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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

基本信息

批准号：
8473195
负责人：
LOUIS S PREMKUMAR
金额：
$ 25.49万
依托单位：
SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8473195
关键词：
Ablation 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 Depressed mood Effectiveness Esthesia Evaluation Exhibits Formalin Frequencies Freund&apos 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 receptor research study restoration sciatic nerve spontaneous pain synaptic failure tibia transmission process vasoactive agent

项目摘要

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.

使用树脂毒素治疗慢性疼痛的新方法树脂毒素 (RTX) 是瞬时受体电位香草酸 1 (TRPV1) 的有效激动剂可用于治疗慢性疼痛的独特特性。 TRPV1，Ca2+ 渗透性，非选择性阳离子通道，被物理和化学刺激激活并介导炎症热感觉。目前，该受体被认为是镇痛药的靶点不同拮抗剂的评价该提案将评估一种利用竞争性活动的方法 RTX 抑制伤害性神经传递。在这个提案中，使用脊髓切片制备，我们将检验以下假设：在短期内，RTX 的给药通过激活突触传递来抑制突触传递突触前 TRPV1 并引起去极化阻滞，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 减轻伤害性炎症疼痛，其效果可能是由于 TRPV1 表达的消融过量 Ca2+ 流入导致的神经末梢。 RTX选择性鞘内给药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，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，从而导致神经末梢去极化和突触传递抑制。此外，鞘内 RTX的施用促进TRPV1表达中央末端的选择性和局部消融背角（DH）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 TRPV1 中枢作用的理解伤害性传播。 RTX 对含有伤害性神经末梢的 TRPV1 的选择性作用是一种可以考虑治疗慢性、衰弱性和终末期疼痛的策略由于内脏器官和骨骼的恶性肿瘤，导致大而难以到达的区域。