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Chronic postoperative pain: Genetic and Neural Circuit Mechanisms

慢性术后疼痛：遗传和神经回路机制

基本信息

批准号：
10618841
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
项目类别：
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/10618841
关键词：
Absence of pain sensation Acute Affect Amputation Animal Model 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 Patients Persistent pain Persons Physiological Postoperative Pain Predisposition Psychological Factors Public Health Rattus Research Risk Risk Factors Role Serotonin Spinal Cord Sprague-Dawley Rats Stimulus Testing Thoracotomy Variant biomarker identification breast surgery chronic pain congenic consomic demographics diffuse noxious inhibitory control dopamine system dopaminergic neuron efficacious treatment efficacy evaluation experience midbrain central gray substance multimodality neural circuit novel optogenetics pharmacologic phenotypic biomarker prevent response surgery outcome

项目摘要

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.

项目摘要慢性（或持续性）术后疼痛（CPOP）是一种潜在的破坏性结果，手术成功它每年影响数百万患者，疼痛持续数月至数年，导致患者痛苦并导致经济困难。慢性并发症发生率最高的手术术后疼痛是截肢、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的强度。尝试预防慢性术后疼痛在很大程度上是不成功的，尽管增加区域和多模式镇痛的使用。因此，还需要进一步的研究来确定生物标志物准确预测那些有发生慢性术后疼痛风险的患者，发病率。我们假设，弥漫性伤害抑制控制（DNIC）的效率是预测谁将出现慢性术后疼痛。因此，更好地了解国家刑事调查局的机制，导致更有效的治疗。我们预计，DNIC效率较低的患者或动物模型当暴露在手术的痛苦刺激下时，会有患慢性疼痛的风险。我们的整体本申请的目的是使用一种新的持续性术后疼痛模型，Dahl S大鼠， 5-羟色胺、儿茶酚胺和多巴胺系统对DNIC的参与，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是 Dahl S大鼠术后持续疼痛的原因。这将在三个项目。项目1：将确定国家刑事调查局和CPOP之间的关系。DNIC的回应将是在Sprague道利大鼠中消除，在Dahl S大鼠中恢复，以及对术后疼痛的影响持久性确定。我们还将检验这样一个假设，即SS大鼠中缺乏DNIC反应是由于通过光遗传学方法观察到延髓头端腹侧的多巴胺能“on细胞”增加了伤害性促进作用，抑制脊髓中的肾上腺素能神经元。项目2将研究中脑导水管周围灰质的作用多巴胺神经元对DNIC和术后疼痛的影响，使用表达多巴胺神经元新变体的Dahl S大鼠。增加多巴胺能张力的儿茶酚胺-O-甲基转移酶基因。项目3将使用强大的生理基因组学方法，使用同系和同系大鼠，鉴定基因多态性 Dahl S大鼠表现出的DNIC反应缺失和持续的术后疼痛。我们预计我们的研究提供了遗传和表型生物标志物，以指导慢性疾病的诊断和治疗决策。术后疼痛