Deletion of vanilloid receptor 1-expressing primary afferent neurons for pain control.
Deletion of vanilloid receptor 1-expressing primary afferent neurons for pain control.
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DOI：
10.1172/jci20449
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发表时间：
2004-05
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影响因子：
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通讯作者：
L. Kárai;D. Brown;A. Mannes;S. T. Connelly;Jacob D. Brown;M. Gandal;O. Wellisch;J. Neubert;Z. Oláh;M. Iadarola
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文献类型：
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作者：
L. Kárai;D. Brown;A. Mannes;S. T. Connelly;Jacob D. Brown;M. Gandal;O. Wellisch;J. Neubert;Z. Oláh;M. Iadarola
对癌症、神经性疼痛和术后疼痛的控制常常不充分或受到使人衰弱的副作用的影响。抑制或去除某些伤害性神经元，同时保留所有其他感觉形式和运动功能，将代表一种新的治疗方法来控制严重疼痛。瞬时受体电位阳离子通道，亚家族V，成员1（TRPV 1;也称为香草素受体，VR 1）在背根和三叉神经节的伤害感受神经元的丰富表达，使我们能够测试这一概念。给神经元胞体施用有效的TRPV 1激动剂树脂毒素（RTX）通过打开TRPV 1离子通道并选择性地消融伤害感受神经元来诱导钙细胞毒性。这种治疗阻断大鼠实验性炎性痛觉过敏和神经源性炎症以及犬自然发生的癌症和使人衰弱的关节炎疼痛。这两个物种的触觉、本体感受和高阈值机械敏感性伤害感受以及运动功能都保持完整。在针对术后疼痛控制的单独实验中，皮下施用RTX短暂破坏伤害性神经末梢，产生可逆镇痛。在人背根神经节培养物中，RTX诱导香草酸敏感神经元细胞内钙的长期增加，而使其他相邻神经元不受影响。结果表明，伤害性神经元或神经末梢的删除将是有效的和广泛适用的疼痛管理的策略。
Control of cancer, neuropathic, and postoperative pain is frequently inadequate or compromised by debilitating side effects. Inhibition or removal of certain nociceptive neurons, while retaining all other sensory modalities and motor function, would represent a new therapeutic approach to control severe pain. The enriched expression of transient receptor potential cation channel, subfamily V, member 1 (TRPV1; also known as the vanilloid receptor, VR1) in nociceptive neurons of the dorsal root and trigeminal ganglia allowed us to test this concept. Administration of the potent TRPV1 agonist resiniferatoxin (RTX) to neuronal perikarya induces calcium cytotoxicity by opening the TRPV1 ion channel and selectively ablates nociceptive neurons. This treatment blocks experimental inflammatory hyperalgesia and neurogenic inflammation in rats and naturally occurring cancer and debilitating arthritic pain in dogs. Sensations of touch, proprioception, and high-threshold mechanosensitive nociception, as well as locomotor function, remained intact in both species. In separate experiments directed at postoperative pain control, subcutaneous administration of RTX transiently disrupted nociceptive nerve endings, yielding reversible analgesia. In human dorsal root ganglion cultures, RTX induced a prolonged increase in intracellular calcium in vanilloid-sensitive neurons, while leaving other, adjacent neurons unaffected. The results suggest that nociceptive neuronal or nerve terminal deletion will be effective and broadly applicable as strategies for pain management.