Spinal Neurokinin and Opioid Release in Nociception

伤害感受中的脊髓神经激肽和阿片类药物释放

• 批准号: 6922375
• 负责人: Juan Carlos Garcia Marvizon
• 金额: $ 21.25万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6922375
• 关键词: GABA receptor; adrenergic receptor; cannabinoid receptor; dorsal horn; endogenous opioid; immunocytochemistry; immunologic assay /test; laboratory mouse; laboratory rat; neuropeptide receptor; neuropeptides; neuropharmacology; neurophysiology; neurotransmitter transport; opioid receptor; pain; periaqueductal gray matter; pons; receptor binding; stimulus /response; substance K; substance P; tachykinin; tissue /cell culture

DESCRIPTION (provided by applicant): The use of opiates to treat pain is a significant cause of addiction, but there are no adequate alternatives. Neurokinins and opioids are two neuropeptides important in acute and chronic pain; hence mechanisms that control their release in the spinal cord could be targets for the development of new analgesics. Neurokinin release from primary afferent terminals appears to be inhibited by muopioid, cannabinoid, alpha2 adrenergic and GABAB receptors, but their mechanisms of action, relative efficacy and physiological relevance have not been established. Receptors that modulate spinal opioid release are virtually unknown. Long term objectives: A) to create a model integrating the actions of receptors that control neurokinin release from primary afferents; B) to understand how different physiological states determine the release of opioids in the spinal cord, identifying the neural pathways and neurotransmitter systems involved. Specific Aims: 1) to determine whether opioid, cannabinoid, adrenergic and GABAB receptors inhibit neurokinin release from primary afferent terminals using a common signalling pathway; 2) to identify neurotransmitter systems that inhibit opioid release in the dorsal horn; 3) to identify neuronal pathways that evoke opioid release in the dorsal horn. Research Design: Rat spinal cord slices will be electrically stimulated at the dorsal root to evoke neurokinin release, or at the dorsal horn or the dorsolateral funiculus to evoke opioid release. Internalization of neurokinin 1 receptors and mu-opioid receptors will be used to measure neurokinin and opioid release, respectively. This will be validated using immunoassays and transgenic mice. In vivo experiments will compare the effect of drugs on behavioral pain responses and receptor internalization in the dorsal horn. They will also determine whether noxious stimuli or stimulation of the periaqueductal gray or the nucleus raphe magnus produce mu-opioid receptor internalization in the spinal cord. The neural pathways involved will be studied using selective spinal cord lesions.

描述（由申请人提供）：使用阿片类药物治疗疼痛是成瘾的一个重要原因，但没有足够的替代品。神经激肽和阿片类药物是两种对急性和慢性疼痛很重要的神经肽。因此，控制它们在脊髓中释放的机制可能成为开发新镇痛药的目标。初级传入末梢的神经激肽释放似乎受到 muopioid、大麻素、α2 肾上腺素能和 GABAB 受体的抑制，但其作用机制、相对功效和生理相关性尚未确定。调节脊髓阿片类药物释放的受体实际上是未知的。长期目标：A) 创建一个模型，整合控制初级传入神经激肽释放的受体的作用； B) 了解不同的生理状态如何决定脊髓中阿片类药物的释放，识别所涉及的神经通路和神经递质系统。具体目标： 1) 确定阿片类、大麻类、肾上腺素能和 GABAB 受体是否使用共同的信号通路抑制初级传入末梢神经激肽的释放； 2）确定抑制背角阿片类药物释放的神经递质系统； 3）确定引起背角阿片类药物释放的神经元通路。研究设计：大鼠脊髓切片将在背根处受到电刺激以引起神经激肽释放，或在背角或背外侧索处受到电刺激以引起阿片类药物释放。神经激肽 1 受体和 mu-阿片受体的内化将分别用于测量神经激肽和阿片类药物的释放。这将使用免疫测定和转基因小鼠进行验证。体内实验将比较药物对行为疼痛反应和背角受体内化的影响。他们还将确定有害刺激或对导水管周围灰质或中缝大核的刺激是否会在脊髓中产生μ阿片受体内化。将使用选择性脊髓损伤来研究所涉及的神经通路。