Current status and future directions of botulinum neurotoxins for targeting pain processing.
Current status and future directions of botulinum neurotoxins for targeting pain processing.
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DOI：
10.3390/toxins7114519
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发表时间：
2015-11-04
期刊：
影响因子：
4.2
通讯作者：
Ramachandran R
中科院分区：
文献类型：
--
作者：
Pellett S;Yaksh TL;Ramachandran R
目前的证据表明，肉毒杆菌神经毒素（BoNT）A1和B1，局部给予外周组织，如皮肤，肌肉和关节，改变伤害性处理，否则在动物模型和人类炎症或神经损伤启动。最近的数据表明，这种局部递送的BoNTs不仅对感觉传入末梢发挥局部作用，而且还转运到中枢传入细胞体（背根神经节）和脊髓背角末梢，在那里它们切割SNARE并阻断递质释放。越来越多的证据支持跨突触运动改变神经元和可能的非神经元（神经胶质）细胞的突触后功能的可能性。这些研究中的绝大多数是在BoNT/A1和BoNT/B1上进行的，这是仅有的两种药物开发的变体。然而，现在已经鉴定出超过40种不同亚型的肉毒杆菌神经毒素（BoNT）。通过结合我们现有的和快速增长的了解BoNT/A1和/B1在改变伤害性处理与探索的具体特点，从这个家庭的各种毒素，我们可能能够发现或设计新的，有效的，和持久的疼痛治疗。这篇综述将集中在我们目前了解的分子机制，使BoNTs改变疼痛处理，以及未来的发展方向，这些药物作为疼痛治疗。
Current evidence suggests that botulinum neurotoxins (BoNTs) A1 and B1, given locally into peripheral tissues such as skin, muscles, and joints, alter nociceptive processing otherwise initiated by inflammation or nerve injury in animal models and humans. Recent data indicate that such locally delivered BoNTs exert not only local action on sensory afferent terminals but undergo transport to central afferent cell bodies (dorsal root ganglia) and spinal dorsal horn terminals, where they cleave SNAREs and block transmitter release. Increasing evidence supports the possibility of a trans-synaptic movement to alter postsynaptic function in neuronal and possibly non-neuronal (glial) cells. The vast majority of these studies have been conducted on BoNT/A1 and BoNT/B1, the only two pharmaceutically developed variants. However, now over 40 different subtypes of botulinum neurotoxins (BoNTs) have been identified. By combining our existing and rapidly growing understanding of BoNT/A1 and /B1 in altering nociceptive processing with explorations of the specific characteristics of the various toxins from this family, we may be able to discover or design novel, effective, and long-lasting pain therapeutics. This review will focus on our current understanding of the molecular mechanisms whereby BoNTs alter pain processing, and future directions in the development of these agents as pain therapeutics.