# Long-term effects of opioid use in a mouse model of repetitive mild traumatic brain injury

> **NIH VA I21** · JAMES A. HALEY VA MEDICAL CENTER · 2021 · —

## Abstract

Individuals who have sustained a traumatic brain injury (TBI) are at a higher risk for substance use disorders,
and while clinicians and researchers widely acknowledge issues with opioid abuse and dependence, pre-
clinical investigations have published data suggesting positive benefits of opioids as a potential therapeutic
strategy for patients of TBI. However, concerns regarding the effect of opioid exposure on neuronal
degeneration have also emerged in both pre-clinical and clinical settings. For example, lesions in white matter
have been documented for methadone, morphine and oxycodone over-dosed patients.
We acknowledge that the neurobiology of opioid use following TBI is difficult to study in clinical
settings, especially in cases where pre-injury assessment may not be possible or accurate. We, therefore,
propose to investigate the long-term effects of opioid use in our well-characterized animal model of repetitive
mTBI (r-mTBI), thereby removing the biases inherent to human studies. As there are confounding data on the
influence of opioid treatment or abuse on chronic outcomes after r-mTBI we hypothesize that investigation of
the chronic effects of opioid treatment in our translational model of r-mTBI will identify any negative or
positive effects on neurobehavior and neuropathology and help guide future, non-addictive, treatment
interventions. The overarching aim of the proposed study is to investigate and refine our understanding of the
chronic effects of two opioid agonists (Oxycodone, Methadone), and a non-selective opiate antagonist
(Naloxone). In addition, this project will investigate the interaction between microglia and opioids; yet the role
of microglia in the context of long-term opioid treatment and after brain injuries remains underexplored within
the literature. In addition to pain relief, understanding the role of microglia after chronic opioid exposure might
also be a way to prevent opioid tolerance and explain opioid induced hyperalgesia.
In the first aim, male animals will be exposed to five mTBIs or five sham anesthesia (controls), and then
treated with one of the two proposed opioid agonists, an opioid antagonist, or saline for a period of 6 months
starting 24h post-last injury. The neurobehavioral performance will then be evaluated at both 1- and 6-months
post-injury. In the second aim, neuropathological and biochemical analyses will be evaluated at 6 months
post-injury. For both aims, we will evaluate the same outcome measures in injured versus control animals
exposed to each pharmacological agent. We believe these findings will have broad applicability in both TBI
and opioid research, as the data generated in this study will further the understanding of the complex
interaction between the chronic exposure of opioid agonists and antagonist, TBI and the microglia cell
population.
By assessing nuanced aspects of neurobehavioral and pathological deficits, we will provide a framework from
which informed decisions can then ...

## Key facts

- **NIH application ID:** 10217284
- **Project number:** 5I21RX003340-02
- **Recipient organization:** JAMES A. HALEY VA MEDICAL CENTER
- **Principal Investigator:** Benoit Christian Mouzon
- **Activity code:** I21 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-08-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217284

## Citation

> US National Institutes of Health, RePORTER application 10217284, Long-term effects of opioid use in a mouse model of repetitive mild traumatic brain injury (5I21RX003340-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10217284. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*