ENHANCED NALOXONE DISTRIBUTION TO BRAIN BY MORPHINE PRETREATMENT IN MICE

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  • 1 January 1977
    • journal article
    • research article
    • Vol. 5  (2) , 167-173
Abstract
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, s.c.) 3 h prior to naloxone has a 28% increase in naloxone concentration in brain (200-260 pmol of naloxone/g of brain) 10 min after 3H-naloxone.cntdot.HCl (0.4 mg/kg, 11.0 .mu.Ci/kg, s.c.) administration. If similar morphine-pretreated mice received a 2nd dose of morphine sulfate (1.0 mg/kg, s.c.) concurrent with 3H-naloxone.cntdot.HCl, the morphine-induced enhancement of 3H-naloxone concentration in brain was unaltered. This drug-treatment protocol paralleled that used by others in pA2[scale for measurement of drug antagonism]-analgesia assays to demonstrate sensitization to naloxone for morphine-pretreated animals. In prior (3 h) morphine-treated animals, administration of 3H-naloxone.cntdot.HCl (0.1 mg/kg, 33.3 .mu.Ci/kg) i.v. resulted in an 11.0% increase in 3H-naloxone brain concentration after 1 min. 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 h after morphine sulfate pretreatment (10 mg/kg, s.c.), a decline in the effect similar to that seen for morphine-induced sensitization to naloxone. When morphine pellet-implanted mice (75 mg of morphine base, 72 h) were administered 3H-naloxone.cntdot.HCl (0.4 mg/kg, 10.0 .mu.Ci/kg, s.c.), 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. 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 2 phenomena.