# Post-TBI Opioid Exposure Exacerbates Chronic Injury-induced Behavioral and  Neuroinflammatory Outcomes

> **NIH VA I01** · JOHN D DINGELL VA MEDICAL CENTER · 2021 · —

## Abstract

Of the more than 300,000 service men and women that have sustained traumatic brain injury (TBI) due to
recent conflicts, 70-80% are treated for pain. Those TBI-injured Veterans that are provided pain management
are more likely to receive opioid-based treatment and engage in higher-risk opioid use. This increase in
prescription opioid use among Veterans with TBI reflects the nationwide opioid abuse and dependence crisis
and highlights the need to understand the long-term, progressive deficits, such as those related to reward and
pain outcomes, that may selectively and disproportionately occur in TBI patients given post-injury opioid
therapy. The exact mechanism(s) underlying a synergy among TBI and early opioid exposure are unknown, but
recent data indicating the prototypical opioid therapeutic, morphine, leads to activation of reactive oxidative
species (ROS) and pro-inflammatory mediators opens the possibility it could enhance or extend the induction
of these systems following TBI, worsening pathological pain for which opioids were intended to alleviate, as
well as contributing to addiction vulnerability. [The preliminary data presented in the application support this
suggestion, as morphine exposure following experimental TBI resulted in synergistic elevations in cortical
levels of ROS and the pro-inflammatory cytokine, interleukin 1 beta, over that observed with either condition
alone in the acute post-injury phase (7 days post-TBI), and was associated with increased microglial
expression in the cortex at more protracted timepoints (30 days post-TBI).] These data warrant further
investigation of the additive effects of TBI and subchronic opioid exposure on long-term TBI outcomes, as well
as indicate that modulators of neuroimmune function, such as the glial attenuator ibudilast, could prevent or
reverse these processes and associated behavioral deficits. [The central hypothesis of this proposal is that
morphine exposure following TBI will heighten injury-induced alterations in reward, pain and their interaction
through exacerbated recruitment of oxidative and inflammatory systems in regions responsible for these
behaviors, and that these will be reversed by neurotherapeutic intervention with a glial attenuator, ibudilast.
This hypothesis will be interrogated with three Specific Aims: (1) Evaluate the long-term impact of TBI on
integrated pain and reward responses and the ability of post-injury morphine to potentiate these outcomes. (2)
Assess glial attenuation with ibudilast to ameliorate TBI-induced pain and reward responses augmented with
post-injury morphine. (3) Quantify the influence of post-injury morphine on TBI-induced oxidative stress and
neuroinflammation, and the efficacy of ibudilast to attenuate these outcomes, in neural reward and pain
centers.] This work would establish that morphine acutely after TBI exacerbates injury-induced oxidative stress
and inflammatory responses in regions mediating reward and pain affect, potentiating ...

## Key facts

- **NIH application ID:** 10128209
- **Project number:** 5I01RX003267-02
- **Recipient organization:** JOHN D DINGELL VA MEDICAL CENTER
- **Principal Investigator:** ALANA C. CONTI
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128209

## Citation

> US National Institutes of Health, RePORTER application 10128209, Post-TBI Opioid Exposure Exacerbates Chronic Injury-induced Behavioral and  Neuroinflammatory Outcomes (5I01RX003267-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10128209. Licensed CC0.

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