DEVELOPMENT OF TOLERANCE TO MORPHINE ANTINOCICEPTION IN MICE TREATED WITH NOCICEPTIVE STIMULANTS

We have examined whether or not the presence of pain can block the dev elopment of tolerance to morphine antinociception in mice. A single in jection of formalin or Freund complete adjuvant into the dorsal part o f one side of the hind paw resulted in a significant swelling of the t reated paw which lasted more than 5 days. In formalin-treated animals that received the initial morphine 2 hr after the stimulant, the devel opment of tolerance to morphine was delayed without affecting morphine antinociception when the effect was measured daily by the tail-pinch (TP) method but not by the tail-flick (TF) method. However, the stimul ant suppressed tolerance development even in the TF method unless the daily measurement was undertaken. When morphine injection was started from 5 days after the formalin injection, tolerance developed in a pat tern similar to that in the control animals. On the other hand, treatm ent with Freund adjuvant did not affect the development of tolerance m easured by both the TP and TF methods, with or without daily measureme nt of antinociception. When acetic acid was used as a stimulant, daily morphine was administered before or after the acetic acid injection, in the presence or absence of pain, tolerance developed to the same ex tent as in the control group, regardless of the time of morphine injec tion. Thus, our results suggest that the development of tolerance to n arcotics may be modified by various factors, such as the type and inte nsity of nociception; and they also suggest that different results may be produced depending on the test method.