Circuitry and Molecular Mechanisms for Descending Pain Facilitation

摘要 慢性疼痛是一个普遍存在的全球健康问题，影响着全球约20%的人，但 对慢性疼痛的治疗仍然不够。几个世纪以来，鸦片类药物一直被用作强效止痛剂，但 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 另一方面，有充分的证据表明，感知到的疼痛程度会受到认知和情绪的强烈影响 状态，揭示了内源性自上而下对疼痛的强大调制的存在。然而， 靶向下行痛觉调制通路治疗慢性疼痛的潜力尚未得到证实 被广泛研究，这在很大程度上是因为我们对电路和分子缺乏了解 这些下行通路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-阿片受体表达途径 延髓嘴腹侧的脊髓投射神经元(OPRM+RVMSC神经元)。我们证明了这一点 OPRM+RVMSC神经元对正常伤害性感觉的贡献有限，但在启动和 维持性神经损伤所致慢性机械性疼痛。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，我们将进一步研究电路(Aim1)和 OPRM+RVMSC神经元参与慢性疼痛的分子(AIM2)机制。这些建议 研究不仅将增进我们对OPRM+RVMSC神经元如何在慢性疼痛中招募的理解， 也启发了新型非阿片类药物治疗慢性疼痛的发展。

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.