# Effects of Long-Term Morphine Treatment on Opioid Receptor Signaling and Inflammation in the Chronic Post-TBI Period

> **NIH VA I21** · JOHN D DINGELL VA MEDICAL CENTER · 2020 · —

## Abstract

Increasing awareness has been placed in understanding the issues related to rehabilitation of the
estimated 330,000 service personnel diagnosed with traumatic brain injury (TBI) since the start of Operation
Enduring Freedom and Operation Iraqi Freedom, who suffer from physical, cognitive, emotional dysfunction
and recurrent pain. Specifically, opioid misuse is a growing epidemic nationwide, and recent evidence indicates
that Veterans who sustain moderate/severe TBI are more likely to receive long-term treatment with opioid-
based medications and engage in higher-risk opioid use patterns. These findings highlight the critical need for
studies to establish what adaptive changes occur in the opioid system in the injured brain that may influence
nociceptive, cognitive and reward/dependence outcomes. Morphine, the prototypical opioid antinociceptive,
binds to the mu opioid receptor (MOR) to stimulate G-protein signaling and downstream effectors, such as
extracellular signal-regulated kinase (ERK). In addition to this classical signaling pathway, morphine can act
through the immunity toll-like like receptor 4 (TLR4) to activate glial cells and stimulate the release of
proinflammatory mediators, like interleukin 1 beta (IL-1). While both signaling pathways contribute to
morphine-induced phenotypes, evidence indicates immune activation disrupts morphine’s efficacy to promote
analgesia, worsens pathological pain and exacerbates dependence and withdrawal. While TBI is recognized to
induce long-term effects on immune system function alone, to date, no published papers have explored the
combined influence of TBI and opioids on these signaling outcomes, adding to the significance and innovation
of the proposed project.
 The current SPiRE proposal will test the hypothesis that repeated exposure to morphine following TBI
will upregulate MOR expression/function and selectively potentiate glial-mediated inflammatory
processes upon subsequent re-exposure to morphine in regions associated with reward, cognition and
pain. The objectives in this proposal will be accomplished through two Specific Aims with tissue
measurements in the nucleus accumbens, ventral tegmental area, prefrontal cortex, periaqueductal gray,
dorsal hippocampus and amygdala. Aim 1 will assess longitudinal changes in MOR status as measured by
radioligand binding density/affinity as well as gene expression (real-time PCR) and immunofluorescent co-
localization on neurons and glia in tissue collected 7 days, 1, 3 and 6 months following TBI/repeated morphine.
Aim 2 will characterize differential activation of classical and inflammatory pathways stimulated by morphine re-
exposure at long-term timepoints (3 and 6 months) following combined TBI and subchronic morphine. Activity
through classical pathways will be evaluated by G-protein (GTPS) activity and extent of phosphorylated ERK
immunofluorescence. Inflammatory pathway signaling will be assessed by measuring the extent of glial
activation with im...

## Key facts

- **NIH application ID:** 9964518
- **Project number:** 5I21RX003198-02
- **Recipient organization:** JOHN D DINGELL VA MEDICAL CENTER
- **Principal Investigator:** Kelly Bosse
- **Activity code:** I21 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964518

## Citation

> US National Institutes of Health, RePORTER application 9964518, Effects of Long-Term Morphine Treatment on Opioid Receptor Signaling and Inflammation in the Chronic Post-TBI Period (5I21RX003198-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9964518. Licensed CC0.

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