法国尼斯大学分子和细胞药物研究所研究人员发现,黑曼巴毒牙里喷出的毒液中含有两种蛋白质,可以让小鼠止住疼痛,并且它的止痛效果和吗啡相当,副作用更小。科学家有望据此研发出新型的止痛药。

-2012年10月25日《自然》


中文翻译


【题目】黑曼巴毒液肽靶向酸敏感性离子通道达到止痛效果

【译文】多肽毒素在理解离子通道的生理学和病理生理学功能中发挥核心作用。在疼痛领域,多肽毒素引发基础研究和临床应用上的重要进展。酸敏感性离子通道(ASICs)通常被认为是疼痛途径中的主要参与者,包括在人类中。一种激活伤害性神经元中外周ASICs的蛇毒素近期被研究表明可以引起疼痛。本研究表明来自另一种蛇黑曼巴中的一类新的三指肽能够通过抑制中枢神经元或外周神经元中表达的ASICs而达到止痛的作用。这些肽,我们称之为曼巴素,在小鼠中无毒,但可以对中枢和外周神经元注射产生一种潜在的镇痛作用,其效果与吗啡一样强。然而,这种效应对纳洛酮耐受,而且曼巴素比吗啡导致的耐受更少,且不会有呼吸性窘迫。通过曼巴素的药理学抑制联合基因敲除动物表明中枢神经元中由ASIC1a 和ASIC2a组成的异侧通道和伤害感受器中含ASIC1b通道的阻断与曼巴素的镇痛作用相关。这些发现为疼痛鉴定了新的潜在治疗靶点,并引进了阻断它们以产生潜在镇痛的自然肽。

英文原稿


[Title]: Black mamba venom peptides target acid-sensing ion channels to abolish pain

 [Authors]:Sylvie Diochot,1, 2, 3, 6 Anne Baron,1, 2, 3, 6 Miguel Salinas,1, 2, 3 Dominique Douguet,1, 2 Sabine Scarzello,1, 2, 7 Anne-Sophie Dabert-Gay,1, 2 Delphine Debayle,1, 2 Valérie Friend,1, 2, 3 Abdelkrim Alloui,4, 5 Michel Lazdunski1, 2 & Eric Lingueglia1, 2, 3

[Abstract]Polypeptide toxins have played a central part in understanding physiological and physiopathological functions of ion channels. In the field of pain, they led to important advances in basic research and even to clinical applications. Acid-sensing ion channels (ASICs) are generally considered principal players in the pain pathway, including in humans. A snake toxin activating peripheral ASICs in nociceptive neurons has been recently shown to evoke pain. Here we show that a new class of three-finger peptides from another snake, the black mamba, is able to abolish pain through inhibition of ASICs expressed either in central or peripheral neurons. These peptides, which we call mambalgins, are not toxic in mice but show a potent analgesic effect upon central and peripheral injection that can be as strong as morphine. This effect is, however, resistant to naloxone, and mambalgins cause much less tolerance than morphine and no respiratory distress. Pharmacological inhibition by mambalgins combined with the use of knockdown and knockout animals indicates that blockade of heteromeric channels made of ASIC1a and ASIC2a subunits in central neurons and of ASIC1b-containing channels in nociceptors is involved in the analgesic effect of mambalgins. These findings identify new potential therapeutic targets for pain and introduce natural peptides that block them to produce a potent analgesia.

原文地址

http://www.nature.com/nature/journal/v490/n7421/full/nature11494.html

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