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A single dose of clonidine developed tolerance to its analgesic effect. The tolerance reached its peak acutely on the 2nd day and lasted more than 5 days. Neither the analgesic effect nor the development of tolerance was modified by the pretreatment with naloxone. On the 2nd day, clonidine tolerant animals were also tolerant to morphine, but morphine tolerant animals, after a single dose of morphine on the 1st day, were not tolerant to clonidine. On the 5th day, however, clonidine tolerant animals were tolerant to morphine, and vice versa. Thus, the interaction between morphine and clonidine was "one-way" on the 2nd day, and cross-tolerance was only demonstrated on the 5th day. With a treatment with clonidine plus naloxone on the 1st day, the development of cross-tolerance to morphine was completely suppressed on the 2nd day but not on the 5th day. These results confirmed our previous finding that acute and delayed tolerance are different in nature, and the development of tolerance to morphine and clonidine are partially underlaid with a common mechanism which is not mediated by opioid receptors.

Single Dose Tolerance to the Analgesic Effect of Clonidine and Cross-Tolerance between Morphine and Clonidine