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

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $326,009

## Abstract

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
...

## Key facts

- **NIH application ID:** 10465102
- **Project number:** 5R01GM142042-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Jeevendra Martyn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $326,009
- **Award type:** 5
- **Project period:** 2020-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10465102

## Citation

> US National Institutes of Health, RePORTER application 10465102, Major Burn Injury and its Effects on Acute and Superimposed Surgical Pain (5R01GM142042-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10465102. Licensed CC0.

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