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

摘要: Antinociceptive tolerance after repetitive administration of morphine severely limits its clinical use. Despite increased mechanistic understanding tolerance, little is known about the influence dosing regimens in development. We hypothesized that starting dose morphine, frequency and increments, antinociception manifestation antinociceptive rats. Male rats were randomly divided into four groups with different intermittent starting-doses daily (b.i.d.) followed by increments single-dose upon development for 2–3 weeks: 2.5 (b.i.d.)→5 → 10→15 mg/kg/day, 5 (b.i.d.)→10 (b.i.d.)→15 10 (b.i.d.)→20 mg/kg/day. Antinociception was assessed pre-treatment at several time-points over 2 h post-administration, using tail-flick hot-plate assays. Tolerance defined as significant desensitization presented reduction maximum total efficacy administration. Rats commenced on mg/kg/day developed faster than those started or (b.i.d.). Comparatively, higher maintenance doses produced prolonged delayed tolerance. Whereas, lower less during course treatment did not delay onset but require smaller dose-increments to reach These results suggest dose, frequency, timing determine extent antinociception. In addition, our also highlight need generally standardized validated assay protocols procedures compare studies, a prerequisite translate pre-clinical clinic.