Melatonin Relieves Neuropathic Pain and Depressive‐Like Behaviors by Inhibiting the ERK/NF‐κB/c‐Fos Signaling Pathway in the Spinal Cord of Spared Nerve Injury Mice

ABSTRACT Neuropathic pain (NP) is marked by ongoing nociceptive signals and accompanied by symptoms resembling depression, which complicates treatment strategies. Melatonin (MT), a hormone known for its neuroprotective properties, has garnered attention for its potential in NP treatment, but its precise mechanisms remain incompletely understood. In this study, a spared nerve injury (SNI) model was established and MT was injected intraperitoneally. As a consequence, SNI mice displayed significantly reduced mechanical paw withdrawal thresholds (PWT) and thermal paw withdrawal latencies (PWL). Additionally, these mice demonstrated depressive‐like symptoms, as evidenced by prolonged immobility durations in both the forced swim test (FST) and the tail suspension test (TST). Further analysis found that there is an increase in the activation of the NF‐κB/ERK/c‐Fos signaling pathway and NLRP3 inflammasome‐related neuroinflammation. MT administration significantly increased PWT, prolonged PWL and reduced immobility time by inhibiting the NF‐κB/ERK/c‐Fos pathway and the subsequent formation of the NLRP3 inflammasome in SNI mice. This study highlights the dual therapeutic potential of MT through the modulation of the NF‐κB/ERK/c‐Fos signaling pathway, providing a novel potential target and strategy for the clinical treatment of NP with certain translational application value.