# Mild Traumatic Brain Injury and Opiate Exposure Crosstalk: Neuropathological, Neurobehavioral, and Neuroproteomic Assessments

> **NIH VA I21** · VETERANS HEALTH ADMINISTRATION · 2020 · —

## Abstract

Traumatic brain injury (TBI) is a major cause of morbidity among the Veteran population. Mild TBI (mTBI) has
been associated with substance abuse as a comorbid condition, hampering rehabilitation and treatment efforts
of either condition. Of particular interest is the rising trend of opiate abuse among Veterans. Existing evidence
indicates overlapping molecular and neural pathways for TBI and opiate abuse; for example, inflammatory
mediators and increased neurodegeneration and microglial activation are observed in both opiate abuse and
mTBI. To the best of our knowledge, there are no reported preclinical studies that have systematically examined
the crosstalk between mTBI and subsequent opiate exposure in terms of neurobehavioral, neuropathological
and neurobiochemical consequences. This study proposes to use a validated rodent model of repeated closed
head injury (rCHI) paired with chronic exposure to fentanyl drug to closely simulate real-world conditions of mTBI
and opiate usage. Fentanyl is a highly effective but addictive analgesic commonly used for treating chronic pain.
The central hypothesis of this proposal is that sustained opiate exposure post-mTBI will induce characteristic
neurofunctional and neuropathological changes that differ from those seen with mTBI or opiate exposure alone,
and that these changes can be identified and evaluated via neurobehavioral, biochemical and neuroproteomic
approaches. This proposal is a new direction for the PI’s laboratory and is potentially paradigm-shifting. Aim 1
will determine the effects of 1 month fentanyl opiate exposure followed by 1 month withdrawal after r-CHI on
cognition, pain sensation, motor activity and spontaneous opiate withdrawal symptoms. Male mice (C57BL6) will
be used and subjected to rCHI or sham procedure (non-injury).There will be four experimental groups: (a)
Sham+saline, (b) rCHI+saline, (c) sham+fentanyl, (d) rCHI-followed by Fentanyl exposure. Functional
assessment tests include: TBI-related cognition (spatial memory performance; Morris water maze) and anxiety-
behavior (elevated plus maze), or opiate-use/withdrawal tests; locomotive activity-related pain sensitivity tests
(warm-water tail withdrawal and Orofacial formalin test) (during drug exposure and withdrawal phases), and drug
withdrawal-dependence symptoms (during the fentanyl withdrawal phase). The results will be compared with the
observations from rCHI or fentanyl exposure alone. Aim 2 will assess key neuropathological, neural cellular
markers and opiate receptor levels in three brain regions (cortex, hippocampus and ventral tegmental area)
implicated in TBI and/or opioid receptor-mediated reward circuits. Brain samples will be analyzed at 2 endpoints
- at the end of fentanyl administration (month 1), and after 1 month of withdrawal (month 2), in animals with or
without rCHI. Neuronal, axonal, astroglial, microglial, synaptic and white matter markers, along with and the
three subtypes of opioid receptors will be ass...

## Key facts

- **NIH application ID:** 9784440
- **Project number:** 1I21RX003192-01
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** KEVIN Ka Wang WANG
- **Activity code:** I21 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2019-11-01 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9784440

## Citation

> US National Institutes of Health, RePORTER application 9784440, Mild Traumatic Brain Injury and Opiate Exposure Crosstalk: Neuropathological, Neurobehavioral, and Neuroproteomic Assessments (1I21RX003192-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9784440. Licensed CC0.

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