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: 10029233
• 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/10029233
• 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; 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; 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.

项目总结 慢性(或持续性)术后疼痛(CPOP)是一种潜在的破坏性后果 手术成功。它每年影响数以百万计的患者，疼痛持续数月至数年， 造成病人痛苦和由此产生的经济困难。慢性病发病率最高的手术 术后疼痛包括截肢、开胸、心脏和乳房手术。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强度。尝试 预防慢性术后疼痛在很大程度上是不成功的，尽管 更多地使用区域和多模式止痛。因此，需要进一步的研究来识别生物标志物。 准确预测有可能发展为慢性术后疼痛的风险人群，并进行治疗以减少 发病率。我们假设扩散有害抑制控制(DNIC)的效率可以预测谁会 出现慢性术后疼痛。因此，更好地了解DNIC的责任机制将 从而产生更有效的治疗方法。我们预计患有效率较低的DNIC的患者或动物模型 当暴露在手术的痛苦刺激下时，会出现慢性疼痛的风险。我们的整体 本应用的目的是使用一种新的持续性术后疼痛模型--DAHL S大鼠来研究 5-羟色胺、儿茶酚胺和多巴胺系统参与DNIC的药理学研究 化学遗传和光遗传方法。我们还将调查哪些遗传多态(S)是 对Dahl S大鼠持续的术后疼痛负有责任。这将在#年完成 三个项目。项目1：将确定DNIC和CPOP之间的关系。DNIC的响应将是 SD大鼠废止和达尔S大鼠恢复及对术后疼痛的影响 持久力已确定。我们还将检验这一假设，即SS大鼠的DNIC反应缺失是 5-羟色胺能“ON细胞”通过光遗传学增强头端腹侧延髓的伤害性易化 抑制脊髓中的5-羟色胺能神经元。项目2将研究导水管周围灰质的作用。 多巴胺能神经元在下丘脑下丘脑核和术后疼痛中的表达 增加多巴胺能张力的儿茶酚胺-O-甲基转移酶基因。项目3将使用一个强大的 生理基因组学方法，利用同系大鼠和同系大鼠鉴定基因多态性(S) 对Dahl S大鼠的DNIC缺失反应和术后持续性疼痛负有责任。我们预计 我们的研究旨在提供遗传和表型生物标记物来指导慢性阻塞性肺疾病的诊断和治疗决策 术后疼痛。