A Novel Approach for Chronic Pain Treatment Using Resiniferatoxin

一种新的治疗慢性疼痛的方法--使用树脂毒素 树脂毒素（RTX）是瞬时受体电位香草酸1（TRPV 1）的有效激动剂， 独特的性能，可用于治疗慢性疼痛状况。TRPV 1是一种Ca 2+可渗透的， 非选择性阳离子通道，被物理和化学刺激激活，介导炎症 热感觉目前，该受体被认为是镇痛剂的靶点，通过 评价不同的拮抗剂。该提案将评估一种利用以下激动活性的方法： RTX抑制伤害性神经传递。在这个建议中，使用脊髓切片制备，我们将 测试这一假设，即在短期内，RTX的管理抑制突触传递，通过激活 突触前TRPV 1和引起去极化阻滞，从而减少伤害性传递。然后， 通过行为学研究，我们将检验以下假设：在长期鞘内注射RTX的情况下， 减轻伤害性炎性疼痛，其作用可能是由于TRPV 1表达的消融。 神经末梢由于过量的Ca 2+流入。选择性鞘内注射RTX 影响脊髓感觉神经元的TRPV 1表达神经末梢，而不影响脊髓感觉神经元的神经末梢。 背根神经节（DRG）神经元。由于表达TRPV 1的DRG神经元履行其他传出功能， 炎性和神经/血管活性物质的释放可以被完整的DRG保存。 初步/已发表的结果表明，RTX导致TRPV 1缓慢而持续的激活， 神经末梢去极化和突触传递的抑制。此外，鞘内 RTX的施用促进TRPV 1表达的中枢终末的选择性和局部消融， 感觉神经元在注射部位的背角（DH），并导致持续的疼痛缓解， 行为模型这些研究将增强我们对中央TRPV 1在以下方面的作用的理解： 伤害性传递RTX对含有TRPV 1的伤害性神经末梢的选择性作用是 一种可能的策略，以考虑治疗慢性，衰弱和终端疼痛的条件所产生的 由于内脏和骨骼的恶性肿瘤，大面积和难以接近的区域。

A NOVEL APPROACH FOR CHRONIC PAIN TREATMENT USING RESINIFERATOXIN Resiniferatoxin (RTX), a potent agonist of Transient Receptor Potential Vanilloid 1 (TRPV1), exhibits unique properties that can be utilized to treat chronic pain conditions. TRPV1, a Ca2+ permeable, nonselective cation channel, is activated by physical and chemical stimuli and mediates inflammatory thermal sensation. Presently, this receptor is being considered as a target for analgesics through the evaluation of different antagonists. This proposal will evaluate an approach utilizing agonistic activity of RTX to inhibit nociceptive neurotransmission. In this proposal, using spinal cord slice preparation, we will test the hypothesis that in the short-term, administration of RTX inhibits synaptic transmission by activating presynaptic TRPV1 and causing a depolarization block, thus reducing nociceptive transmission. Then, using behavioral studies, we will test the hypothesis that in the long-term, intrathecal administration of RTX alleviates nociceptive inflammatory pain and the effect is likely to be due to ablation of TRPV1 expressing nerve terminals as a result of the excessive Ca2+ influx. The intrathecal administration of RTX selectively affects TRPV1 expressing nerve terminals of the sensory neurons at the spinal cord without affecting the dorsal root ganglion (DRG) neurons. Since TRPV1 expressing DRG neurons fulfill other efferent functions, the release of inflammatory and neuro/vasoactive substances can be preserved by the intact DRG. Preliminary/published results indicate that RTX causes a slow and sustained activation of TRPV1 leading to nerve terminal depolarization and depression of synaptic transmission. Further, intrathecal administration of RTX promotes a selective and localized ablation of TRPV1 expressing central terminals of sensory neurons at the injection site in the dorsal horn (DH), and leads to sustained pain relief in behavioral models. These studies will enhance our understanding of the role of central TRPV1 in nociceptive transmission. The selective action of RTX on TRPV1 containing nociceptive nerve terminals is a possible strategy to consider for treating chronic, debilitating and terminal pain conditions arising from large and inaccessible areas, due to malignancies of internal organs and bone.