Major Burn Injury and its Effects on Acute and Superimposed Surgical Pain

严重烧伤及其对急性和叠加手术疼痛的影响

基本信息

批准号：
10684657
负责人：
Jeevendra Martyn
金额：
$ 32.6万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2020-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10684657
关键词：
Acute Adult Afferent Pathways Age Agonist Analgesics Anti-Inflammatory Agents Antibiotic Therapy Antibiotics Antiinflammatory Effect Bacteria Bacterial Translocation Brain Burn injury Burning Pain Cell physiology Cells Cellular Metabolic Process Cervical Childhood Injury Communication Data Decontamination Denervation Distant Efferent Pathways Epigenetic Process Etiology Exhibits Female Flow Cytometry GTS-21 Goals Grant Harvest Health Human IL6 gene Immune Immune response Immunologic Memory Inflammation Inflammatory Inflammatory Response Injury Interleukin-1 beta Intestinal permeability Ligands Literature Macrophage Mediating Metabolic dysfunction Microglia Molecular Morphology N-Methyl-D-Aspartate Receptors NF-kappa B Nerve Neurons Neuropathy Nociception Operative Surgical Procedures Opioid Oral Pain Pain Threshold Pain management Pathogenicity Pathologic Pathway interactions Patients Persons Phenotype Play Postoperative Pain Procedures Property Proteins Rattus Reporting Rodent Role Serum Signal Pathway Signal Transduction Signaling Protein Site Skin graft Sodium Butyrate Spinal Spinal Cord Spine pain Surgical Injuries Surgical incisions TLR4 gene TNF gene Testing Vagotomy Vagus nerve structure Vertebral column afferent nerve age related antagonist antinociception cytokine gut dysbiosis gut health gut microbiome gut microbiota improved injured innovation male metabolomics methyllycaconitine monocyte neuroinflammation non-opioid analgesic novel pain inhibition pain relief pain sensitivity pain signal prevent procedural pain protein expression receptor response side effect surgical pain systemic inflammatory response vagus nerve stimulation

项目摘要

Intense baseline pain and its further exaggeration with procedures (e.g., skin graft surgery) is a concomitant feature of burn Injury (BI). Opioids, the main stay of pain treatment after major BI, have poor analgesic effects. Immature 3-week old (uninjured) subjects exhibit higher pain sensitivity, together with age-associated altered immune responses after injury. Untreated BI pain has long-term complications. Thus, elucidating the etiological factors and molecular mechanisms underlying intense background pain and exaggerated surgical pain in young BI subjects and discover novel non-opioid therapeutics to mitigate exaggerated pain are the goals of the grant. Non-burn literature supports the strong gut-microbiome-brain-axis communication, possibly mediated by both circulating macrophages and vagal afferent nerves from the gut, to induce neuropathic changes via microglia activation. BI causes marked gut dysbiosis with evidence of microglia activation and neuro-inflammation. We posit that background BI pain and superimposed exaggerated surgical pain is due to innate immune memory of microglia. Cervical efferent vagus nerve stimulation (VNS) has anti-inflammatory properties mediated via α7acetylcholine receptors (α7AChRs) expressed in monocytes and microglia. The proposed studies harness endogenous pathways to curtail microglia activation by using a selective ligand, GTS-21, or VNS to activate α7AChRs in monocyte/microglia or improve gut dysbiosis by exogenous oral therapies, all of which will provide novel non-opioid strategies to abrogate the exaggerated BI pain and avoid opioid side effects. Specific Aim 1 tests the hypothesis that spinal microglia inflammatory phenotype contributes to the lowered pain thresholds in uninjured immature rats (IR) and exaggerated procedural pain after major BI. These studies will show: (a) naive IR have a lower pain threshold compared to mature rats (MR); (b) BI to IR prolongs and enhances post-surgical pain by exaggerated spinal microglia activation and increased spinal pain-signaling protein expression. Both male and female rats will be compared. Specific Aim 2 tests the hypothesis that BI-induced altered gut health and gut-spinal cord axis signaling plays a pivotal role in microglia priming in IR. These studies will show (a) BI induces gut dysbiosis (altered gut flora, increased gut permeability and translocation of bacteria and their metabolites), which contributes to microglia activation, (b) metabolomics will demonstrate immune cell metabolic dysfunction of inflammatory phenotype; (c) sub-diaphragmatic vagotomy or macrophage depletion decreases inflammation, microglia activation and BI pain. Specific Aim 3 tests the hypothesis that selective agonist ligand, GTS-21, stimulation or VNS of α7AChRs to decrease inflammation, or gut microbiome manipulation to improve gut health will prevent microglia activation and decrease BI pain. This aim will show: (a) anti-nociceptive and anti-inflammatory effects after GTS-21 stimulation or VNS in BI and incisional pain; (b) oral sodium butyrate or selective antibiotic treatment promotes gut microbiome health, reduces gut permeability, systemic inflammation, microglia activation and BI pain.

