Midazolam impairs the acquisition of conditioned analgesia if rats are tested with an acute but not a chronic noxious stimulus.

Three experiments investigated the effects of midazolam on acquisition of fear-mediated analgesic responses in rats conditioned on the heated floor of a hot-plate apparatus. Experiment 1 demonstrated that a moderate dose (1.25 mg/kg) of midazolam administered prior to conditioning impaired acquisition of conditioned analgesia in rats retested on the heated floor 24 h later. This effect of midazolam was reversed by the benzodiazepine receptor antagonist flumazenil. In contrast, in Experiment 2, the same or higher (2.5 mg/kg) dose of midazolam did not appear to affect the acquisition of conditioned analgesia in rats tested 24 h later with a formalin-injected paw on the non-heated floor of the hot plate apparatus. By testing rats with the opioid antagonist naloxone, Experiment 3 revealed that the higher dose of midazolam did disrupt the acquisition of conditioned analgesia in rats tested with formalin, but only by preventing acquisition of an immediate but brief analgesic response that was insensitive to naloxone. Midazolam was shown to have no effect on the acquisition of the enduring naloxone-reversible analgesia. These results are discussed in terms of benzodiazepines acting within the amygdala to produce a retrieval deficit whereby fear conditioning that takes place under the influence of a benzodiazepine can only be accessed if the animal is tested in the presence of ongoing noxious stimulation.