Moody E J, Skolnick P
Laboratory of Neuroscience, NIDDK, Bethesda, MD 20892.
Life Sci. 1988;43(16):1269-76. doi: 10.1016/0024-3205(88)90581-4.
Parenteral administration of the imidazobenzodiazepine Ro 15-4513 (a high affinity ligand of the benzodiazepine receptor with partial inverse agonist qualities) produced a dose dependent reduction in sleep time of mice exposed to the inhalation anesthetic, methoxyflurane. The reductions in methoxyflurane sleep time ranged from approximately 20% at 4 mg/kg to approximately 38% at 32 mg/kg of Ro 15-4513. Co-administration of the benzodiazepine receptor antagonist Ro 15-1788 (16 mg/kg) or the inverse agonists DMCM (5-20 mg/kg) and FG 7142 (22.5 mg/kg) blocks this effect which suggests that the reductions in methoxyflurane sleep time produced by Ro 15-4513 are mediated via occupation of benzodiazepine receptors. Moreover, neither DMCM (5-20 mg/kg) nor FG 7142 (22.5 mg/kg) reduced methoxyflurane sleep time which suggests this effect of Ro 15-4513 cannot be attributed solely to its partial inverse agonist properties. These observations support recent findings that inhalation anesthetics may produce their depressant effects via perturbation of the benzodiazepine/GABA receptor chloride channel complex, and suggest that Ro 15-4513 may serve as a prototype of agents capable of antagonizing the depressant effects of inhalation anesthetics such as methoxyflurane.
经肠胃外途径给予咪唑并苯二氮䓬Ro 15 - 4513（一种具有部分反向激动剂特性的苯二氮䓬受体高亲和力配体），可使吸入麻醉剂甲氧氟烷麻醉的小鼠睡眠时间呈剂量依赖性缩短。Ro 15 - 4513剂量为4mg/kg时，甲氧氟烷睡眠时间缩短约20%；剂量为32mg/kg时，缩短约38%。同时给予苯二氮䓬受体拮抗剂Ro 15 - 1788（16mg/kg）或反向激动剂DMCM（5 - 20mg/kg）及FG 7142（22.5mg/kg）可阻断此效应，这表明Ro 15 - 4513导致的甲氧氟烷睡眠时间缩短是通过占据苯二氮䓬受体介导的。此外，DMCM（5 - 20mg/kg）和FG 7142（22.5mg/kg）均未缩短甲氧氟烷睡眠时间，这表明Ro 15 - 4513的这种效应不能仅归因于其部分反向激动剂特性。这些观察结果支持了最近的研究发现，即吸入麻醉剂可能通过干扰苯二氮䓬/GABA受体氯离子通道复合物产生其抑制作用，并表明Ro 15 - 4513可能作为一种能够拮抗甲氧氟烷等吸入麻醉剂抑制作用的药物原型。
