Abstract

To investigate the development of dependence to a single dose of morphine sulfate (MS) and its modulation by naloxone hydrochloride (NLX), mice were pretreated with a single dose of MS, 100 mg/kg s.c. and, at various times after this pretreatment, a priming dose of 10 mg/kg of MS s.c. was administered. Two hours later various doses of NLX were injected s.c. to precipitate jumping behavior, a sign of withdrawal and ED50 values of NLX were determined. Twenty-four and 72 hr after the MS pretreatment, NLX ED50 values were 18 and 21 mg/kg, respectively, which were significantly lower than those of the control groups which did not receive the 100 mg/kg of MS pretreatment. If the withdrawn mice were reprimed with a 10 mg/kg s.c. dose of MS 24 and 72 hr after the first priming dose, they displayed even more sensitivity to NLX with the NLX ED50 values lowered to 3 and 4 mg/kg, respectively. In addition, mice pretreated with 100 mg/kg of MS and treated with 32 mg/kg of NLX either 1 or 3 days later required smaller amounts of NLX to precipitate withdrawal after the priming dose of MS. NLX ED50 values in the former group were 5 and 4 mg/kg 24 and 72 hr after MS injection, respectively. In the latter group NLX ED50 values were 2, 19 and 25 mg/kg after 4, 6 and 9 days after MS injection, respectively. All these values were significantly lower than those of control groups which did not receive NLX at 3 or 72 hr after 100 mg/kg of MS. These results suggest that administration of the opioid antagonist naloxone in morphine-pretreated mice can lead to the maintenance of the dependent state.