Echizenya Masaru, Mishima Kazuo, Satoh Kohtoku, Kusanagi Hiroaki, Sekine Atsushi, Ohkubo Tadashi, Shimizu Tetsuo, Hishikawa Yasuo
Department of Neuropsychiatry, Akita University School of Medicine, Japan.
Neuropsychopharmacology. 2003 Jun;28(6):1198-206. doi: 10.1038/sj.npp.1300160. Epub 2003 Apr 2.
In spite of the accumulation of knowledge regarding the neuropharmacological action of benzodiazepines (Bz), the physiological process by which their sedative/hypnotic effects are induced remains poorly understood. We conducted a single-blind, crossover trial to evaluate the role of the thermoregulatory process in sleepiness and impaired psychomotor performance induced by a standard Bz, diazepam (DZP). Each of the eight healthy young male volunteers (mean age, 19.75 years; range, 18-23 years) was given a single oral dose of either 5 or 10 mg of DZP or placebo 12 h after his average sleep onset time. Changes in plasma DZP concentration, proximal body temperature (p-BT), distal body temperature (d-BT), subjective sleepiness measured by the Visual Analog Scale and Stanford Sleepiness Scale, and psychomotor performance measured by Choice Reaction Time were monitored under a modified constant routine condition in which various factors affecting thermoregulation, alertness, and psychomotor performances were strictly controlled. Orally administered DZP induced a significant transient decrease in p-BT and psychomotor performance as well as an increase in d-BT and subjective sleepiness. Distal-p-BT gradient (DPG; difference between d-BT and p-BT), which is an indicator of blood flow in distal skin regions, showed a strong positive correlation with the plasma DZP concentration, indicating that DZP in clinical doses promotes heat loss in a dose-dependent manner. The DPG also correlated positively with the magnitude of subjective sleepiness and impaired psychomotor performance. These findings indicate that the sedative/hypnotic effects of Bz could be due, at least in part, to changes in thermoregulation, especially in the process of heat loss, in humans.
尽管关于苯二氮䓬类药物（Bz）的神经药理作用已有大量知识积累，但其诱导镇静/催眠作用的生理过程仍知之甚少。我们进行了一项单盲交叉试验，以评估体温调节过程在由标准Bz药物地西泮（DZP）诱导的嗜睡和精神运动功能受损中所起的作用。八名健康年轻男性志愿者（平均年龄19.75岁；范围18 - 23岁）中的每一位在其平均入睡时间12小时后，单次口服5毫克或10毫克DZP或安慰剂。在改良的固定日常条件下监测血浆DZP浓度、近端体温（p - BT）、远端体温（d - BT）、通过视觉模拟量表和斯坦福嗜睡量表测量的主观嗜睡程度以及通过选择反应时间测量的精神运动功能变化，在该条件下，影响体温调节、警觉性和精神运动功能的各种因素均得到严格控制。口服DZP导致p - BT和精神运动功能显著短暂下降，以及d - BT和主观嗜睡程度增加。远端 - p - BT梯度（DPG；d - BT与p - BT之间的差值）是远端皮肤区域血流的一个指标，与血浆DZP浓度呈强正相关，表明临床剂量的DZP以剂量依赖方式促进热量散失。DPG还与主观嗜睡程度和精神运动功能受损程度呈正相关。这些发现表明，Bz的镇静/催眠作用至少部分可能归因于人体体温调节的变化，尤其是热量散失过程的变化。
