POA.081 - Morphine Amplifies Traumatic Brain Injury-Induced Neuroinflammation via the Kynurenine Pathway

Document Type

Conference Proceeding

Publication Date

7-9-2025

Publication Title

J Neurotrauma

Abstract

Chronic pain affects over 50% of traumatic brain injury (TBI) patients, which has been strongly linked to neuroinflammation. Although opioids like morphine (MOR) are prescribed for post-TBI pain, they paradoxically worsen neuroinflammation, producing opioid-induced hyperalgesia. Therefore, identification of mechanisms underlying post-TBI pain, inflammation, and MOR action, are necessary to optimize post-TBI analgesia. The kynurenine pathway (KP) responds robustly to inflammation, producing kynurenic acid (KYNA, anti-inflammatory) and quinolinic acid (QUIN, proinflammatory), although their roles in TBI-induced pain, inflammation and MOR action remain unclear. Therefore, the KP was examined after 5 days of escalating MOR treatment (1-2 days post-injury (dpi), 4 mg/kg; 3-5 dpi, 8 mg/kg) in C57Bl/6 male mice (n=4-6) following closed-skull impact. Tactile thresholds (Von Frey), inflammatory cytokines (enzyme-linked immunosorbent assays), and KP metabolites (liquid-chromatography tandem mass spectrometry) were measured by 30 dpi. Tactile threshold in TBI-saline mice was significantly reduced at 5 dpi (p<0.0001 vs. sham-saline), which was reversed by MOR. However, at 30 dpi TBI-MOR mice exhibited significantly lower tactile thresholds than TBI-saline controls (p<0.0001). At 30 dpi, MOR exacerbated TBI-induced elevations in the pro-inflammatory cytokines, interleukin-1 beta and tumor necrosis factor-alpha, within the prefrontal and anterior cingulate cortices (all p<0.0001 vs. TBIsaline). TBI-induced elevations in cortical QUIN were further elevated by MOR at 30 dpi (p=0.04 vs. TBI-saline). These findings suggest that MOR treatment exacerbates TBIinduced elevations in chronic pain, neuroinflammation, and the central KP response, warranting future studies to explore the KP as a therapeutic target for post-TBI pain management.

Volume

42

Issue

13-14

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