N-Methyl-D-aspartate antagonists and neuropathic pain:: The search for relief
N-Methyl-D-aspartate antagonists and neuropathic pain:: The search for relief
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DOI：
10.1021/jm060728b
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发表时间：
2007-05-31
影响因子：
7.3
通讯作者：
Baudy, Reinhardt B.
中科院分区：
文献类型：
--
作者：
Childers, Wayne E., Jr.;Baudy, Reinhardt B.
神经病理性疼痛，通常被定义为由外周或中枢神经损伤引起的慢性疼痛状态，可严重影响患者及其家人和朋友的生活。疼痛可能由急性事件（截肢、背部损伤）和全身性疾病状态（如病毒感染、糖尿病和多发性硬化症）引起，通常在组织损伤消退后持续很长时间。症状因病情而异，但通常是异常性疼痛（对非疼痛刺激的疼痛反应）和/或痛觉过敏（对疼痛刺激的敏感性增加）的表现。周围神经和脊髓的病理变化与慢性疼痛的诱导有关。[1]大脑的变化也有报道，但对这些变化知之甚少。2-4目前可用于神经性疼痛的治疗，包括三环类抗抑郁药和目前的“金标准”加巴喷丁，通常在大多数患者中显示出有限的疗效。[5]大量证据表明，谷氨酸受体的激活在与外周组织和神经损伤相关的疼痛诱导中起主要作用。5，7在正常（伤害性）疼痛的条件下，从脊髓背角中的传入神经元接收的兴奋性信号主要由谷氨酸受体的快速失活的红藻氨酸和AMPAa亚型介导。然而，更长时间和强度的疼痛刺激导致累积的、延长的、缓慢去极化的突触电位，其将谷氨酸受体的N-甲基-D-天冬氨酸（NMDA）亚型从其被Mg 2+离子的强直性阻断中释放。NMDA受体的激活加剧了持续的去极化，并有助于增加背角伤害性神经元的放电，这一过程被称为“windup”。NMDA受体在突触可塑性和长时程增强中的作用也是众所周知的。NMDA受体的延长激活可导致细胞信号传导途径的改变，其增强伤害感受神经元对被称为“中枢致敏”的过程集合中的激活的响应性。中枢致敏包括短期可逆成分（如蛋白质的翻译后修饰）和长期成分。认为与神经性疼痛相关的一个这样的长期因素是NMDA受体本身通过上调调节性酪氨酸激酶Src对兴奋性输入的增强的响应。[8]从20世纪80年代后期开始，人们开始寻求NMDA受体拮抗剂来缓解神经性疼痛，当时发现NMDA拮抗剂可抑制“发条”反应。9、10 NMDA受体位于外周组织和脊髓中的神经上，并广泛分布于脑中。涉及局部注射谷氨酸或NMDA，随后通过局部注射NMDA拮抗剂阻断所产生的伤害性行为的研究表明，外周作用的NMDA拮抗剂具有潜在的效用。4.外周注射NMDA拮抗剂可以减轻炎症引起的痛觉过敏。[11]然而，导致神经性疼痛的超敏反应只能部分地用外周的变化来解释。发生在脊髓背角的中枢敏化被广泛认为是导致神经病理性疼痛的途径中的重要事件。因此，中枢作用的NMDA拮抗剂可能需要广谱疗效。然而，对基于NMDA的药物的研究受到许多拮抗剂在剂量下显示拟精神病“PCP样”行为副作用的倾向的阻碍。
Neuropathic pain, generally defined as a chronic pain state resulting from peripheral or central nerve injury, can devastate the lives of patients and their families and friends. The pain, which can result from both acute events (amputation, back injury) and systemic disease states (eg, viral infection, diabetes, and multiple sclerosis), often persists long after tissue injury has subsided. Symptoms vary depending on the condition but are usually the manifestations of allodynia (painful response to nonpainful stimuli) and/or hyperalgesia (increased sensitivity to painful stimuli). Pathological changes to the peripheral nerve (s) and spinal cord have been implicated in the induction of chronic pain. 1 Changes in the brain have also been reported, but less is known about these alterations. 2-4 Currently available treatments for neuropathic pain, including tricyclic antidepressants and the current “gold standard” gabapentin, typically show limited efficacy in the majority of patients. 5 Considerable evidence suggests that activation of glutamate receptors plays a major role in the induction of pain associated with peripheral tissue and nerve injury. 5, 7 Under conditions of normal (nociceptive) pain, the excitatory signal received from afferent neurons in the spinal cord dorsal horn is mediated primarily by the fast-inactivating kainate and AMPAa subtypes of the glutamate receptor. However, painful stimuli of greater duration and intensity result in accumulating, prolonged, slowly depolarizing synaptic potentials that relieve the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor from its tonic block by Mg2+ ions. Activation of NMDA receptors accentuates the sustained depolarization and contributes to an increase in the discharge of dorsal horn nociceptive neurons in a process called “windup”. The NMDA receptor is also wellknown for its roles in synaptic plasticity and long-term potentiation. Prolonged activation of NMDA receptors can lead to modifications in cellular signaling pathways that enhance the responsiveness of the nociceptive neuron to activation in a collection of processes referred to as “central sensitization”. Central sensitization includes both short-term reversible components (such as post-translational modification of proteins) and long-term elements. One such long-term element thought to be associated with neuropathic pain is an enhanced response of the NMDA receptor itself to excitatory input through upregulation of the modulatory tyrosine kinase Src. 8 The pursuit of an NMDA receptor antagonist for the relief of neuropathic pain dates from the late 1980s, when it was shown that NMDA antagonists inhibit the “windup” response. 9, 10 NMDA receptors are located on nerves in peripheral tissues and in the spinal cord and are widely distributed in the brain. Studies involving local injections of glutamate or NMDA and subsequent blockade of the resulting nociceptive behavior by local injections of NMDA antagonists suggest a potential utility for peripherally acting NMDA antagonists. 4 It has been shown that peripherally administered NMDA antagonists can attenuate the hyperalgesia induced by inflammation. 11 However, the hypersensitivity that results in neuropathic pain can only be partially explained by changes in the periphery. The central sensitization that occurs in the spinal dorsal horn is widely held to be an important event in the pathway leading to neuropathic pain. Consequently, centrally acting NMDA antagonists may be required for broad-spectrum efficacy. However, the search for an NMDA-based drug has been hindered by the propensity for many antagonists to display psychotomimetic “PCP-like” behavioral side effects at doses that …