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 development of tolerance to morphine antinociception in mice. A single injection of formalin or Freund complete adjuvant into the dorsal part of one side of the hind paw resulted in a significant swelling of the treated paw which lasted more than 5 days. In formalin-treated animals that received the initial morphine 2 hr after the stimulant, the development 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 stimulant 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 pattern similar to that in the control animals. On the other hand, treatment with Freund adjuvant did not affect the development of tolerance measured by both the TP and TF methods, with or without daily measurement 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 extent as in the control group, regardless of the time of morphine injection. Thus, our results suggest that the development of tolerance to narcotics may be modified by various factors, such as the type and intensity of nociception; and they also suggest that different results may be produced depending on the test method.