Kushikata T, Hirota K, Yoshida H, Kudo M, Lambert D G, Smart D, Jerman J C, Matsuki A
Department of Anesthesiology, University of Hirosaki School of Medicine, Zaifu-cho 5, Hirosaki, Japan 036-8562.
Neuroscience. 2003;121(4):855-63. doi: 10.1016/s0306-4522(03)00554-2.
Orexins (OXs) regulate sleep with possible interactions with brain noradrenergic neurons. In addition, noradrenergic activity affects barbiturate anesthesia. As we have also recently reported that OXs selectively evoke norepinephrine release from rat cerebrocortical slices we hypothesized that barbiturate anesthesia may result from of an interaction with central orexinergic systems. To test this hypothesis, we performed a series of in vivo and in vitro studies in rats. In vivo, the effects of i.c.v. OX A, B and SB-334867-A (OX1 receptor antagonist) on pentobarbital, thiopental or phenobarbital-induced anesthesia times (loss of righting reflex) was assessed. In vitro effects of barbiturates and SB-334867-A on OX-evoked norepinephrine release from cerebrocortical slice was examined. In Chinese hamster ovary cells expressing human OX1/OX2 receptors OX A- and B-evoked increases in intracellular Ca2+ were measured with and without barbiturates. OX A and B significantly decreased pentobarbital, thiopental and phenobarbital anesthesia times by 15-40%. SB-334867-A increased thiopental-induced anesthesia time by approximately by 40%, and reversed the decrease produced by OX A. In vitro, all anesthetic barbiturates inhibited OX-evoked norepinephrine release with clinically relevant IC50 values. A GABAA antagonist, bicuculline, did not modify the inhibitory effects of thiopental and the GABAA agonist, muscimol, did not inhibit norepinephrine release. In addition there was no interaction of barbiturates with either OX1 or OX2 receptors. Collectively our data suggest that orexinergic neurons may be an important target for barbiturates, and GABAA, OX1 and OX2 receptors may not be involved in this interaction.
食欲素（OXs）通过与脑去甲肾上腺素能神经元的潜在相互作用来调节睡眠。此外，去甲肾上腺素能活性会影响巴比妥类麻醉。由于我们最近还报道了食欲素能选择性地引起大鼠脑皮质切片释放去甲肾上腺素，因此我们推测巴比妥类麻醉可能是与中枢食欲素能系统相互作用的结果。为了验证这一假设，我们在大鼠身上进行了一系列体内和体外研究。在体内，评估了脑室内注射OX A、B和SB - 334867 - A（OX1受体拮抗剂）对戊巴比妥、硫喷妥钠或苯巴比妥诱导的麻醉时间（翻正反射消失）的影响。在体外，检测了巴比妥类药物和SB - 334867 - A对食欲素诱导的脑皮质切片去甲肾上腺素释放的影响。在表达人OX1/OX2受体的中国仓鼠卵巢细胞中，测定了有无巴比妥类药物时OX A和B诱导的细胞内Ca2+增加情况。OX A和B显著缩短了戊巴比妥、硫喷妥钠和苯巴比妥的麻醉时间15 - 40%。SB - 334867 - A使硫喷妥钠诱导的麻醉时间延长了约40%，并逆转了OX A引起的缩短。在体外，所有麻醉性巴比妥类药物均以临床相关的IC50值抑制食欲素诱导的去甲肾上腺素释放。一种GABAA拮抗剂荷包牡丹碱并未改变硫喷妥钠的抑制作用，而GABAA激动剂蝇蕈醇并未抑制去甲肾上腺素释放。此外，巴比妥类药物与OX1或OX2受体之间没有相互作用。我们的数据总体表明，食欲素能神经元可能是巴比妥类药物的重要作用靶点，且GABAA、OX1和OX2受体可能不参与这种相互作用。
