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

Abstract 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 We performed morphological and single-cell transcriptomic analysis on spinal microglia from opioid-withdrawn and saline-treated mice, and found that while morphological changes recapitulated prior reports, transcriptomic changes in these cells were modest.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 Δ/ΔFIRE 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.