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: 8267070
• 负责人: LOUIS S PREMKUMAR
• 金额: $ 26.55万
• 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/8267070
• 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' 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

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.

一种使用树脂干扰素治疗慢性疼痛的新方法