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.

项目概要 此补充设备要求是完整的电生理学设置，以确认功能正常 项目 1 和 2 中描述的实验中 DREADD 和视蛋白的变化。慢性（或持续性）术后疼痛 (CPOP) 是一次成功的外科手术可能带来的毁灭性后果。 每年有数名患者遭受持续数月至数年的疼痛，给患者带来痛苦并造成经济损失 慢性术后疼痛发生率最高的手术是截肢术、开胸手术、 其他危险因素包括术前疼痛、心理因素、人口统计、 以及急性术后疼痛的强度已在很大程度上预防慢性术后疼痛。 不成功，尽管增加了区域和多模式镇痛的使用，但发病率没有变化。 因此，需要进一步研究来识别生物标志物，以准确预测那些有发展风险的人 慢性术后疼痛和减少其发生率的治疗方法我们捕捉到了弥漫性有害疼痛。 抑制控制 (DNIC) 效率可以预测谁会出现慢性术后疼痛。 了解 DNIC 的机制将导致更有效的治疗。 预计 DNIC 效率较低的患者或动物模型在以下情况下将面临发展为慢性疼痛的“风险”： 我们在此应用程序中的总体目标是使用一种新的模型。 持续性术后疼痛，Dahl S 大鼠，研究血清素、儿茶酚胺和 使用药理学、化学遗传学和光遗传学方法对 DNIC 上的多巴胺系统进行研究。 这些实验的切片电生理学将为我们提供重要的额外机制见解 我们还将研究哪些基因多态性是造成这种现象的原因。 Dahl S 大鼠术后持续疼痛 这将通过三个项目来完成。 1：将确定DNIC和CPOP之间的关系，响应将在Sprague被废除。 Dawley 大鼠和 Dahl S 大鼠恢复，并确定了对术后疼痛持续性的影响。 我们还将检验以下假设：SS 大鼠中缺乏 DNIC 反应是由于伤害性感受增加所致 通过光遗传学抑制血清素能促进延髓头端腹侧细胞上的血清素能 项目 2 将检查导水管周围灰色多巴胺神经元对 DNIC 的作用。 使用表达儿茶酚胺-O-甲基转移酶新变体的 Dahl S 大鼠进行术后镇痛 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，即使用 对同体和同系大鼠进行研究，以确定导致 DNIC 反应缺失的基因多态性 Dahl S 大鼠表现出持续的术后疼痛，我们希望我们的研究能够提供遗传和持续性疼痛。 表型生物标志物指导慢性术后疼痛的诊断和治疗决策。