Antagonism of peripheral opioid receptors by methylnaltrexone does not prevent morphine tolerance in rats.

Autor: Blomqvist KJ; Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Dudek KA; Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Viisanen H; Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Mätlik K; Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Ahlström FHG; Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Laitila J; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki University Hospital, Finland., Kalso EA; Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Department of Anaesthesiology, Intensive Care Medicine, and Pain Medicine, University of Helsinki, Helsinki University Hospital, Helsinki, Finland., Rauhala PV; Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Lilius TO; Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.; Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki University Hospital, Finland.; Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Jazyk: angličtina
Zdroj: Journal of neuroscience research [J Neurosci Res] 2022 Jan; Vol. 100 (1), pp. 329-338. Date of Electronic Publication: 2020 May 27.
DOI: 10.1002/jnr.24638
Abstrakt: Opioids are effective analgesics in the management of severe pain. However, tolerance, leading to dose escalation and adverse effects are significant limiting factors in their use. The role of peripheral opioid receptors in analgesia has been discussed especially under inflammatory conditions. The results from pharmacological and conditional knockout studies together do not provide a clear picture of the contribution of peripheral opioid receptors on antinociceptive tolerance and this needs to be evaluated. Therefore, we studied whether the peripherally restricted opioid receptor antagonist, methylnaltrexone (MNTX), could prevent morphine tolerance without attenuating the antinociceptive effect of morphine. Male Sprague-Dawley rats were treated for 7 days with increasing subcutaneous doses of morphine (5-30 mg/kg) and were coadministered saline, MNTX (0.5 or 2 mg/kg), or naltrexone (NTX; 2 mg/kg). Nociception was assessed with tail-flick, hotplate, and von Frey tests. Morphine, MNTX, and NTX concentrations in the plasma, brain, and spinal cord were measured by liquid chromatography-tandem mass spectrometry. In acute coadministration, NTX, but not MNTX, abolished the acute antinociceptive effects of morphine in all nociceptive tests. The antinociceptive tolerance after repeated morphine administration was also prevented by NTX but not by MNTX. MNTX penetrated to the spinal cord and the brain to some extent after repeated administration. The results do not support the use of MNTX for preventing opioid tolerance and also suggest that morphine tolerance is mediated by central rather than peripheral opioid receptors in the rat.
(© 2020 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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