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.

伴有强烈的基线疼痛，并随着手术（如植皮手术）进一步加剧