Subanesthetic Dose of Ketamine Improved CFA-induced Inflammatory Pain and Depression-like Behaviors Via Caveolin-1 in Mice Background: Ketamine, a commonly used nonbarbiturate anesthetic drug, possesses antidepressant properties at subanesthetic doses; however, the underlying mechanisms remain unclear. Materials and Methods: The analgesic and antidepressant effects of ketamine were explored using a complete Freund adjuvant (CFA)-induced peripheral inflammatory pain model in vivo. Mice were first divided into sham or CFA injection group randomly, and were observed for mechanical hyperalgesia, depression-like behavior, and mRNA expression of caveolin-1. Then ketamine was administered in CFA-treated mice at day 7. Results: The behavioral testing results revealed mechanical hyperalgesia and depression in mice from days 7 to 21 after CFA injection. Ketamine reversed depression-like behaviors induced by CFA injection. It also restored the brain-regional expression levels of caveolin-1 in CFA-treated mice. In addition, caveolin-1 mRNA and protein expression were increased in the prefrontal cortex and nucleus accumbens of CFA-treated mice. However, ketamine reversed the increase in caveolin-1 expression in the ipsilateral and contralateral prefrontal cortex and nucleus accumbens, supporting the distinct roles of specific brain regions in the regulation of pain and depression-like behaviors. Conclusions: In CFA-treated mice that exhibited pain behavior and depression-like behavior, ketamine reversed depression-like behavior. The prefrontal cortex and nucleus accumbens are the important brain regions in this regulation network. Despite these findings, other molecules and their mechanisms in the signal pathway, as well as other regions of the brain in the pain matrix, require further exploration. J.L. and R.H. contributed equally to this work. J.W. and Q.Z. are co-first authors. This work was funded by the Beijing Municipal Administration of Hospitals’ Ascent Plan (code number DFL20180502) and Clinical Medicine Development of Special Funding Support (code number ZYLX201708). R.H. is a member of the Editorial Board of the Journal of Neurosurgical Anethesiology. The authors have no conflicts of interest to disclose. Address correspondence to: Ruquan Han, MD, PhD. E-mail: ruquan.han@ccmu.edu.cn. Received November 21, 2018 Accepted April 8, 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved