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

• 批准号: 10465102
• 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
• 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/10465102
• 关键词: Acute; Adult; Afferent Pathways; Aftercare; Age; Agonist; Analgesics; Anti-Inflammatory Agents; Antibiotic Therapy; Antibiotics; Antiinflammatory Effect; Bacteria; Bacterial Translocation; Brain; Burn injury; 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; Lead; Ligands; Literature; 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; Respiratory Diaphragm; 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; afferent nerve; age related; antagonist; base; cytokine; gut dysbiosis; gut health; gut microbiome; gut microbiota; improved; injured; innovation; macrophage; 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

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.

强烈的基线疼痛及其进一步夸张的程序（例如，皮肤移植手术）是一种伴随的 烧伤受伤的特征（BI）。阿片类药物是主要BI后疼痛治疗的主要停留时间，其镇痛作用差。 未成熟的3周老（未受伤）受试者暴露了较高的疼痛敏感性，与年龄相关的改变 受伤后免疫反应。未经治疗的BI疼痛具有长期并发症。那阐明了病因 因素和分子机制强烈的背景疼痛和年轻人的夸大手术疼痛 BI受试者并发现新颖的非阿片类药物治疗以减轻夸张的疼痛是赠款的目标。 非燃烧文献支持强烈的肠道微生物组 - 脑轴交流，可能由两者介导 从肠道中循环巨噬细胞和迷走神经神经，通过小胶质细胞诱导神经性变化 激活。 BI引起的标志性肠道营养不良，有小胶质细胞激活和神经炎症的证据。 我们指出背景BI疼痛和叠加的夸张手术疼痛是由于先天的免疫记忆而引起的 小胶质细胞。宫颈效率迷走神经刺激（VNS）具有通过 在单核细胞和小胶质细胞中表达的α77乙酰胆碱受体（α7ACHR）。拟议的研究线束 通过使用选择性配体，GTS-21或VNS激活的内源性途径减少小胶质细胞激活 单核细胞/小胶质细胞中的α7ACHR或通过外源口服疗法改善肠道营养不良，所有这些都将提供 消除夸张的BI疼痛并避免阿片类药物副作用的新型非阿片类药物策略。 特定目标1检验了脊柱小胶质细胞炎症表型有助于降低的假设 主要BI后未受伤的未成熟大鼠（IR）和夸张的程序疼痛中的疼痛阈值。这些研究 将显示：（a）与成熟大鼠相比，天真的红外具有较低的疼痛阈值（MR）； （b）bi以延长和 通过夸张的脊柱小胶质细胞激活增强手术后疼痛并增加脊柱疼痛信号 蛋白表达。将比较雄性和雌性大鼠。 特定的目标2检验了以下假设：双诱导的肠道健康改变和肠脊髓轴信号播放 IR中的小胶质细胞启动中的关键作用。这些研究将表明（a）BI诱发肠道营养不良（改变的肠道菌群， 肠道渗透性增加和细菌及其代谢产物的易位），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； （C） 次肌迷走术或巨噬细胞部署可减少炎症，小胶质细胞激活和BI疼痛。 特定目标3检验了选择性激动剂配体，GTS-21，α7ACHRS刺激或VNS的假设 减少炎症或肠道微生物组操纵以改善肠道健康将防止小胶质细胞激活 并减轻BI疼痛。该目标将显示：（a）GTS-21后的抗伤害感受和抗炎作用 BI和切口疼痛的刺激或VN； （b）丁酸钠或选择性抗生素治疗促进 肠道微生物组健康，可降低肠道通透性，全身注射，小胶质细胞激活和BI疼痛。