INTRATHECAL AMITRIPTYLINE ACTS AS AN N-METHYL-D-ASPARATE RECEPTOR ANTAGONIST IN THE PRESENCE OF INFLAMMATORY HYPERALGESIA IN RATS
INTRATHECAL AMITRIPTYLINE ACTS AS AN N-METHYL-D-ASPARATE RECEPTOR ANTAGONIST IN THE PRESENCE OF INFLAMMATORY HYPERALGESIA IN RATS
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DOI：
10.1097/00000542-199511000-00018
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发表时间：
1995-11-01
期刊：
影响因子：
8.8
通讯作者：
GEBHART, GF
中科院分区：
文献类型：
--
作者：
EISENACH, JC;GEBHART, GF
背景：阿米替林和其他三环类抗抑郁药在体外表现出与 N-甲基-D-天冬氨酸 (NMDA) 受体的高亲和力结合，并抑制海马切片中 NMDA 受体激活诱导的神经可塑性。由于脊髓 NMDA 受体激活被认为是痛觉过敏疼痛产生和维持的核心，因此本研究的目的是测试鞘内注射阿米替林是否能减少大鼠炎症引起的痛觉过敏。方法：给大鼠准备慢性腰椎鞘内和股骨静脉导管，通过后爪缩回辐射热刺激来评估伤害性阈值。大鼠一只后爪注射角叉菜胶，3小时后进行热缩爪测试，并鞘内注射阿米替林和/或静脉注射吗啡。在其他大鼠中，鞘内注射 NMDA 之前先鞘内注射生理盐水或 60 μg 阿米替林。结果：鞘内注射阿米替林以剂量依赖性方式逆转热痛觉过敏，但对未注射的对侧爪子的缩回潜伏期没有影响。除最低剂量外，鞘内注射酚妥拉明加美西麦角不会改变阿米替林的作用。静脉注射吗啡以剂量依赖性方式增加发炎爪子和对照爪子的缩爪潜伏期，并且吗啡与鞘内阿米替林相互作用以逆转痛觉过敏。 NMDA引起的热痛觉过敏可被鞘内阿米替林完全拮抗。结论：阿米替林和其他三环类抗抑郁药已被证明在全身给药后对临床神经性疼痛表现出适度的活性。这些数据表明鞘内给药可能会获得更深刻的疼痛缓解。阿米替林通过与单胺再摄取抑制无关的机制逆转大鼠的痛觉过敏，可能是由于 NMDA 受体拮抗作用。
Background: Amitriptyline and other tricyclic antidepressants exhibit high affinity binding to N-methyl-D-aspartate (NMDA) receptors in vitro and inhibit NMDA receptor activation-induced neuroplasticity In hippocampal slices. Because spinal NMDA receptor activation is believed to be central to generation and maintenance of hyperalgesic pain, the purpose of this study was to test whether intrathecal amitriptyline reduced inflammation-induced hyperalgesia in the rat.Methods: Rats were prepared with chronic lumbar intrathecal and femoral intravenous catheters and nociceptive threshold was assessed by hind paw withdrawal to a radiant heat stimulus. Rats received an injection of carrageenin in one hind paw followed by thermal paw withdrawal testing 3 hr later and intrathecal amitriptyline and/or intravenous morphine injection. In other rats, intrathecal NMDA injection was preceded by either intrathecal saline or 60 mu g amitriptyline.Results: Intrathecal amitriptyline reversed thermal hyperalgesia in a dose-dependent manner, but had no effect on withdrawal latency of the contralateral, noninjected paw. Intrathecal phentolamine plus methysergide did not alter amitriptyline's effect, except at the lowest dose. Intravenous morphine increased paw withdrawal latency in both inflamed and control paws in a dose-dependent fashion, and morphine interacted additively with intrathecal amitriptyline to reverse hyperalgesia. Thermal hyperalgesia Induced by NMDA was completely antagonized by intrathecal amitriptyline.Conclusions: amitriptyline and other tricyclic antidepressants have been demonstrated to exhibit modest activity against clinical neuropathic pain after systemic administration. These data suggest that more profound pain relief might be obtained by intrathecal administration. Amitriptyline reverses hyperalgesia in rats by a mechanism unrelated to monoamine reuptake inhibition, and likely due to NMDA receptor antagonism.