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:
    10465102
  • 负责人:
  • 金额:
    $ 32.6万
  • 依托单位:
  • 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

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.
伴有强烈的基线疼痛,并随着手术(如植皮手术)进一步加剧

项目成果

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Jeevendra Martyn其他文献

Jeevendra Martyn的其他文献

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{{ truncateString('Jeevendra Martyn', 18)}}的其他基金

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:
    10033365
  • 财政年份:
    2020
  • 资助金额:
    $ 32.6万
  • 项目类别:
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:
    10684657
  • 财政年份:
    2020
  • 资助金额:
    $ 32.6万
  • 项目类别:
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:
    10237933
  • 财政年份:
    2020
  • 资助金额:
    $ 32.6万
  • 项目类别:
Synaptic and Nerve Terminal Changes and Associated Muscle Weakness of Burn Injury
突触和神经末梢变化以及烧伤相关的肌肉无力
  • 批准号:
    9247895
  • 财政年份:
    2016
  • 资助金额:
    $ 32.6万
  • 项目类别:
APOPTOSIS IN SKELETAL MUSCLE FOLLOWING BURN INJURY
烧伤后骨骼肌细胞凋亡
  • 批准号:
    6520273
  • 财政年份:
    2000
  • 资助金额:
    $ 32.6万
  • 项目类别:
APOPTOSIS IN SKELETAL MUSCLE FOLLOWING BURN INJURY
烧伤后骨骼肌细胞凋亡
  • 批准号:
    6636472
  • 财政年份:
    2000
  • 资助金额:
    $ 32.6万
  • 项目类别:
APOPTOSIS IN SKELETAL MUSCLE FOLLOWING BURN INJURY
烧伤后骨骼肌细胞凋亡
  • 批准号:
    6363354
  • 财政年份:
    2000
  • 资助金额:
    $ 32.6万
  • 项目类别:
APOPTOSIS IN SKELETAL MUSCLE FOLLOWING BURN INJURY
烧伤后骨骼肌细胞凋亡
  • 批准号:
    6135371
  • 财政年份:
    2000
  • 资助金额:
    $ 32.6万
  • 项目类别:
Molecular Pharmacology of Insulin Resistance in Burns
烧伤胰岛素抵抗的分子药理学
  • 批准号:
    6729136
  • 财政年份:
    1997
  • 资助金额:
    $ 32.6万
  • 项目类别:
Molecular Pharmacology of Insulin Resistance in Burns
烧伤胰岛素抵抗的分子药理学
  • 批准号:
    7585601
  • 财政年份:
    1997
  • 资助金额:
    $ 32.6万
  • 项目类别:

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