Brain orexinergic-noradrenergic neurons and mechanism of general anesthesia

目前的数据支持我们的假设，抑制和过度兴奋的去甲肾上腺素能神经元的GABA型和NMDA型的麻醉剂，分别有助于全身麻醉的机制（=意识丧失）。食欲素增加去甲肾上腺素能神经元的活动，但增加是饱和的约250%的基础，其水平的去甲肾上腺素能神经元的活动可能会导致最大的觉醒，在我们的假设。此外，目前的数据表明，食欲素能神经元可能是GABA型和NMDA型麻醉剂的靶点，因为食欲素减少了巴比妥类（GABA型）和氯胺酮（NMDA型）产生的麻醉时间。食欲素也拮抗硫喷妥钠引起的抑制和氯胺酮引起的去甲肾上腺素能活动的过度兴奋。育亨宾10 mg/kg ip可使脑去甲肾上腺素释放增加至基础水平的500%，这一增加延长了GABA型麻醉剂丙泊酚产生的麻醉时间。这意味着去甲肾上腺素能神经元活动的过度兴奋也可以增强GABA型麻醉剂产生的麻醉。已知DSP-4损伤蓝斑起源的去甲肾上腺素能神经元。病变增加硫喷妥钠麻醉时间，减少氯胺酮麻醉时间。此外，脑去甲肾上腺素含量与硫喷妥钠麻醉时间的增加或氯胺酮麻醉时间的减少显著相关。因此，我们证明了我们的假设，抑制和过度兴奋的去甲肾上腺素能神经元有助于意识丧失。

The present data support our hypothesis that both inhibition and overexcitation of noradrenergic neurons by GABA-type and NMDA-type of anesthetics, respectively, contribute to the mechanism of general anesthesia (=loss of consciousness). Orexin increases noradrenergic neuronal activity but the increase is saturable around 250% of the basal, whose level of noradrenergic neuronal activity may induce the maximal wakefulness in our hypothesis. In addition, the present data indicates that orexinergic neurons could be a target for both GABA-type and NMDA-type of anesthetic agents as orexin decreased both barbiturates (GABA-type) and ketamine (NMDA-type)-produced anesthesia time. Orexin also antagonized thiopental-induced inhibition of and ketamine-caused overexcitatio of noradrenergic activity. Yohimbin 10 mg/kg ip increased cerebral noradrenaline release to ~500% of the basal, and this increase prolonged GABA-type anesthetic propofol-produced anesthesia time. This means that overexcitation of noradrenergic neuronal activity could also enhance GABA-type anesthetics-produced anesthesia. It is known that DSP-4 lesions locus coeruleus-originated noradrenergic neurons. The lesion increased thiopental anesthesia time and decreased ketamine anesthesia time. In addition, there were significant correlations between cerebral noradrenaline contents and increase in thiopental anesthesia time or decrease in ketamine anesthesia time. Therefore, we proved our hypothesis that both inhibition and overexcitation of noradrenergic neurons contribute to loss of consciousness.