Bulleyaconitine A depresses neuropathic pain and potentiation at C-fiber synapses in spinal dorsal horn induced by paclitaxel in rats
Bulleyaconitine A depresses neuropathic pain and potentiation at C-fiber synapses in spinal dorsal horn induced by paclitaxel in rats
复制标题
Bulleyaconitine A 抑制紫杉醇诱导的大鼠神经性疼痛和脊髓背角 C 纤维突触增强
DOI：
10.1016/j.expneurol.2015.09.006
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发表时间：
2015-11-01
影响因子：
5.3
通讯作者：
Liu, Xian-Guo
中科院分区：
文献类型：
--
作者：
Zhu, He-Quan;Xu, Jing;Liu, Xian-Guo
紫杉醇是一种广泛使用的化疗药物，常引起疼痛性周围神经病变，目前尚无有效药物可治疗其严重副作用。在这里，我们测试了胃内应用bulleyaconitine A (BLA)是否可以缓解紫杉醇引起的神经性疼痛，该药物自1985年起在中国被批准用于临床治疗慢性疼痛。单剂量的 BLA 可以剂量依赖性地减弱紫杉醇引起的机械异常性疼痛和热痛觉过敏。在紫杉醇治疗期间或之后重复给药（0.4和0.8 mg/kg，t.i.d.，持续7天）对热痛觉过敏产生持久的抑制作用，但对机械异常性疼痛没有抑制作用。与行为结果一致，体内电生理学实验表明，C 纤维而非 A 纤维介导的脊髓突触传递得到增强，并且与未接受紫杉醇治疗的大鼠相比，相同高频刺激诱导的 C 纤维突触的长时程增强 (LTP) 幅度相似，高出 50%。脊髓或静脉注射 BLA 可降低脊髓 LTP，且呈剂量依赖性。此外，脊髓切片中的膜片钳记录显示，在紫杉醇治疗的大鼠中，第二层神经元中自发性兴奋性突触后电流（sEPSC）和微型兴奋性突触后电流（mEPSC）的频率增加，但幅度没有增加，并且BLA的灌注降低了紫杉醇治疗的大鼠中sEPSC和mEPSC的频率，但在幼稚大鼠中则没有。总而言之，我们提供了新的证据，表明 BLA 可以减轻帕紫杉醇引起的神经性疼痛，并且通过抑制突触前递质释放来抑制 C 纤维突触的脊髓 LTP 可能有助于这种效果。 (C) 2015 Elsevier Inc. 保留所有权利。
Paclitaxel, a widely used chemotherapeutic agent, often induces painful peripheral neuropathy and at present no effective drug is available for treatment of the serious side effect. Here, we tested if intragastrical application of bulleyaconitine A (BLA), which has been approved for clinical treatment of chronic pain in China since 1985, could relieve the paclitaxel-induced neuropathic pain. A single dose of BLA attenuated the mechanical allodynia, thermal hyperalgesia induced by paclitaxel dose-dependently. Repetitive administration of the drug (0.4 and 0.8 mg/kg, t.i.d. for 7 d) during or after paclitaxel treatment produced a long-lasting inhibitory effect on thermal hyperalgesia, but not on mechanical allodynia. In consistency with the behavioral results, in vivo electrophysiological experiments revealed that spinal synaptic transmission mediated by C-fiber but not A fiber was potentiated, and the magnitude of long-term potentiation (LTP) at C-fiber synapses induced by the same high frequency stimulation was similar to 50% higher in paclitaxel-treated rats, compared to the naive rats. Spinal or intravenous application of BLA depressed the spinal LTP, dose-dependently. Furthermore, patch clamp recordings in spinal cord slices revealed that the frequency but not amplitude of both spontaneous excitatory postsynaptic current (sEPSCs) and miniature excitatory postsynaptic currents (mEPSCs) in lamina II neurons was increased in paclitaxel-treated rats, and the superfusion of BLA reduced the frequency of sEPSCs and mEPSCs in paclitaxel-treated rats but not in naive ones. Taken together, we provide novel evidence that BLA attenuates paditaxel-induced neuropathic pain and that depression of spinal LTP at C-fiber synapses via inhibiting presynaptic transmitter release may contribute to the effect. (C) 2015 Elsevier Inc. All rights reserved.