Lee Y W, Yaksh T L
Department of Anesthesiology, University of California, San Diego, La Jolla 92093-0818.
Anesthesiology. 1995 Mar;82(3):741-8. doi: 10.1097/00000542-199503000-00016.
Spinally delivered alpha 2-adrenoceptor agonists and N-methyl-D-aspartate antagonists each have been shown to have actions attenuating the hyperesthesia in rat models of nerve injury pain. Using a fixed-dose analysis and an isobolographic paradigm, the spinal interaction between the alpha 2-adrenoceptor agonist clonidine and the N-methyl-D-aspartate antagonist MK-801 is characterized in a rat model of nerve injury-induced tactile hyperesthesia.
Male Sprague Dawley rats were anesthetized with halothane, and the left L5 and L6 spinal nerves were ligated (Chung model). After 7-10 days' recovery, a Polyethylene tubing catheter was implanted into the lumbar intrathecal space. After recovery from catheter implantations (5-7 days), intrathecal dose-response curves were established for the antihyperesthesia effects of clonidine (3, 6, 10, and 20 micrograms) and MK-801 (1, 3, 10, and 20 micrograms) alone to obtain the ED50 for each agent. In separate studies, three doses of clonidine (1, 3, and 10 micrograms) were injected mixed with one dose of MK-801 (1 microgram) for fixed-dose analysis, and three doses of the two agents (2, 6, and 20 micrograms) were injected jointly in a fraction of the dose ratio 1:1 for isobolographic analysis. Thresholds for left hind paw withdrawal to von Frey hair application were assessed.
Rats with nerve ligation showed a reliable tactile hyperesthesia (mechanical threshold 1-3 g vs. normal > 15 g). Intrathecal clonidine and MK-801 alone produced dose-dependent reductions of tactile hyperesthesia: ED50 9 micrograms and 10 micrograms, respectively. With the fixed-dose analysis, the log dose-response curves showed a left shift that considerably exceeds the theoretical curve made by a simple sum of the effects of clonidine alone and with MK-801 (1 microgram). With the isobolographic analysis, the combination ED50 was found to be statistically less than the theoretical additive dose combination. Intrathecal atipamezole, an alpha 2 antagonist, reversed the effects of clonidine and the clonidine/MK-801 mixture but not MK-801 alone. The side effect of clonidine was sedation and urination and that of MK-801 was motor weakness at doses above 10 micrograms. These effects were considerably less severe in rats after equiactive doses in the combination group.
The neuropathic pain is mediated by low-threshold mechanoreceptors, sympathetically dependent, and sensitive to both alpha 2 agonists and N-methyl-D-aspartate antagonists. Intrathecal clonidine may act to diminish sympathetic outflow, whereas MK-801 blocks the N-methyl-D-aspartate receptor that is associated with other spinal systems related to pain transmission mechanism. The two separate mechanisms may account for the powerful synergy observed in this study. Such combinations might be useful in neuropathic pain states to potentiate the antihyperpathic effects and to reduce the side effects of each agents.
脊髓给予的α2 -肾上腺素能受体激动剂和N -甲基-D -天冬氨酸拮抗剂在神经损伤性疼痛的大鼠模型中均已显示出具有减轻感觉过敏的作用。采用固定剂量分析和等效应线图范式，在神经损伤诱导的触觉感觉过敏大鼠模型中对α2 -肾上腺素能受体激动剂可乐定和N -甲基-D -天冬氨酸拮抗剂MK - 801之间的脊髓相互作用进行了表征。
雄性Sprague Dawley大鼠用氟烷麻醉，结扎左侧L5和L6脊神经（Chung模型）。恢复7 - 10天后，将聚乙烯管导管植入腰段鞘内间隙。从导管植入恢复后（5 - 7天），分别建立可乐定（3、6、10和20微克）和MK - 801（1、3、10和20微克）鞘内给药的抗感觉过敏效应的剂量反应曲线，以获得每种药物的半数有效剂量（ED50）。在单独的研究中，注射三种剂量的可乐定（1、3和10微克）与一种剂量的MK - 801（1微克）混合进行固定剂量分析，以1:1的剂量比联合注射三种剂量的两种药物（2、6和20微克）进行等效应线图分析。评估左后爪对von Frey毛发刺激的退缩阈值。
神经结扎的大鼠表现出可靠的触觉感觉过敏（机械阈值为1 - 3克，而正常大鼠>15克）。单独鞘内注射可乐定和MK - 801可产生剂量依赖性的触觉感觉过敏减轻：ED50分别为9微克和10微克。通过固定剂量分析，对数剂量反应曲线显示向左移位，大大超过了仅由可乐定和MK - 801（1微克）单独作用简单相加所形成的理论曲线。通过等效应线图分析，发现联合用药的ED50在统计学上小于理论相加剂量组合。鞘内注射α2拮抗剂阿替美唑可逆转可乐定和可乐定/MK - 801混合物的作用，但不能逆转单独MK - 801的作用。可乐定的副作用是镇静和排尿，MK - 801在剂量高于10微克时的副作用是运动无力。在联合用药组中，等效应剂量的大鼠这些效应明显较轻。
神经性疼痛由低阈值机械感受器介导，依赖交感神经，对α2激动剂和N -甲基-D -天冬氨酸拮抗剂均敏感。鞘内注射可乐定可能通过减少交感神经传出起作用，而MK - 801阻断与其他与疼痛传递机制相关的脊髓系统有关的N -甲基-D -天冬氨酸受体。这两种不同的机制可能解释了本研究中观察到的强大协同作用。这种联合用药可能对神经性疼痛状态有用，可增强抗痛觉过敏作用并减少每种药物的副作用。
