The development of opioid tolerance in the formalin test in the rat

The formalin test produces persistent pain in animals and is believed to provide a better model of the pain experienced by humans than do tests that measure reflex nociceptive thresholds. The present study evaluated whether tolerance to morphine develops in the formalin test in the rat. Morphine (75 mg) or vehicle pellets were implanted subcutaneously for 5 consecutive days. On the 6th day, a subcutaneous (s.c.) dose of either morphine (10 mg/kg) or saline was given 30 min prior to the injection of 50 microliters of 5% formalin into the left hindpaw of the rats. In vehicle-pelleted rats administered saline, formalin evoked characteristic pain behavior consisting of licking, biting and flinching of the affected hindpaw. The pain behavior in morphine-tolerant rats given morphine did not differ significantly from the saline control; i.e., tolerance to the analgesic effect of morphine was demonstrable in the formalin test. These results do not agree with previous published reports. Rather, these results suggest that the mechanisms involved in morphine analgesia in the formalin test and in reflex nociceptive tests are similar and subject to the same problem of tolerance with chronic opioid administration.