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

Antinociceptive tolerance after repetitive administration of morphine severely limits its clinical use.Despite increased mechanistic understanding of morphine tolerance, little is known about the influenceof dosing regimens in its development. We hypothesized that the starting dose of morphine, dosingfrequency and dose increments, influence antinociception and the manifestation of antinociceptivetolerance in rats. Male rats were randomly divided into four groups with different intermittent startingdosesof daily morphine (b.i.d.) followed by different increments of single-dose morphine upon developmentof 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 dailypre-treatment and at several time-points over 2 h post-administration, using tail-flick and hot-plateassays. Tolerance was defined as significant antinociceptive desensitization and was presented as significantreduction 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 5or 10 mg/kg/day (b.i.d.). Comparatively, higher starting and maintenance doses of morphine producedprolonged antinociception and delayed tolerance. Whereas, lower starting and maintenance doses ofmorphine produced less total antinociception during the course of treatment and did not delay the onsetof tolerance, but require smaller dose-increments to reach antinociception after development of antinociceptivetolerance. These results suggest that morphine starting dose, dosing frequency, incrementsand timing determine the manifestation of antinociceptive tolerance and extent of antinociception. Inaddition, our results also highlight the need for generally standardized and validated assay protocols andprocedures to compare different studies, as a prerequisite to translate pre-clinical results into the clini