STUDIES ON TOLERANCE DEVELOPMENT TO SINGLE DOSES OF MORPHINE IN MICE

  • 1 January 1976
    • journal article
    • research article
    • Vol. 198  (2) , 318-329
Abstract
Single-dose tolerance to the antinociceptive effect of morphine can be demonstrated using an adequate initial priming dose of morphine and allowing an interval of 48-72 h for its development. The threshold does necessary to produce tolerance was about 3-4 times greater than that for producing analgesia but higher doses of morphine did not enhance further tolerance development. Evidence of tolerance was indicated by the fact that when the antinociceptive response to morphine was assessed by the hot-plate and the tail-flick procedures, a shift in the dose-response curve of morphine to the right occurred after an adequate single priming dose of morphine. Cross-tolerance was evidenced by a decrease in analgetic response to methadone 3 days after a single priming dose of morphine and a decrease in morphine response after a single dose of methadone. The development of single-dose tolerance was inhibited by cycloheximide. Single-dose tolerance was also blocked by 5,6-dihydroxytryptamine and perhaps enhanced by L-tryptophan. Cyclic AMP did not affect single-dose tolerance development significantly although the direction was in favor of augmentation. Morphine uptake by the brain was not modified by the development of single-dose tolerance. Physical dependence, as measured by naloxone-precipitated withdrawal jumping, was not observed when single-dose analgetic tolerance was maximal. Single-dose tolerance to morphine apparently involves the synthesis of some marcomolecule, thus supporting previous findings in this laboratory involving as association with serotonin (5-hydroxytryptamine).