Circuitry and Molecular Mechanisms for Descending Pain Facilitation

下行疼痛促进的电路和分子机制

• 批准号: 10565197
• 负责人: Xiaoke Chen
• 金额: $ 44.82万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10565197
• 关键词: Adult; Affect; American; Analgesics; Automobile Driving; Brain; Brain Stem; Calcium; Cell Nucleus; Cells; Chronic; Classification; Cognitive; Dependovirus; Development; Enterobacteria phage P1 Cre recombinase; Genes; Genetic; Individual; Infusion procedures; Injury; Knock-in Mouse; Lateral; Maintenance; Mechanics; Molecular; Moods; Morphine; Mus; Neural Pathways; Neurons; Neuropeptides; Nociception; Nociceptive Stimulus; Opioid; Opioid Receptor; Overdose; Pain; Pathway interactions; Persistent pain; Play; Rabies virus; RiboTag; Role; Spinal Cord; Testing; Therapeutic; Viral; cellular targeting; chronic pain; chronic pain management; experimental study; global health; interest; knock-down; mechanical allodynia; mechanical drive; mutant; nerve injury; non-opioid analgesic; novel; opioid epidemic; painful neuropathy; prevent; rabies viral tracing; receptor; recruit; response; spared nerve; superior colliculus Corpora quadrigemina; tissue injury; tool; transmission process

Abstract Chronic pain is a pervasive global health issue affecting about 20% of individuals worldwide, but available treatments for chronic pain are still inadequate. Opiates have been used for centuries as potent analgesics, but issues with tolerance, abuse, and overdose have contributed to current opioid crisis in the US. On the other hand, it is well documented that the level of perceived pain can be strongly influenced by cognitive and mood states, revealing the existence of powerful endogenous top-down modulation of pain. However, the therapeutic potential of targeting descending pain modulation pathway in treating chronic pain has not been extensively explored, in a large part because of our poor understanding of the circuitry and molecular mechanisms underlying how these descending pathways engage in chronic pain. In our preliminary studies, we developed novel genetic and viral tools, and gained robust access to the -opioid receptor expressing spinal cord projecting neurons in the rostroventral medulla (OPRM+ RVMSC neurons). We demonstrated that the OPRM+ RVMSC neurons has limited contribution to normal nociception but is required for both initiation and maintenance of nerve injury induced chronic mechanical pain. We therefore established these neurons as a potent cellular target for treating chronic pain. In this proposal, we will further examine the circuitry (Aim1) and molecular (Aim2) mechanisms that engage the OPRM+ RVMSC neurons in chronic pain. These proposed studies will not only advance our understanding of how the OPRM+ RVMSC neurons is recruited in chronic pain, but also inspire the development of novel non-opioid treatment for chronic pain.

摘要 慢性疼痛是一个普遍的全球性健康问题，影响着全球约20%的人， 对慢性疼痛的治疗仍然不足。阿片类药物作为强效镇痛药已经使用了几个世纪， 耐受性，滥用和过量的问题导致了美国目前的阿片类药物危机。另 一方面，有充分的证据表明，感知疼痛的水平可以受到认知和情绪的强烈影响 国家，揭示了强大的内源性自上而下的疼痛调制的存在。但 靶向下行疼痛调节通路在治疗慢性疼痛中的治疗潜力还没有被 广泛探索，在很大程度上是因为我们对电路和分子的理解不足， 这些下行通路如何参与慢性疼痛的潜在机制。在我们的初步研究中， 我们开发了新的遗传和病毒工具，并获得了强大的获得阿片受体表达， 脊髓前腹侧髓质投射神经元（OPRM+ RVMSC神经元）。我们证明了 OPRM+ RVMSC神经元对正常伤害感受的贡献有限，但对于起始和 维持神经损伤诱发的慢性机械性疼痛。因此，我们将这些神经元建立为 治疗慢性疼痛的有效细胞靶点。在本提案中，我们将进一步检查电路（Aim1）， 在慢性疼痛中参与OPRM+ RVMSC神经元的分子（Aim2）机制。这些拟议 研究不仅将促进我们对OPRM+ RVMSC神经元如何在慢性疼痛中募集的理解， 而且还启发了慢性疼痛的新型非阿片类药物治疗的发展。