Noncompetitive antagonism of morphine analgesia by diazepam in the formalin test

The effects of diazepam on morphine analgesia dose effect curves in the formalin test and in two forms of the tail flick test were examined. In one form of the tail flick test the animals were restrained in wire restrainers (a stressful procedure) while in the other they were left free and briefly handheld for testing. Morphine analgesia in the restrained form of the test is known to depend on raphe magnus 5HT projections to the spinal cord while the other tests do not involve this system. Diazepam (0.2 and 1.0 mg/kg) noncompetitively antagonized morphine analgesia in the formalin test but had no effect on morphine analgesia in the tail flick test. It is concluded that diazepam does not antagonize morphine analgesia through its antianxiety action reducing the serotonergic response to stress. It is suggested that the sensitivity of the formalin test to diazepam antagonism of morphine analgesia may be of clinical significance since formalin test pain resembles postoperative pain in humans.