Role of habituation and classical conditioning in the development of morphine tolerance.

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Abstract
Rats were tested for the development of analgesic tolerance to low (5 mg/kg) and high (15 mg/kg) doses of morphine once every 12 or 48 hr in distinctive or nondistinctive environments. Results indicated that in a nondistinctive environment, development of analgesic tolerance to morphine (a) is a function of repeated presentation of morphine, (b) is more rapid with massed than with spaced presentations of morphine, (c) is not dependent on variation in drug levels, (d) shows spontaneous recovery across time, and (e) is not sensitive to marked alteration in the environment. It is suggested that in nondistinctive environments the development of tolerance to morphine is mediated by a habituation process. Results show that in a distinctive environment development of analgesic tolerance to morphine (a) is a function of repeated presentation of morphine, (b) is slightly more rapid with spaced than with massed presentations of morphine, (c) is not dependent on variation in drug levels, (d) shows persistence across time, and (e) is sensitive to alteration in the environment. It is suggested that in a distinctive environment the development of tolerance to morphine is mediated by a classical conditioning process that is superimposed on the habituation process.

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