Enhanced naloxone distribution to the brain by morphine pretreatment in mice.
An increase in the disposition of naloxone to the mouse brain was observed for animals previously exposed to morphine. Compared to controls, mice receiving morphine sulfate (10 mg/kg, sc) 3 hr prior to naloxone had a 28% increase in naloxone concentration in brain (200 to 260 pmol of naloxone per g of brain) 10 min after 3H-naloxone-HCl (0.4 mg/kg, 11.0 micronCi/kg, sc) administration. Also, if similar morphine-pretreated mice received a second dose of morphine sulfate (1.0 mg/kg, sc) concurrent with 3H-naloxone-HCl, the morphine-induced enhancement of 3H-naloxone concentration in brain was unaltered. This drug-treatment protocol paralleled that used by others in pA2-analgesia assays to demonstrate sensitization to naloxone for morphine-pretreated animals. In prior (3 hr) morphine-treated animals, administration of 3H-naloxone-HCl (0.1 mg/kg, 33.3 micronCi/kg) iv resulted in an 11.0% increase in 3H-naloxone brain concentration after 1 min. Thus, the enhancement of naloxone brain concentration was independent of the route of naloxone administration. No enhancement of 3H-naloxone brain concentration could be seen 24 hr after morphine sulfate pretreatment (10 mg/kg, sc), a decline in the effect similar to that seen for morphine-induced sensitization to naloxone. Finally, when morphine pellet-implanted mice (75 mg of morphine base, 72 hr) were administered 3H-naloxone-HCl (0.4 mg/kg, 10.0 micronCi/kg, sc), only a 22.5% enhancement of 3H-naloxone concentration in brain was obtained, as opposed to a reported 8-fold increase in the potency of naloxone. Thus, although a number of similarities exist between the enhancement by morphine of naloxone concentration in brain and its sensitization to the antagonistic activity of naloxone, a quantitative correlation appears to be lacking between the two phenomena.
Enhanced naloxone distribution to the brain by morphine pretreatment in mice. An increase in the disposition of naloxone to the mouse brain was observed for animals previously exposed to morphine. Compared to controls, mice receiving morphine sulfate (10 mg/kg, sc) 3 hr prior to naloxone had a 28% increase in naloxone concentration in brain (200 to 260 pmol of naloxone per g of brain) 10 min after 3H-naloxone-HCl (0.4 mg/kg, 11.0 micronCi/kg, sc) administration. Also, if similar morphine-pretreated mice received a second dose of morphine sulfate (1.0 mg/kg, sc) concurrent with 3H-naloxone-HCl, the morphine-induced enhancement of 3H-naloxone concentration in brain was unaltered. This drug-treatment protocol paralleled that used by others in pA2-analgesia assays to demonstrate sensitization to naloxone for morphine-pretreated animals. In prior (3 hr) morphine-treated animals, administration of 3H-naloxone-HCl (0.1 mg/kg, 33.3 micronCi/kg) iv resulted in an 11.0% increase in 3H-naloxone brain concentration after 1 min. Thus, the enhancement of naloxone brain concentration was independent of the route of naloxone administration. No enhancement of 3H-naloxone brain concentration could be seen 24 hr after morphine sulfate pretreatment (10 mg/kg, sc), a decline in the effect similar to that seen for morphine-induced sensitization to naloxone. Finally, when morphine pellet-implanted mice (75 mg of morphine base, 72 hr) were administered 3H-naloxone-HCl (0.4 mg/kg, 10.0 micronCi/kg, sc), only a 22.5% enhancement of 3H-naloxone concentration in brain was obtained, as opposed to a reported 8-fold increase in the potency of naloxone. Thus, although a number of similarities exist between the enhancement by morphine of naloxone concentration in brain and its sensitization to the antagonistic activity of naloxone, a quantitative correlation appears to be lacking between the two phenomena.