Morphine self-administration induces region-specific brain volume changes and microglial phenotypic alterations without affecting neuronal density in male Wistar rats

Elizarraras-Herrera, A. D.; Medina-Sanchez, D.; Serrano-Ramirez, M. S.; Angeles Valdez, D.; Trujillo-Villarreal, L. A.; Carbajo-Mata, M. A.; Carranza-Aguilar, C.; Garza-Villarreal, E. A.

doi:10.1101/2025.02.20.639378

bioRxiv · 10.1101/2025.02.20.639378

Morphine self-administration induces region-specific brain volume changes and microglial phenotypic alterations without affecting neuronal density in male Wistar rats

Elizarraras-Herrera, A. D.·Medina-Sanchez, D.·Serrano-Ramirez, M. S.·Angeles Valdez, D.·Trujillo-Villarreal, L. A.·Carbajo-Mata, M. A.·Carranza-Aguilar, C.·Garza-Villarreal, E. A.

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Abstract

Addiction to opioids, including morphine, is a major public health crisis in the U.S. It has been associated with brain volume changes in reward-related regions, neuronal death, and neuroinflammation. However, the link between structural changes and neuroinflammation is not well understood. In this study, we used operant conditioning to induce morphine self-administration in rats and examined brain volume and cellular changes, focusing on microglial phenotypes. Male Wistar rats were conditioned to morphine self-administration (0.01 mg/kg) for 20 days under a fixed-ratio 1 schedule. In vivo structural Magnetic Resonance Imaging (MRI) scans were conducted at the beginning and end of self-administration. Brains were stained for Iba1 and NeuN proteins, and confocal images were analyzed for cell counts and microglial morphology. We used Deformation-Based Morphometry for MRI volume analysis and Principal Component Analysis with K-means clustering for microglial phenotyping. Our results showed that morphine self-administration led to volume changes in addiction-related brain regions, including increased globus pallidus and decreased insular cortex volume. Additionally, morphine caused widespread neuroinflammation, evidenced by elevated microglial density in the caudate-putamen, dentate gyrus, globus pallidus, and insular cortex, without affecting neuron counts. Finally, we observed region-specific variations in microglial phenotypes, suggesting region-specific neuroinflammatory roles. In conclusion, our study shows that morphine self-administration induces structural and microglial changes in addiction-related brain regions without neuronal loss, highlighting the role of neuroinflammation in opioid-induced adaptations. The variability in microglial phenotypes underscores their complexity, emphasizing the need to study their progression in addiction and their potential as therapeutic targets.

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Elizarraras-Herrera, A. D., Medina-Sanchez, D., Serrano-Ramirez, M. S., Angeles Valdez, D., Trujillo-Villarreal, L. A., Carbajo-Mata, M. A., Carranza-Aguilar, C., Garza-Villarreal, E. A.. 2025-02-25. Morphine self-administration induces region-specific brain volume changes and microglial phenotypic alterations without affecting neuronal density in male Wistar rats. https://doi.org/10.1101/2025.02.20.639378

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