Circadian disruption increases the risk of neurological disorders, yet its impact on neuropathic pain (NP), a type of pain caused by nerve lesion, remains poorly understood. This study examined how three weeks of repetitive circadian disruption affects mechanical sensory thresholds and the spinal transcriptome in male C57BL/6JRj mice subjected to spared nerve injury (SNI) by using the chronic jet lag (JL) model. We also compared behavioural and transcriptomic outcomes between SNI and sham-operated control mice under either JL or a regular light/dark (LD) schedule. Mechanical hypersensitivity was assessed using von Frey tests at baseline and on post-surgical days 7, 14, and 21. Ipsilateral spinal cord tissues were collected four-hourly for 24 h for RNA sequencing. Differentially expressed genes (DEGs) were identified, and rhythmic transcripts analysed to compare changes in mesor, amplitude, and phase. Repetitive circadian disruption reduced mechanical thresholds in sham controls and in the uninjured paw of SNI mice, indicating increased mechanical hypersensitivity. Under JL, there were 137 upregulated and 25 downregulated spinal DEGs in SNI, enriched for immune-related processes. Rhythmicity analysis revealed 140 rhythmic transcripts in SNI and 801 in sham mice under JL. SNI mice exhibited a marked reduction in rhythmic transcripts under JL (140) relative to LD (680), whereas sham mice maintained similar rhythmic transcript numbers across conditions (801 in JL; 758 in LD). Three DEGs showed significant JL-related changes in rhythmic parameters and were rhythmic only in sham mice. These findings demonstrate that JL-induced circadian disruption exacerbates pain sensitivity and alters spinal transcriptional rhythms.
