Ambroxol, a Nav 1.8-preferring Na+ channel blocker, effectively suppresses pain symptoms in animal models of chronic, neuropathic and inflammatory pain
Ambroxol, a Nav 1.8-preferring Na+ channel blocker, effectively suppresses pain symptoms in animal models of chronic, neuropathic and inflammatory pain
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DOI：
10.1016/j.neuropharm.2005.08.004
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发表时间：
2005-12-01
影响因子：
4.7
通讯作者：
Weiser, T
中科院分区：
文献类型：
--
作者：
Gaida, W;Klinder, K;Weiser, T
神经性疼痛影响许多患者，今天的治疗还远远不够完美。Nav1.8钠离子通道是由小纤维感觉神经元表达的，是新型镇痛药的有前途的靶点。然而，目前使用的Na+通道阻断剂对该通道亚型仅显示有限的选择性，并且可能导致剂量限制性副作用。最近，发现溶泌剂氨溴索优先抑制Nav1.8通道。我们使用这种化合物作为工具来研究Nav1.8偏好阻滞剂是否可以在动物模型中抑制慢性，神经性和炎症性疼痛的症状。在福尔马林爪模型、两种单神经病模型和一种大鼠单关节炎模型中测试了该药物。比较氨溴索与加巴喷丁的作用。大鼠必须给予1 g/kg剂量的氨溴索，以达到临床使用中达到的血浆水平（用于治疗婴儿和急性呼吸窘迫综合征）。氨溴索（1 g/kg）在急性疼痛模型中的作用很弱，但在所有其他模型中有效减轻了疼痛症状;在某些情况下，它完全逆转了疼痛行为。在大多数情况下，效果比加巴喷丁（100 mg/kg）更明显。这些数据表明，Nav1.8偏好性Na+通道阻滞剂可以在血浆水平有效抑制慢性、神经性和炎性疼痛的各种模型中的疼痛症状，这可以在临床上实现。(c)2005爱思唯尔有限公司保留所有权利。
Neuropathic pain affects many patients, and treatment today is far from being perfect. Nav1.8 Na+ channels, which are expressed by small fibre sensory neurons, are promising targets for novel analgesics. Na+ channel blockers used today, however, show only limited selectivity for this channel subtype, and can cause dose-limiting side effects. Recently, the secretolytic ambroxol was found to preferentially inhibit Nav1.8 channels. We used this compound as a tool to investigate whether a Nav1.8-preferring blocker can suppress symptoms of chronic, neuropathic and inflammatory pain in animal models. The drug was tested in the formalin paw model, two models of mononeuropathy, and a model of monoarthritis in rats. Ambroxol's effects were compared with those of gabapentin. Ambroxol at a dose of 1 g/kg had to be administered to rats to achieve the plasma levels that are reached in clinical use (for the treatment of infant and acute respiratory distress syndrome). Ambroxol (1 g/kg) was only weakly effective in models for acute pain, but effectively reduced pain symptoms in all other models; in some cases it completely reversed pain behaviour. In most cases the effects were more pronounced than those of gabapentin (at 100 mg/kg). These data show that a Nav1.8-preferring Na+ channel blocker can effectively suppress pain symptoms in a variety of models for chronic, neuropathic and inflammatory pain at plasma levels, which can be achieved in the clinic. (c) 2005 Elsevier Ltd. All rights reserved.