Department of Anesthesiology, Kyushu University, Fukuoka, Japan.
Anesthesiology. 2010 Aug;113(2):429-37. doi: 10.1097/ALN.0b013e3181e19bd4.
Substantia gelatinosa of the spinal dorsal horn is crucial for transmission and modification of noxious stimuli. Previous studies have demonstrated that intrathecal midazolam, a benzodiazepine agonist, enhanced perioperative analgesia. Not only synaptic but also extrasynaptic inhibitory currents contribute to modification of noxious stimuli. Thus, the effects of midazolam on extrasynaptic gamma-aminobutyric acid (GABA) type A receptors in substantia gelatinosa neurons and interaction with noradrenaline, a transmitter of the descending inhibitory systems, were investigated.
Using whole cell patch-clamp technique in the adult rat spinal cord slices, extrasynaptic GABAergic currents were recorded in substantia gelatinosa neurons in the presence of gabazine (1 microm), which blocked synaptic GABAergic currents, and then midazolam (5 microm) and noradrenaline (20 microm) were applied.
Bath application of midazolam induced tonic outward currents in the presence of gabazine. Although the decay time of synaptic current was prolonged, neither frequency nor amplitude was affected by midazolam. In contrast, the application of noradrenaline markedly increased both frequency and amplitude of synaptic currents with a slight enhancement of tonic currents. Coapplication of noradrenaline and midazolam markedly increased tonic currents, and the increase was much greater than the sum of currents induced by noradrenaline and midazolam.
Midazolam had much larger effects on extrasynaptic GABA type A receptors than the synaptic receptors, suggesting a role of the enhancement of GABAergic extrasynaptic currents in the midazolam-induced analgesia. Because noradrenaline is shown to increase extrasynaptic GABA concentration, simultaneous administration of noradrenaline and midazolam may enhance the increased GABA action by midazolam, thereby resulting in an increase in tonic extrasynaptic currents.
脊髓背角胶状质对于伤害性刺激的传递和调制至关重要。先前的研究表明，鞘内注射苯二氮䓬类激动剂咪达唑仑可增强围手术期镇痛。不仅突触内，而且突触外抑制性电流也有助于伤害性刺激的调制。因此，研究了咪达唑仑对胶状质神经元突触外γ-氨基丁酸（GABA）A 型受体的作用及其与去甲肾上腺素（下行抑制系统的递质）的相互作用。
在成年大鼠脊髓切片上使用全细胞膜片钳技术，在gabazine（1μm）存在的情况下记录胶状质神经元的突触外 GABA 能电流，gabazine 可阻断突触 GABA 能电流，然后应用咪达唑仑（5μm）和去甲肾上腺素（20μm）。
gabazine 存在时，咪达唑仑诱导持续外向电流。虽然突触电流的衰减时间延长，但咪达唑仑既不影响频率也不影响幅度。相比之下，去甲肾上腺素的应用明显增加了突触电流的频率和幅度，同时轻微增强了持续电流。去甲肾上腺素和咪达唑仑的共同应用明显增加了持续电流，增加幅度远大于去甲肾上腺素和咪达唑仑单独应用引起的电流之和。
咪达唑仑对突触外 GABA A 型受体的作用远大于对突触受体的作用，提示增强 GABA 能突触外电流在咪达唑仑诱导的镇痛中起作用。因为去甲肾上腺素被证明可以增加突触外 GABA 浓度，所以同时给予去甲肾上腺素和咪达唑仑可能会增强咪达唑仑对 GABA 作用的增强，从而导致持续的突触外电流增加。
