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: 6572683
• 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/6572683
• 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）：迄今为止，使用神经肽靶向细胞毒素来制造选择性神经损伤在疼痛研究中取得了一项值得注意的成功，即物质P-皂草素。这一首次成功的普遍适用性尚不清楚，本提案试图将这种方法扩展到表达 mu 阿片受体 (MOR) 的目标神经元，使用由 mu 阿片肽、皮吗啡组成的靶向毒素来靶向核糖体失活蛋白，皂草素，选择性地进入表达 MOR 的神经元。假定中枢神经系统疼痛回路的许多位置神经元都表达 MOR。本提案中选择的部位是脊髓背角的胶质质。本提案的目标是确定 dermorphin-saporin 是否具有所需的靶向能力，破坏 MOR 表达神经元，并使用两种热痛觉测定（一种反射和一种操作）确定鞘内 dermorphin-saporin 对疼痛感知的影响。毒素将被注入腰椎蛛网膜下腔，解剖学研究将确定病变的范围和特异性。热痛觉测试将确定病变是否不同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吗啡皂苷在体内是否有效且具有选择性，以及选择性破坏表达 MOR 的层板 II 神经元是否会改变疼痛感知或鞘内吗啡的镇痛效果。如果皮吗啡皂素被证明是有效的，许多有价值的未来实验和临床应用可能是可能的。