MOR expressing neurons in pain and morphine analgesia

MOR 表达神经元在疼痛和吗啡镇痛中的作用

• 批准号: 6668493
• 负责人: RONALD Gordon WILEY
• 金额: $ 12.6万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6668493
• 关键词: analgesia; apoptosis; behavior test; confocal scanning microscopy; dorsal horn; fluorescence microscopy; immunocytochemistry; in situ hybridization; laboratory rat; messenger RNA; morphine; neurons; neurotoxins; oligopeptides; opioid receptor; pain; protein structure function

DESCRIPTION (provided by applicant): The use of neuropeptide-targeted cytotoxins to make selective neural lesions has achieved one noteworthy success in pain research to date, substance P-saporin. The general applicability of this first success in unknown, the present proposal seeks to extend this approach to target neurons that express the mu opiate receptor (MOR) using a targeted toxin composed of the mu opiate peptide, dermorphin, to target the ribosome inactivating protein, saporin, selectively into neurons expressing MOR. There are numerous locations with putative central nervous system pain circuits where neurons express MOR. The site chosen in the present proposal is the substantia gelatinosa of the spinal cord dorsal horn. The goals of the present proposal are to determine if dermorphin-saporin has the desired targeting capability, to destroy MOR-expressing neurons, and to determine the effect of intrathecal dermorphin-saporin on pain perception using two thermal algesia assays, one reflex and one operant. Toxin will be administered into the lumbar subarachnoid space, and anatomic studies will determine the extent and specificity of the lesion. Thermal algesia testing will determine if the lesion differentially affects responses to high and low intensity noxious heat and if the lesion affects the analgesic potency of intrathecal morphine. Results of these experiments will establish if dermorphin-saporin is effective and selective in vivo, and if selective destruction of lamina II MOR-expressing neurons alters pain perception or the analgesic effects of intrathecal morphine. Many valuable future experiments and clinical applications may be possible if dermorphin-saporin proves effective.

描述（由申请人提供）：使用靶向神经肽的细胞毒素使选择性神经病变的使用已在迄今为止疼痛研究中取得了一个值得注意的成功，Persance p-saporin p-saporin。本提案在未知中的首次成功的一般适用性，试图将这种方法扩展到靶向神经元的靶向神经元，该神经元使用由Mu opepiate肽染色体组成的靶向毒素靶向核糖体灭活蛋白质，saporin，saporin，saporin，选择性地表达神经元。有许多位置，具有假定的中枢神经系统疼痛回路，神经元表达MOR。本提案中选择的位置是脊髓背角的质质明胶。本提案的目标是确定皮肤球蛋白是否具有所需的靶向能力，破坏表达神经元的神经元，并确定使用两种热质量测定法，一个反射和一个操作者，确定鞘内皮肤甲帕蛋白对疼痛感知的影响。毒素将被施用到腰蛛网膜下腔中，解剖学研究将决定病变的程度和特异性。热层测试将确定病变是否会差异地影响对高强度和低强度有害热的反应，以及病变是否影响鞘内吗啡的镇痛效力。这些实验的结果将确定皮肤嘌呤 - 六泊蛋白是在体内有效且有选择性的，并且是否有选择性地破坏了表达神经元的神经元的结果，会改变疼痛感知或胸膜内吗啡的镇痛作用。如果证明有效，可能会有许多有价值的未来实验和临床应用。