A Novel Approach for Chronic Pain Treatment Using Resiniferatoxin

一种使用树脂毒素治疗慢性疼痛的新方法 树脂素(RTX)是一种有效的瞬时受体电位香草素1(TRPV1)激动剂。 独特的特性，可用于治疗慢性疼痛。TRPV1，一种钙离子渗透性， 非选择性阳离子通道，由物理和化学刺激激活，并介导炎症 热感。目前，这种受体被认为是止痛药的靶点，通过 不同拮抗剂的评价。这项提案将评估一种利用激励性活动的方法 RTX抑制伤害性神经传递。在这项提案中，使用脊髓切片准备，我们将 检验这一假设，即短期内，给予RTX通过激活 突触前TRPV1并引起去极化阻断，从而减少伤害性信息的传递。然后, 利用行为学研究，我们将检验长期鞘内给药RTX的假设 减轻伤害性炎症性疼痛，其作用机制可能是通过抑制TRPV1的表达 神经末梢由于钙离子内流过多所致。鞘内选择性给药的RTX 影响脊髓感觉神经元表达TRPV1的神经末梢而不影响 背根节(DRG)神经元。由于表达TRPV1的DRG神经元具有其他传出功能， 完整的背根节可以保护炎性物质和神经/血管活性物质的释放。 初步/已发表的结果表明，RTX导致TRPV1导联缓慢而持续的激活 神经末梢去极化和突触传递抑制。此外，鞘内 应用RTX促进TRPV1表达的中央终末选择性和局部消融 在背角注射部位的感觉神经元，并导致持续的疼痛缓解 行为模型。这些研究将加深我们对中央TRPV1在 伤害性传播。RTX对含有伤害性神经末梢的TRPV1的选择性作用 一种治疗慢性、衰弱和终末期疼痛的可能策略 由于内脏和骨骼的恶性肿瘤而导致的大而难以触及的区域。

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.