A New Potential Antidepressant: Dexmedetomidine Alleviates Neuropathic Pain-Induced Depression by Increasing Neurogenesis in the Hippocampus

Abstract

<b><i>Introduction:</i></b> Studies have suggested dexmedetomidine (DEX) as a potential antidepressant. However, no relevant research exists on its effects and mechanisms in curing depression caused by chronic pain. Therefore, an understanding of DEX’s role in depressive disorders proposes new approaches for antidepressant treatment. <b><i>Methods:</i></b> In this study, C57Bl/6 mice (<i>n</i> = 80) were divided into sham (<i>n</i> = 8) and chronic constrictive injury (CCI, <i>n</i> = 72) groups. The CCI group was further divided into six subgroups: CCI + normal saline (NS), CCI + DEX6.25, CCI + DEX12.5, CCI + DEX25, CCI + DEX50, and CCI + DEX100. Fourteen days after CCI, mice that did not develop a depressive phenotype were excluded through sucrose preference test (SPT), forced swimming test (FST), paw thermal withdrawal latency (PTWL), and serum corticosterone (CORT). Subsequently, mice in the sham group were administered 0.1 mL/10 g NS once daily. However, mice in the CCI subgroups were administered NS (0.1 mL/10 g), DEX (6.25 µg/kg), DEX (12.5 µg/kg), DEX (25 µg/kg), DEX (50 µg/kg), and DEX (100 µg/kg) intraperitoneally once daily for 1 week, respectively. Afterward, bromodeoxyuridine (BrdU) was injected intraperitoneally once daily as well for 3 consecutive days before sampling, following BrdU- and doublecortex (DCX)-positive cell detection in the hippocampus through immunofluorescence. <b><i>Results:</i></b> The success rate of the chronic pain-depression (CPD) model was 62.5%. As observed, DEX dose-dependently affected sucrose preferences during the SPT and immobility time during FST. Results also showed that 25 µg/kg DEX had the best promotion effect during increased sucrose preference and reduced immobility time. Moreover, although DEX improved PTWL and serum CORT, no improvement over the DEX 25 µg/kg treatment was observed. Compared to the sham group, the percentage of BrdU+ and DCX+ cells was also significantly lower in the CCI + NS group. Besides, DEX dose-dependently affected cell proliferation and neuronal differentiation. Additionally, the percentage of BrdU+ and DCX+ cells in the dentate gyrus (DG) region of the hippocampus was highest in the CCI + DEX25 group. <b><i>Conclusion:</i></b> Therefore, DEX dose-dependently alleviates depression induced by chronic pain through neurogenesis promotion in the DG region of the hippocampus.