Neurobiology and Pain Therapeutics Section, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda MD 20892, USA.
Curr Top Med Chem. 2011;11(17):2171-9. doi: 10.2174/156802611796904942.
The idea of selectively targeting nociceptive transmission at the level of the peripheral nervous system is attractive from multiple perspectives, particularly the potential lack of non-specific (non-targeted) CNS side effects. Out of the multiple TRP channels involved in nociception, TRPV1 is a strong candidate based on its biophysical conductance properties and its expression in inflammation-sensitive dorsal root ganglion neurons and their axons and central and peripheral nerve terminals. While TRPV1 antagonists have undergone extensive medicinal chemical and pharmacological investigation, for TRPV1 agonists nature has provided an optimized compound in RTX. RTX is not suitable for systemic administration, but it is highly adaptable to a variety of pain problems when used by local administration. This can include routes as diverse as subcutaneous, intraganglionic or intrathecal (CSF space around the spinal cord). The present review focuses on the molecular and preclinical animal experiments that form the underpinnings of our clinical trial of intrathecal RTX for pain in advanced cancer. As such this represents a new approach to pain control that emerges from a long line of research on capsaicin and other vanilloids, their physiological actions, and the molecular biology of the capsaicin receptor TRPV1.
从多个角度来看，选择性靶向外周神经系统中伤害性传递的想法很有吸引力，特别是潜在的缺乏非特异性（非靶向）中枢神经系统副作用。在涉及伤害感受的多个瞬时受体电位 (TRP) 通道中， TRPV1 是一个强有力的候选者，因为它具有生物物理电导特性，并且在炎症敏感的背根神经节神经元及其轴突以及中枢和外周神经末梢中表达。虽然 TRPV1 拮抗剂已经经过广泛的药物化学和药理学研究，但对于 TRPV1 激动剂，自然界在 RTX 中提供了一种优化的化合物。RTX 不适合全身给药，但当通过局部给药使用时，它非常适合各种疼痛问题。这可以包括皮下、神经节内或鞘内（脊髓周围的脑脊液空间）等多种途径。本综述重点介绍了构成我们晚期癌症鞘内 RTX 疼痛临床试验基础的分子和临床前动物实验。因此，这代表了一种从辣椒素和其他香草素、它们的生理作用以及辣椒素受体 TRPV1 的分子生物学的长期研究中涌现出来的新的疼痛控制方法。
