Morphine-3-glucuronide causes antinociceptive cross-tolerance to morphine and increases spinal substance P expression.

Autor: Blomqvist KJ; Department of Pharmacology, Faculty of Medicine, Haartmaninkatu 8 (Biomedicum 1), 00014, University of Helsinki, Finland; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Tukholmankatu 8C, FI-00290, Helsinki, Finland., Viisanen H; Department of Pharmacology, Faculty of Medicine, Haartmaninkatu 8 (Biomedicum 1), 00014, University of Helsinki, Finland; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Tukholmankatu 8C, FI-00290, Helsinki, Finland., Ahlström FHG; Department of Pharmacology, Faculty of Medicine, Haartmaninkatu 8 (Biomedicum 1), 00014, University of Helsinki, Finland; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Tukholmankatu 8C, FI-00290, Helsinki, Finland., Jokinen V; Department of Pharmacology, Faculty of Medicine, Haartmaninkatu 8 (Biomedicum 1), 00014, University of Helsinki, Finland; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Tukholmankatu 8C, FI-00290, Helsinki, Finland., Sidorova YA; Laboratory of Molecular Neuroscience, Institute of Biotechnology, HiLIFE, Viikinkaari 5D, 00014, University of Helsinki, Finland., Suleymanova I; Laboratory of Molecular Neuroscience, Institute of Biotechnology, HiLIFE, Viikinkaari 5D, 00014, University of Helsinki, Finland., Rauhala PV; Department of Pharmacology, Faculty of Medicine, Haartmaninkatu 8 (Biomedicum 1), 00014, University of Helsinki, Finland; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Tukholmankatu 8C, FI-00290, Helsinki, Finland., Kalso EA; Department of Pharmacology, Faculty of Medicine, Haartmaninkatu 8 (Biomedicum 1), 00014, University of Helsinki, Finland; Division of Pain Medicine, Department of Anaesthesiology, Intensive Care Medicine and Pain Medicine, Helsinki University Hospital and University of Helsinki, Haartmaninkatu 2A, P.O. Box 140, 00029, Helsinki, Finland., Lilius TO; Department of Pharmacology, Faculty of Medicine, Haartmaninkatu 8 (Biomedicum 1), 00014, University of Helsinki, Finland; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Tukholmankatu 8C, FI-00290, Helsinki, Finland; Department of Clinical Pharmacology, Faculty of Medicine, Tukholmankatu 2C (Biomedicum 2C), 00014, University of Helsinki, Finland; Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Norre Allé 14, DK-2200, Copenhagen, Denmark. Electronic address: tuomas.lilius@helsinki.fi.
Jazyk: angličtina
Zdroj: European journal of pharmacology [Eur J Pharmacol] 2020 May 15; Vol. 875, pp. 173021. Date of Electronic Publication: 2020 Feb 26.
DOI: 10.1016/j.ejphar.2020.173021
Abstrakt: Morphine-3-glucuronide (M3G), the main metabolite of morphine, has been implicated in the development of tolerance and of opioid-induced hyperalgesia, both limiting the analgesic use of morphine. We evaluated the acute and chronic effects of M3G and morphine as well as development of antinociceptive cross-tolerance between morphine and M3G after intrathecal administration and assessed the expression of pain-associated neurotransmitter substance P in the spinal cord. Sprague-Dawley rats received intrathecal M3G or morphine twice daily for 6 days. Nociception and tactile allodynia were measured with von Frey filaments after acute and chronic treatments. Substance P levels in the dorsal horn of the spinal cord were determined by immunohistochemistry after 4-day treatments. Acute morphine caused antinociception as expected, whereas acute M3G caused tactile allodynia, as did both chronic M3G and morphine. Chronic M3G also induced antinociceptive cross-tolerance to morphine. M3G and morphine increased substance P levels similarly in the nociceptive laminae of the spinal cord. This study shows that chronic intrathecal M3G sensitises animals to mechanical stimulation and elevates substance P levels in the nociceptive laminae of the spinal cord. Chronic M3G also induces antinociceptive cross-tolerance to morphine. Thus, chronic M3G exposure might contribute to morphine-induced tolerance and opioid-induced hyperalgesia.
Competing Interests: Declaration of competing interest E.K. is a member of advisory boards (Orion Pharma, Espoo, Finland, and Pierre Fabre, Toulouse, France). Other authors have no conflicts of interest to be reported.
(Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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