.Journal of medicinal chemistry · 2020Article
- Advances in the Physicochemical Profiling of Opioid Compounds of Therapeutic Interest.ChemistryOpen · 2019Review
- Efficacy-Based Perspective to Overcome Reduced Opioid Analgesia of Advanced Painful Diabetic Neuropathy in Rats.Frontiers in pharmacology · 2019Article
- Evaluation of morphine-like effects of the mixed mu/delta agonist morphine-6-Pharmacology research & perspectives · 2018Article
- Evaluation of Analgesia, Tolerance, and the Mechanism of Action of Morphine-6-O-Sulfate Across Multiple Pain Modalities in Sprague-Dawley Rats.Anesthesia and analgesia · 2017Article
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9 authors at 1 institution in 1 country.
Funding
Abstract
This study determined the antinociceptive effects of morphine and morphine-6-O-sulfate (M6S) in both normal and diabetic rats, and evaluated the comparative role of mu-opioid receptors (mu-ORs) and delta-opioid receptors (delta-ORs) in the antinociceptive action of these opioids. In vitro characterization of mu-OR and delta-OR-mediated signaling by M6S and morphine in stably transfected Chinese hamster ovary (CHO-K1) cells showed that M6S exhibited a 6-fold higher affinity for delta-ORs and modulated G-protein and adenylyl cyclase activity via delta-ORs more potently than morphine. Interestingly, while morphine acted as a full agonist at delta-ORs in both functional assays examined, M6S exhibited either partial or full agonist activity for modulation of G-protein or adenylyl cyclase activity, respectively. Molecular docking studies indicated that M6S but not morphine binds equally well at the ligand binding site of both mu- and delta-ORs. In vivo analgesic effects of M6S and morphine in both normal and streptozotocin-induced diabetic Sprague-Dawley rats utilizing the hot water tail flick latency test showed that M6S produced more potent antinociception than morphine in both normal rats and diabetic rats. This difference in potency was abrogated following antagonism of delta- but not mu- or kappa (kappa-ORs) opioid receptors. During 9days of chronic treatment, tolerance developed to morphine-treated but not to M6S-treated rats. Rats that developed tolerance to morphine still remained responsive to M6S. Collectively, this study demonstrates that M6S is a potent and efficacious mu/delta opioid analgesic with a delayed tolerance profile when compared to morphine in both normal and diabetic rats. PERSPECTIVE: This study demonstrates that M6S acts at both mu- and delta-ORs, and adds to the growing evidence that the use of mixed mu/delta opioid agonists in pain treatment may have clinical benefit.
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