剧烈的基线疼痛及其随着手术（例如植皮手术）而进一步加剧是伴随的烧伤（BI）的特点是阿片类药物是继BI之后的主要疼痛治疗药物，但镇痛效果较差。未成熟的 3 周大（未受伤）受试者表现出较高的疼痛敏感性，以及与年龄相关的改变损伤后的免疫反应。未经治疗的 BI 疼痛会产生长期并发症，因此阐明了其病因。年轻人剧烈背景疼痛和夸张手术疼痛的因素和分子机制该资助的目标是研究 BI 受试者并发现新型非阿片类药物疗法来减轻过度疼痛。非烧伤文献支持强大的肠道-微生物组-脑轴通讯，可能是由两者介导的来自肠道的循环巨噬细胞和迷走神经传入神经，通过小胶质细胞诱导神经病理性变化 BI 会导致明显的肠道菌群失调，并有小胶质细胞激活和神经炎症的证据。我们假设背景 BI 疼痛和叠加的夸大手术疼痛是由于先天免疫记忆造成的颈部传出迷走神经刺激 (VNS) 具有通过介导的抗炎特性。 α7乙酰胆碱受体（α7AChR）在单核细胞和小胶质细胞中表达。通过使用选择性配体 GTS-21 或 VNS 来激活抑制小胶质细胞激活的内源性途径单核细胞/小胶质细胞中的 α7AChR 或通过外源性口服疗法改善肠道菌群失调，所有这些都将提供新颖的非阿片类药物策略可以消除夸张的脑损伤并避免阿片类药物的副作用。具体目标 1 检验了脊髓小胶质细胞炎症表型有助于降低这些研究显示未受伤的未成熟大鼠 (IR) 的疼痛阈值和严重 BI 后夸大的程序性疼痛。将显示：（a）幼稚 IR 与成熟大鼠（MR）相比具有较低的疼痛阈值；（b）BI 至 IR 延长并且通过过度激活脊髓小胶质细胞和增加脊髓疼痛信号来增强术后疼痛将比较雄性和雌性大鼠的蛋白质表达。具体目标 2 测试了 BI 引起的肠道健康改变和肠道-脊髓轴信号传导作用的假设这些研究将表明 (a) BI 会导致肠道菌群失调（肠道菌群改变，肠道通透性增加以及细菌及其代谢物的易位），这有助于小胶质细胞激活，(b) 代谢组学将证明炎症表型的免疫细胞代谢功能障碍；膈下迷走神经切断术或巨噬细胞耗竭可减少炎症、小胶质细胞激活和脑损伤疼痛。具体目标 3 检验以下假设：选择性激动剂配体、GTS-21、α7AChR 的刺激或 VNS 减少炎症，或改善肠道健康的肠道微生物组调控将阻止小胶质细胞激活并减少 BI 疼痛。该目标将显示：(a) GTS-21 后的抗伤害和抗炎作用。刺激或 VNS 对 BI 和切口痛有促进作用；(b) 口服丁酸钠或选择性抗生素治疗可促进肠道微生物组健康状况下降、肠道通透性、全身炎症、小胶质细胞激活和脑损伤疼痛。