Morphine dosing strategy plays a key role in the generation and duration of the produced antinociceptive tolerance
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]
PDF (Final version (pdf) with restricted access) Pending copyright assessment - Request a copy 1Mb
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.