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: 10581162
• 负责人: Norman Taylor
• 金额: $ 21.2万
• 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/10581162
• 关键词: Absence of pain sensation; Acute; Affect; Amputation; Animal Model; Biological Markers; Body Regions; Body part; Calcium; Calcium Signaling; Candidate Disease Gene; Cardiac Surgery procedures; Catecholamines; Cells; Chronic; Diagnosis; Dopamine; Economics; Electrophysiology (science); Equipment; Exhibits; Exposure to; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genomic approach; Goals; Image; Inbred Dahl Rats; Incidence; Measures; Membrane Potentials; Methyltransferase Gene; Modeling; Neurons; Nociception; Nociceptive Stimulus; Operative Surgical Procedures; Opsin; Outcome; Pain; Pain management; Parents; Patients; Persistent pain; Persons; Pharmaceutical Preparations; Pharmacology; Physiological; Postoperative Pain; Psychological Factors; Public Health; Rattus; Research; Risk; Risk Factors; Role; Serotonin; Signal Transduction; Slice; Spinal Cord; Sprague-Dawley Rats; Stimulus; Surgical incisions; Techniques; Testing; Thoracotomy; Variant; breast surgery; chronic pain; congenic; consomic; demographics; designer receptors exclusively activated by designer drugs; diffuse noxious inhibitory control; dopamine system; dopaminergic neuron; efficacious treatment; experience; experimental study; insight; midbrain central gray substance; multimodality; neural circuit; novel; optogenetics; pain inhibition; phenotypic biomarker; prevent; programs; response; surgery outcome

PROJECT SUMMARY This supplemental equipment request is for a complete electrophysiology setup to confirm the proper functioning of DREADDs and opsins in experiments described in Projects 1 and 2. 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. The addition of slice electrophysiology to these experiments would provide important additional mechanistic insight into the actions of these transmitters. 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 此补充设备要求是完整的电生理设置，以确认正确的功能 在项目1和2中描述的实验中的恐惧和opsin的术后疼痛 （CPOP）是原本成功的外科手术的潜在毁灭性结果。它影响数百万 每年患者的疼痛持续数月至数年，导致患者痛苦和经济 艰辛。慢性术后疼痛事件最高的手术是截肢，胸痛， 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， 以及急性后疼痛的强度。试图预防慢性后疼痛的尝试很大程度上是 失败，事件任务没有变化，增加了区域和多模式镇痛的使用。 因此，需要进一步的研究来识别生物标志物以准确预测有发展风险的生物标志物 慢性术后疼痛和治疗减少发病率。我们假设这种弥漫性有害 抑制性控制（DNIC）效率可预测谁将出现慢性术后疼痛。那，更好 了解负责DNIC的机制将导致更有效的治疗方法。我们会的 预计当患者或动物模型效率较低的患者或动物模型在 暴露于手术的疼痛刺激。我们在此应用程序中的总体目标是使用新的模型 持续的术后疼痛，达尔的大鼠，以研究5-羟色胺，儿茶酚胺和 使用药物学，化学遗传学和光遗传学方法的DNIC上的多巴胺系统。添加 这些实验的切片电生理学将为您提供重要的额外机械洞察力 这些发射机的作用。我们还将调查哪些遗传多态性负责 达尔的大鼠持续术后疼痛。这将在三个项目中完成。项目 1：将确定DNIC和CPOP之间的关系。 Sprague将废除DNIC回应 Dawley大鼠在Dahl s大鼠中恢复，并确定术后疼痛持续性的影响。 我们还将检验以下假设，即SS大鼠缺乏DNIC反应是伤害性增加的结果 通过光学抑制塞拉顿式塞拉顿能的促进，在腹腹髓质中促进尖锐的“在细胞上”促进 脊髓中的神经元。项目2将检查周围灰色多巴胺神经元对DNIC的作用 使用Dahl S大鼠表达儿茶酚胺-O-甲基转移酶的新型变体的术后疼痛 增加多巴胺能张力的基因。项目3将使用强大的生理基因组学方法，该方法 综合大鼠和先天性大鼠，以识别负责缺乏DNIC反应的基因多态性 Dahl S大鼠暴露于术后疼痛。我们希望我们的研究提供遗传和 表型生物标志物指导慢性术后疼痛中的诊断和治疗决策。