Studies on tolerance. I. The role of the interval between doses on the development of tolerance to morphine.

The effect of varying the interval between doses on the rate of development of tolerance to a series of injections of morphine was studied in two strains of rats. Morphine sulfate injections (15 mg/kg s.c.) were given at intervals of 1, 2, 3, 7, 10, 14 or 21 days to adult male Wistar/Furth or Wistar-Lewis rats and drug effect was measured by means of the hot-plate assay technique. A diminution of morphine effect on the second or subsequent injections of drug was considered to be the result of the development of tolerance. Little or no tolerance was observed with the Wistar/Furth animals when a second injection or morphine was administered 7 days after the first, although there was marked tolerance when there were shorter or longer intervals between the first two injections. Subsequent injections of morphine sulfate, given to the animals at the predetermined intervals, resulted in wiping out out the differences between all interval groups, with the exception of the 1-day group, by the fifth injection. Although the differences between the 7-day and longer or shorter intervals were not as great with the Wistar-Lewis animals, they were significant and may reflect a slightly different rate of tolerance development in the latter strain. These observations are consistent with the hypothesis that there may be two types of tolerance, one appearing very rapidly, the other taking a longer period of time to develop.