Chronic postoperative pain: Genetic and Neural Circuit Mechanisms

慢性术后疼痛：遗传和神经回路机制

• 批准号: 10413127
• 负责人: Norman Taylor
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10413127
• 关键词: Absence of pain sensation; Acute; Affect; Amputation; Animal Model; Biological Markers; Cardiac Surgery procedures; Catecholamines; Cells; Chronic; Diagnosis; Economics; Exhibits; Exposure to; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genomic approach; Goals; Inbred Dahl Rats; Incidence; Methyltransferase Gene; Modeling; Neurons; Nociception; Operative Surgical Procedures; Outcome; Pain; Pain management; Patients; Persistent pain; Persons; Pharmacology; Physiological; Postoperative Pain; Psychological Factors; Public Health; Rattus; Research; Risk; Risk Factors; Role; Serotonin; Spinal Cord; Sprague-Dawley Rats; Stimulus; Testing; Thoracotomy; Variant; breast surgery; chronic pain; congenic; consomic; demographics; diffuse noxious inhibitory control; dopamine system; dopaminergic neuron; efficacious treatment; experience; midbrain central gray substance; multimodality; neural circuit; novel; optogenetics; phenotypic biomarker; prevent; response; surgery outcome

PROJECT SUMMARY Chronic (or persistent) postoperative pain (CPOP) is a potentially devastating outcome from an otherwise successful surgical procedure. It affects millions of patients every year, with pain lasting for months to years, resulting in patient suffering and resulting economic hardship. The surgeries with the highest incidence of chronic postoperative pain are amputations, thoracotomies, cardiac, and breast surgery. Other risk factors include preoperative pain, psychological factors, demographics, and the intensity of acute postoperative pain. Attempts to prevent chronic postoperative pain have largely been unsuccessful, with no change in the incidence despite increased use of regional and multimodal analgesia. Therefore, further research is needed to identify biomarkers to accurately predict those at risk for developing chronic postoperative pain and treatments that reduce the incidence. We hypothesize that Diffuse Noxious Inhibitory Control (DNIC) efficiency is predictive of who will develop chronic postoperative pain. Thus, a better understanding of the mechanisms responsible for DNIC will result in more efficacious treatments. We would expect that patients or animal models with less efficient DNIC would be ‘at risk’ for developing chronic pain when exposed to the painful stimulus of surgery. Our overall objectives in this application are to use a new model of persistent postoperative pain, the Dahl S rat, to investigate the involvement of serotonin, catecholamine and dopamine systems on DNIC using pharmacologic, chemogenetic and optogenetic approaches. We will also investigate which genetic polymorphism(s) are responsible for the persistent postoperative pain experienced by the Dahl S rat. This will be accomplished in three projects. Project 1: will determine the relationship between DNIC and CPOP. DNIC responses will be abolished in Sprague Dawley rats and restored in Dahl S rats, and the resultant effects on postoperative pain persistence ascertained. We will also test the hypothesis that the absent DNIC response in SS rats is a result of increased nociceptive facilitation by serotonergic “on cells” in the rostral ventral medulla by optogenetically inhibiting serotonergic neurons in the spinal cord. Project 2 will examine the role of periaqueductal gray dopamine neurons on DNIC and postoperative pain using a Dahl S rat expressing a novel variant of the Catecholamine-O-methyltransferase gene that increases dopaminergic tone. Project 3 will use a powerful physiologic genomics approach, the use of consomic and congenic rats, to identify the gene polymorphism(s) responsible for the absent DNIC response and persistent postoperative pain exhibited by Dahl S rats. We expect our studies to provide genetic and phenotypic biomarkers to guide diagnosis and treatment decisions in chronic postoperative pain.

项目概要 慢性（或持续性）术后疼痛 (CPOP) 是一种潜在的破坏性后果 成功的手术过程。它每年影响数百万患者，疼痛持续数月至数年， 导致患者痛苦并造成经济困难。慢性病发生率最高的手术 术后疼痛包括截肢、开胸手术、心脏手术和乳房手术。其他风险因素包括 术前疼痛、心理因素、人口统计学和术后急性疼痛的强度。尝试 预防慢性术后疼痛的方法在很大程度上并不成功，尽管发生率没有变化 增加区域镇痛和多模式镇痛的使用。因此，需要进一步研究来识别生物标志物 准确预测那些有发生慢性术后疼痛风险的人以及减少疼痛的治疗方法 发生率。我们假设扩散有害抑制控制 (DNIC) 效率可以预测谁会 出现慢性术后疼痛。因此，更好地理解负责 DNIC 的机制将 从而获得更有效的治疗。我们预计 DNIC 效率较低的患者或动物模型 当暴露于手术的疼痛刺激时，将有患慢性疼痛的“风险”。我们的整体 本申请的目标是使用一种新的术后持续疼痛模型（Dahl S 大鼠）来研究 血清素、儿茶酚胺和多巴胺系统对 DNIC 的药理学作用， 化学遗传学和光遗传学方法。我们还将研究哪些遗传多态性 Dahl S 大鼠术后持续疼痛的原因。这将在 三个项目。项目1：将确定DNIC和CPOP之间的关系。 DNIC 的响应将是 在 Sprague Dawley 大鼠中被废除，在 Dahl S 大鼠中被恢复，以及由此产生的对术后疼痛的影响 持久性确定。我们还将检验以下假设：SS 大鼠中缺乏 DNIC 反应是结果 通过光遗传学方法，通过延髓头端腹侧细胞上的血清素能增加伤害感受的促进 抑制脊髓中的血清素能神经元。项目 2 将研究导水管周围灰质的作用 使用表达新变体的 Dahl S 大鼠对 DNIC 上的多巴胺神经元和术后疼痛进行观察 儿茶酚胺-O-甲基转移酶基因可增加多巴胺能张力。项目3将使用强大的 生理基因组学方法，使用同体和同源大鼠来鉴定基因多态性 这是 Dahl S 大鼠缺乏 DNIC 反应和持续术后疼痛的原因。我们期望 我们的研究提供遗传和表型生物标志物来指导慢性病的诊断和治疗决策 术后疼痛。