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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：
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
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/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

项目摘要

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.

项目总结