A Novel Approach for Chronic Pain Treatment Using Resiniferatoxin

描述（由申请人提供）：一种瞬时受体电位香草样蛋白1 （TRPV1）的强效激动剂，具有独特的特性，可用于治疗慢性疼痛。TRPV1是一种Ca2+可渗透的非选择性阳离子通道，可被物理和化学刺激激活并介导炎症性热感觉。目前，通过对不同拮抗剂的评价，该受体被认为是镇痛药的靶点。本提案将评估利用RTX的激动性活性来抑制伤害性神经传递的方法。在本提案中，我们将使用脊髓切片制备，验证RTX在短期内通过激活突触前TRPV1并引起去极化阻断来抑制突触传递的假设，从而减少伤害性传递。然后，通过行为学研究，我们将验证这样的假设，即从长期来看，鞘内给药RTX减轻了伤害性炎症性疼痛，这种效果可能是由于过量的Ca2+内流导致表达TRPV1的神经末梢消融。鞘内给药RTX选择性地影响脊髓感觉神经元表达TRPV1的神经末梢，而不影响背根神经节（DRG）神经元。由于TRPV1表达的DRG神经元还具有其他传出功能，因此完整的DRG可以保留炎症和神经/血管活性物质的释放。初步和已发表的研究结果表明，RTX引起TRPV1缓慢而持续的激活，导致神经末梢去极化和突触传递抑制。此外，鞘内给药RTX可促进脊髓背角（DH）注射部位感觉神经元中枢末端TRPV1表达的选择性和局部消融，并在行为模型中导致持续的疼痛缓解。这些研究将增强我们对中枢TRPV1在伤害性传递中的作用的理解。RTX对含有伤害性神经末梢的TRPV1的选择性作用是一种可能的策略，可用于治疗由内脏和骨骼恶性肿瘤引起的大且难以接近的区域引起的慢性、衰弱性和终末期疼痛。公共卫生相关性：难治性慢性疼痛是一个主要问题，特别是在绝症患者。吗啡是目前唯一可用的治疗方法，但会产生严重的副作用，从镇静到呼吸抑制，导致过早死亡。树脂素毒素（RTX）是一种瞬时受体电位香草样蛋白1 （TRPV1）的强效激动剂，具有独特的特性，可用于治疗慢性疼痛。鞘内给药RTX有效和选择性地激活TRPV1，导致短期中枢神经末梢的去极化阻滞，长期在脊髓水平上消融包含感觉神经元中枢神经末梢的TRPV1。由于RTX的作用对中枢神经末梢具有选择性，因此可以保留其他神经元功能。这些包括DRG神经元的外周传出功能，如通过trpv1介导的炎症和神经/血管活性物质的释放来调节微血管循环。最后，使用RTX在脊髓水平上预防伤害性传递将是一种有用的策略，用于治疗由大而难以进入的区域（如内脏和骨骼的恶性肿瘤）引起的慢性、衰弱性和难治性疼痛。

Description (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Refractory chronic pain is a major problem especially in terminally ill patients. Treatment with morphine is currently the only available option, which causes significant side effects, ranging from sedation to respiratory depression leading to premature death. Resiniferatoxin (RTX), a potent agonist of Transient Receptor Potential Vanilloid 1 (TRPV1) exhibits unique properties that can be utilized to treat chronic pain conditions. Intrathecal administration of RTX potently and selectively activates TRPV1 causing a depolarization block of the central nerve terminals in the short-term, and ablating TRPV1 containing central nerve terminals of the sensory neuron in the long-term at the level of the spinal cord. Since RTX action is selective to the central nerve terminals, other neuronal functions can be preserved. These include the peripheral efferent functions of DRG neurons, such as the regulation of microvascular circulation by TRPV1-mediated release of inflammatory and neuro/vasoactive agents. Finally, preventing nociceptive transmission at the level of the spinal cord using RTX will be a useful strategy in chronic, debilitating and intractable pain arising from large and inaccessible areas, such as malignancies of internal organs and bone.