Lee, K. V. | bioRxiv Science

bioRxiv2026

Spinal microglia are dispensable for the development of opioid-induced hyperalgesia

Adverse side effects of chronic opioid use, including analgesic tolerance, opioid-induced hyperalgesia, and addiction, are serious clinical challenges for pain management and opioid deprescribing. Microglia have been implicated in the development of these adverse effects, but the extent to which opioids alter microglia and the mechanisms behind opioid effects on microglia are poorly understood. We performed morphological and single-cell transcriptomic analysis on spinal microglia from opioid-withdrawn and saline-treated mice, and found that while morphological changes recapitulated prior reports, transcriptomic changes in these cells were modest. Furthermore, peripherally, but not centrally, restricted opioid administration was sufficient to induce both hyperalgesia and microglial morphological changes in mice. Finally, complete loss of microglia in Csf1r{Delta}{Delta}FIRE mice did not prevent the development of opioid-induced hyperalgesia, analgesic tolerance, and somatic withdrawal symptoms. These data argue against any microglial involvement in the development of these phenomena.

neuroscience↗

bioRxiv2022

Social isolation produces a brain-region specific expansion of microglia structure and reorganization of neural activity

Social isolation is a profound form of psychological stress that impacts the mental health of a large proportion of society. Other experimental models of stress and injury have demonstrated microglia activation and alterations in neural activity. Microglia and neural activity undergo coordinated changes under physiological and pathological states. However, the effect of social isolation on microglia and neural activity has not been thoroughly investigated. Here we show that the dorsal medial hypothalamus and hippocampal CA2 region of male mice undergo an increased microglia volume and branching following social isolation, whereas females exhibit this increase in the hypothalamus only. The prefrontal cortex, central amygdala, nucleus accumbens shell, and visual cortex did not exhibit changes in microglia structure in either male or female mice. The home cage resting level of neural activity, as measured by the immediate early gene c-fos, was reduced in CA2 and the prefrontal cortex of female but not male mice following isolation. However, the co-variation in neural activity across brain regions was abolished in male but not female isolated mice. These data show that different brain regions undergo independent and dissociable changes in microglia structure and network activity following social isolation which may account for changes in cognition and behavior associated with this form of psychological stress.

neuroscience↗