Abstract
BACKGROUND: Neuropathic pain is commonly associated with disturbances in sleep architecture and circadian rhythms, leading to fragmented sleep, body temperature fluctuations, and altered locomotion. While pregabalin and morphine are frequently prescribed for neuropathic pain management, their effects on sleep and circadian regulation are poorly understood. METHODS: To identify the effects of spared nerve injury (SNI) on sleep architecture and circadian rhythms, male and female C57BL/6JRJ mice were implanted with wireless transmitters for continuous monitoring of electroencephalogram, electromyogram, locomotion, and body temperature. After baseline recordings, SNI was performed, and mechanical and dynamic allodynia was assessed on days 3, 7, and 14 after the surgeries. Pregabalin (11 mg/kg each day) or morphine (6 mg/kg each day) was administered continuously to male mice via intraperitoneal osmotic minipumps. Recordings were repeated on postoperative days 7 and 14. RESULTS: SNI significantly disrupted the sleep-wake cycle by reducing rapid eye movement (REM) sleep duration during the light phase (the habitual sleeping phase for mice) in both sexes and increasing wakefulness in females, without significantly affecting non-REM sleep. Additionally, SNI significantly impaired the circadian rhythmicity of locomotion and body temperature. Pregabalin, but not morphine, significantly restored REM sleep to presurgical levels and restored locomotor activity and body temperature rhythmicity more effectively than morphine. At the molecular level, SNI altered spinal cord circadian gene expression, which pregabalin significantly reversed, whereas morphine showed mixed effects. Furthermore, pregabalin increased sleep spindle occurrence during sleep stage transitions and enhanced the power spectra within the 3.5- to 5.5-Hz range during REM sleep. Morphine did not significantly alter either sleep architecture or microstructure in SNI mice. CONCLUSIONS: Pregabalin, unlike morphine, restores SNI-disrupted sleep architecture, circadian rhythms, and spinal circadian gene expression.