PHYSICAL-DEPENDENCE ON MORPHINE-INDUCED IN DOGS VIA THE USE OF MINIOSMOTIC PUMPS

The difference between the development of physical dependence on morphine administered via Alzet miniosmotic pumps as well as syringe injection (twice a day) at fixed times was examined in conscious dogs. Physical dependence was quantified by polygraphically measuring naloxone-precipitated withdrawal signs on the day 8 after the subcutaneous implantation of miniosmotic pumps which supplied morphine at 1-5 mg/kg/day. Morphine plasma levels were maintained at 19-25 and 41-47 ng/mL during infusions of morphine at doses of 2.5 and 5 mg/kg/day, respectively. Morphine withdrawal was characterized by hyperactivity, biting, digging, tremors, nausea, hyperthermia, and increased wakefulness, and by electroencephalographic (EEG) activation in the amygdala and hippocampus, followed by dissociation of the EEG in the cortex (fast wave) from that in the limbic (slow wave) system, increased heart rates, and raised blood pressure. These morphine withdrawal signs seemed to be more severe than those exhibited in animals that had received syringe injections of morphine at the same doses. These results suggest that the use of miniosmotic pumps in dogs may be a very convenient and useful method for both evaluating drug dependence and studying its mechanisms.