Diazepam pretreatment suppresses morphine withdrawal signs in the mouse.
The effect of diazepam on the development of physical dependence on morphine and on the naloxone-precipitated increase in cortical NA turnover were investigated in mice. Co-administration of diazepam (1-4 mg/kg, i.p.) during chronic morphine treatment suppressed the expression of naloxone (3 mg/kg, s.c.)-precipitated withdrawal signs (jumping, exploratory rearing and weight loss). However, a single injection of diazepam (4 mg/kg, i.p.) in morphine-dependent mice did not affect the expression of naloxone-precipitated withdrawal signs. The 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) level and noradrenaline (NA) turnover (MHPG/NA) in the cerebral cortex were increased by naloxone (3 mg/kg) challenge. These increases in the cortical MHPG level and NA turnover were significantly prevented by co-administration of diazepam (4 mg/kg, i.p.) during chronic morphine treatment. These findings suggest that the co-administration of diazepam during chronic morphine treatment may prevent some neurochemical changes in the central noradrenergic system during chronic morphine treatment, and may suppress the development of physical dependence on morphine. Therefore, the inhibitory action of GABA via benzodiazepine binding sites may play an important role in the development of physical dependence on morphine.
Department of Pharmacology, School of Pharmacy, Hoshi University, Tokyo, Japan.
T
T
Suzuki
M
M
Tsuda
M
M
Narita
M
M
Funada
H
H
Mizoguchi
M
M
Misawa
D000316:Adrenergic alpha-Agonists / Q000378:metabolism; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000927:Anticonvulsants / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology*; D004338:Drug Combinations; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000378:metabolism; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009021:Morphine Dependence / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009638:Norepinephrine / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000517:prevention & control*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000316:Adrenergic alpha-Agonists; D000701:Analgesics, Opioid; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D004338:Drug Combinations; D009292:Narcotic Antagonists; D011963:Receptors, GABA-A; D009270:Naloxone; D008734:Methoxyhydroxyphenylglycol; D005680:gamma-Aminobutyric Acid; D009020:Morphine; D003975:Diazepam; D009638:Norepinephrine