Anticipatory hyperexcitability and tolerance to the narcotizing effect of morphine in the rat.

The role of Pavlovian conditioning in tolerance to the narcotizing effect of a high dose of morphine in the rat was examined. Initially, two groups received nine injections of morphine (40 mg/kg), and two groups received nine injections of saline. One group administered each substance was injected in one of two distinctive environments: the animal colony or a distinctive room. Subsequently, rats in all groups received five morphine injections in the distinctive room. Analyses of videotape records of postinjection behavior indicated that rats tested in the presence of the usual predrug cues were more tolerant to the narcotizing effect of morphine than rats tested with cues different from those previously associated with morphine. In addition, rats tested with the usual predrug cues exhibited more anticipatory "hyperexcitable" behavior than rats tested in the absence of the usual predrug cues. These results provide further evidence that compensatory pharmacological conditional responses partially mediate tolerance, and they suggest that these drug-anticipatory responses contribute to so-called "withdrawal symptoms."