Differential expression of response-disruptive and somatic indices of opiate withdrawal during the initiation and development of opiate dependence.

The current study examined the conditions that are necessary and sufficient for the initiation and progression of acute morphine dependence using two indices of opiate withdrawal: suppression of operant response rates and a somatic withdrawal rating scale. Separate groups of rats were pretreated with morphine (5 mg/kg, s.c.) a total of three times at intervals of 24 h, 1, 3, or 6 weeks. Rats received a single dose of naloxone 4 h after each morphine pretreatment. Naloxone-induced suppression of operant responding (0.33 mg/kg, s.c.) was significantly potentiated with repeated exposure to morphine even at the 6-week inter-treatment interval (ITI). At 24-h, 1-week and 3-week ITIs, rats treated with naloxone only after the third and final morphine pretreatment showed similar suppression of operant responding following naloxone to rats treated with naloxone after all three morphine pretreatments. However, at the 6-week ITI, the response-disruptive effects of naloxone administered for the first time after the third morphine pretreatment were no greater than the effects of naloxone administered after a single morphine pretreatment. In contrast to results seen with suppression of operant responding as the withdrawal index, potentiation of somatic signs of withdrawal was observed only at the 24-h ITI. These results indicate that a neuroadaptive state resembling opiate dependence can be initiated after just one injection of morphine, and that the response-disruptive effects of naloxone appear to be a particularly sensitive index of the initiation and progression of acute opiate dependence.