Intrathecal α-conotoxins Vc1.1, AuIB and MII acting on distinct nicotinic receptor subtypes reverse signs of neuropathic pain
Intrathecal α-conotoxins Vc1.1, AuIB and MII acting on distinct nicotinic receptor subtypes reverse signs of neuropathic pain
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DOI：
10.1016/j.neuropharm.2012.01.016
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发表时间：
2012-06-01
影响因子：
4.7
通讯作者：
Christie, M. J.
中科院分区：
文献类型：
--
作者：
Napier, I. A.;Klimis, H.;Christie, M. J.
来自有毒生物的肽的巨大多样性与参与神经性疼痛的发展和维持的分子具有高亲和力，导致了毒液衍生镇痛剂研究的激增。来自芋螺的α-芋螺毒素家族的一些成员特异性靶向烟碱乙酰胆碱受体（nAChR）的亚型，已显示在神经性疼痛模型中有效减少机械性异常性疼痛。我们试图确定在大鼠神经性疼痛模型中鞘内给药后三种这样的肽Vc1.1、AuIB和MII是否有效，因为它们对α-芋螺毒素的主要推定疼痛缓解靶点表现出不同的亲和力。鞘内给药α-芋螺毒素，VC1.1，AuIB和MII到神经病大鼠减少机械异常性疼痛长达6小时，没有显着的副作用。初级传入突触传递的体外膜片钳电生理学显示，这些毒素的作用模式不是通过GABA（B）依赖性机制，更可能与它们对含有α 3、α 7或其他亚基组合的nAChRs的作用有关。因此，鞘内nAChR亚基选择性芋螺毒素是有效治疗神经病理性疼痛的有前途的工具。(C)2012爱思唯尔有限公司保留所有权利。
The large diversity of peptides from venomous creatures with high affinity for molecules involved in the development and maintenance of neuropathic pain has led to a surge in venom-derived analgesic research. Some members of the alpha-conotoxin family from Conus snails which specifically target subtypes of nicotinic acetylcholine receptors (nAChR) have been shown to be effective at reducing mechanical allodynia in neuropathic pain models. We sought to determine if three such peptides, Vc1.1, AuIB and MII were effective following intrathecal administration in a rat neuropathic pain model because they exhibit different affinities for the major putative pain relieving targets of alpha-conotoxins. Intrathecal administration of alpha-conotoxins, Vc1.1, AuIB and MII into neuropathic rats reduced mechanical allodynia for up to 6 h without significant side effects. In vitro patch-clamp electrophysiology of primary afferent synaptic transmission revealed the mode of action of these toxins was not via a GABA(B)-dependant mechanism, and is more likely related to their action at nAChRs containing combinations of alpha 3, alpha 7 or other subunits. Intrathecal nAChR subunit-selective conotoxins are therefore promising tools for the effective treatment of neuropathic pain. (C) 2012 Elsevier Ltd. All rights reserved.