Spontaneous withdrawal in intermittent morphine administration in rats and mice: effect of clonidine coadministration and sex-related differences.

Treating animals repeatedly with intermittent and increasing morphine doses has been suggested to allow some withdrawal during each dosing interval, which causes repeated stress. The present study aimed to test this hypothesis and assess sex-related differences in withdrawal signs and their suppression by clonidine. Male and female rats and mice were administered with increasing doses of morphine twice daily at different dosing intervals. Rats were given clonidine in drinking water (5 μg/mL). Spontaneous and naloxone-precipitated withdrawal signs and novelty-induced grooming were evaluated. Male rats and male and female rats displayed manifestations of morphine withdrawal at the end of 14-h and 24-h dosing intervals, respectively. Clonidine attenuated the severity of the withdrawal signs. Male but not female mice displayed withdrawal signs at the end of 12-h and 17-h dosing intervals. Female mice exhibited less pronounced naloxone-precipitated withdrawal syndrome. Grooming did not reflect a "stress-like state" in morphine-treated animals. These findings indicate intermittent morphine treatment-induced spontaneous withdrawal in rats and mice and sex-related differences in spontaneous and naloxone-precipitated withdrawal signs in mice. Since the treatment protocol closely parallels the drug use pattern in opioid addicts, further experiments are needed to clarify the stress associated with the treatment and the efficacy of sedatives.