Jin Young-Ho, Bailey Timothy W, Doyle Mark W, Li Bai-Yan, Chang Kyoung S K, Schild John H, Mendelowitz David, Andresen Michael C
Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, Oregon 97201-3098, USA.
Anesthesiology. 2003 Jan;98(1):121-32. doi: 10.1097/00000542-200301000-00021.
Ketamine increases blood pressure and heart rate by unknown mechanisms, but studies suggest that an intact central nervous system and arterial baroreceptors are required. In the brain stem, medial nucleus tractus solitarius receives afferents from nodose neurons that initiate cardiovascular autonomic reflexes. Here, the authors assessed ketamine actions on afferent medial nucleus tractus solitarius synaptic transmission.
Ketamine was applied to horizontally sliced brain stems. Solitary tract (ST) stimulation evoked excitatory postsynaptic currents (eEPSCs) in medial nucleus tractus solitarius neurons. Capsaicin (200 nm) block of ST eEPSCs sorted neurons into sensitive (n = 19) and resistant (n = 23). In nodose ganglion slices, shocks to the peripheral vagal trunk activated afferent action potentials in sensory neurons classified by conduction velocities and capsaicin.
Ketamine potently (10-100 mciro m) blocked small, ST-evoked -methyl-d-aspartate synaptic currents found only in a subset of capsaicin-resistant neurons (6 of 12). Surprisingly, ketamine reversibly inhibited ST eEPSC amplitudes and induced synaptic failure at lower concentrations in capsaicin-sensitive than in capsaicin-resistant neurons (P < 0.005; n = 11 and 11). Spontaneous EPSCs using non- -methyl-d-aspartate receptors were insensitive even to 1-3 mm ketamine, suggesting that ST responses were blocked presynaptically. Similarly, ketamine blocked C-type action potential conduction at lower concentrations than A-type nodose sensory neurons.
The authors conclude that ketamine inhibits postsynaptic -methyl-d-aspartate receptors and presynaptic afferent processes in medial nucleus tractus solitarius. Unexpectedly, capsaicin-sensitive (C-type), unmyelinated afferents are significantly more susceptible to block than capsaicin-resistant (A-type), myelinated afferents. This differentiation may be related to tetrodotoxin-resistant sodium currents. Since C-type afferents mediate powerful arterial baroreflexes effects, these differential actions may contribute to ketamine-induced cardiovascular dysfunction.
氯胺酮通过未知机制升高血压和心率，但研究表明完整的中枢神经系统和动脉压力感受器是必需的。在脑干中，孤束核内侧核接收来自结状神经元的传入神经纤维，这些神经元启动心血管自主反射。在此，作者评估了氯胺酮对孤束核内侧核传入突触传递的作用。
将氯胺酮应用于水平切片的脑干。孤束（ST）刺激在孤束核内侧核神经元中诱发兴奋性突触后电流（eEPSCs）。用辣椒素（200 nM）阻断ST eEPSCs将神经元分为敏感型（n = 19）和耐药型（n = 23）。在结状神经节切片中，对外周迷走神经干的电刺激激活了根据传导速度和辣椒素分类的感觉神经元中的传入动作电位。
氯胺酮（10 - 100 μM）有效阻断仅在一部分辣椒素耐药神经元（12个中的6个）中发现的小的、由ST诱发的N - 甲基 - D - 天冬氨酸突触电流。令人惊讶的是，氯胺酮在辣椒素敏感神经元中比在辣椒素耐药神经元中以更低浓度可逆地抑制ST eEPSC幅度并诱导突触传递失败（P < 0.005；n = 11和11）。使用非N - 甲基 - D - 天冬氨酸受体的自发性EPSCs即使对1 - 3 mM氯胺酮也不敏感，表明ST反应在突触前被阻断。同样，氯胺酮在比A型结状感觉神经元更低的浓度下阻断C型动作电位传导。
作者得出结论，氯胺酮抑制孤束核内侧核中的突触后N - 甲基 - D - 天冬氨酸受体和突触前传入过程。出乎意料的是，辣椒素敏感的（C型）无髓传入神经比对辣椒素耐药的（A型）有髓传入神经更容易被阻断。这种差异可能与河豚毒素抗性钠电流有关。由于C型传入神经介导强大的动脉压力反射效应，这些不同的作用可能导致氯胺酮引起的心血管功能障碍。
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