A Novel Approach for Chronic Pain Treatment Using Resiniferatoxin

使用树脂毒素治疗慢性疼痛的新方法

• 批准号: 7869275
• 负责人: LOUIS S PREMKUMAR
• 金额: $ 27.37万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7869275
• 关键词: Ablation; Acute; Acute Pain; Adverse effects; Affect; Afferent Neurons; Agonist; Amides; Analgesics; Animal Model; Animals; Area; Behavior; Behavioral; Behavioral Model; Binding; Blood Circulation; Canis familiaris; Capsaicin; Carrageenan; Cations; Cessation of life; Chemicals; Chronic; Chronic inflammatory pain; Depressed mood; Effectiveness; Esthesia; Evaluation; Exhibits; Formalin; Frequencies; Freund' s Adjuvant; Hyperalgesia; Hypersensitivity; Immunohistochemistry; Inflammation; Inflammatory; Infusion procedures; Injection of therapeutic agent; Injury; Intractable Pain; Intrathecal Injections; Label; Ligation; Long-Term Effects; Malignant Bone Neoplasm; Malignant Epithelial Cell; Malignant Neoplasms; Mammary gland; Mechanics; Mediating; Mental Depression; Modeling; Morphine; Natural regeneration; Nerve; Neurons; Nociception; Organ; Pain; Patients; Peripheral; Preparation; Property; Publishing; Pump; Rat-1; Rattus; Refractory; Regulation; Resiniferatoxin; Role; Sedation procedure; Site; Skin; Slice; Spinal Cord; Spinal Ganglia; Staining method; Stains; Stimulus; Streptozocin; Synapses; Synaptic Transmission; Techniques; Terminally Ill; Testing; Vanilloid; Ventilatory Depression; bone; cancer pain; chronic neuropathic pain; chronic pain; constriction; diabetic; dorsal horn; inflammatory pain; neurotransmission; novel strategies; osteosarcoma; pain behavior; premature; presynaptic; prevent; public health relevance; receptor; research study; restoration; sciatic nerve; spontaneous pain; synaptic failure; tibia; transmission process; vasoactive agent

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.

描述（由申请人提供）：瞬时受体电位香草酸 1 (TRPV1) 的有效激动剂，具有独特的特性，可用于治疗慢性疼痛。 TRPV1 是一种 Ca2+ 渗透性、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热感觉。目前，通过评估不同的拮抗剂，该受体被认为是镇痛药的靶点。该提案将评估一种利用 RTX 的激动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来测试以下假设：在短期内，RTX 的给药通过激活突触前 TRPV1 并引起去极化阻滞来抑制突触传递，从而减少伤害性传递。然后，通过行为研究，我们将检验以下假设：长期鞘内注射 RTX 可减轻伤害性炎症疼痛，其效果可能是由于过量 Ca2+ 流入导致 TRPV1 表达神经末梢消融所致。鞘内注射 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。由于表达 TRPV1 的 DRG 神经元履行其他传出功能，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/已发表的结果表明，RTX 会导致 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，鞘内注射 RTX 可促进背角 (DH) 注射部位感觉神经元中央末端表达 TRPV1 的选择性和局部消融，并导致行为模型中的持续疼痛缓解。这些研究将加深我们对中枢 TRPV1 在伤害性传播中的作用的理解。 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，用于治疗由于内脏器官和骨骼的恶性肿瘤而导致大而难以接近的区域引起的慢性、衰弱性和末期疼痛。公共卫生相关性：难治性慢性疼痛是一个主要问题，尤其是对于绝症患者。吗啡治疗是目前唯一可用的选择，会导致严重的副作用，包括镇静作用和呼吸抑制，导致过早死亡。树脂毒素 (RTX) 是瞬时受体电位香草酸 1 (TRPV1) 的有效激动剂，具有独特的特性，可用于治疗慢性疼痛。鞘内注射RTX可有效且选择性地激活TRPV1，在短期内引起中枢神经末梢的去极化阻滞，并在长期内消融含有感觉神经元中枢神经末梢的TRPV1。由于 RTX 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，例如通过 TRPV1 介导的炎症和神经/血管活性剂的释放来调节微血管循环。最后，使用 RTX 预防脊髓水平的伤害性传播将是治疗因大而难以接近的区域（例如内脏器官和骨骼的恶性肿瘤）引起的慢性、衰弱性和顽固性疼痛的有效策略。