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Morphine dosing strategy plays a key role in the generation and duration of the produced antinociceptive tolerance

Citation

Paul, AK and Gueven, N and Dietis, N, Morphine dosing strategy plays a key role in the generation and duration of the produced antinociceptive tolerance, Neuropharmacology, 121 pp. 158-166. ISSN 0028-3908 (2017) [Refereed Article]

Copyright Statement

Copyright 2017 Elsevier Ltd.

DOI: doi:10.1016/j.neuropharm.2017.04.034

Abstract

Antinociceptive tolerance after repetitive administration of morphine severely limits its clinical use. Despite increased mechanistic understanding of morphine tolerance, little is known about the influence of dosing regimens in its development. We hypothesized that the starting dose of morphine, dosing frequency and dose increments, influence antinociception and the manifestation of antinociceptive tolerance in rats. Male rats were randomly divided into four groups with different intermittent startingdoses of daily morphine (b.i.d.) followed by different increments of single-dose morphine upon development of antinociceptive tolerance, for 2e3 weeks: 2.5 (b.i.d.)/5 / 10/15 mg/kg/day, 5 (b.i.d.)/ 10 mg/kg/day, 5 (b.i.d.)/15 mg/kg/day, 10 (b.i.d.)/20 mg/kg/day. Antinociception was assessed daily pre-treatment and at several time-points over 2 h post-administration, using tail-flick and hot-plate assays. Tolerance was defined as significant antinociceptive desensitization and was presented as significant reduction of the maximum and total antinociceptive efficacy upon morphine administration. Rats commenced on 2.5 mg/kg/day (b.i.d.) morphine developed tolerance faster than those started on 5 or 10 mg/kg/day (b.i.d.). Comparatively, higher starting and maintenance doses of morphine produced prolonged antinociception and delayed tolerance. Whereas, lower starting and maintenance doses of morphine produced less total antinociception during the course of treatment and did not delay the onset of tolerance, but require smaller dose-increments to reach antinociception after development of antinociceptive tolerance. These results suggest that morphine starting dose, dosing frequency, increments and timing determine the manifestation of antinociceptive tolerance and extent of antinociception. In addition, our results also highlight the need for generally standardized and validated assay protocols and procedures to compare different studies, as a prerequisite to translate pre-clinical results into the clinic

Item Details

Item Type:Refereed Article
Keywords:opioids, morphine, tolerance
Research Division:Medical and Health Sciences
Research Group:Pharmacology and Pharmaceutical Sciences
Research Field:Pharmacology and Pharmaceutical Sciences not elsewhere classified
Objective Division:Expanding Knowledge
Objective Group:Expanding Knowledge
Objective Field:Expanding Knowledge in the Medical and Health Sciences
Author:Paul, AK (Mr Alok Paul)
Author:Gueven, N (Associate Professor Nuri Gueven)
Author:Dietis, N (Dr Nikolas Dietis)
ID Code:116563
Year Published:2017
Deposited By:Pharmacy
Deposited On:2017-05-12
Last Modified:2017-09-04
Downloads:0

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