Differential Effects of Pregabalin and Morphine on the Sleep-Wake Cycle and Circadian Rhythms in Mice with Neuropathic Pain

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 (EEG), electromyogram (EMG), locomotion, and body temperature. After baseline recordings, SNI was performed, and mechanical and dynamic allodynia assessed on days 3, 7, and 14 post-surgeries. Pregabalin (11 mg/kg/day) or morphine (6 mg/kg/day) was administered continuously to male mice via intraperitoneal osmotic minipumps. Recordings were repeated on post-operative 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 pre-surgical levels and more effectively restored locomotor activity and body temperature rhythmicity 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 3.5-5.5 Hz range during REM sleep. Morphine did not significantly alter either sleep architecture or microstructure in SNI mice. Conclusion: Pregabalin, unlike morphine, restores SNI-disrupted sleep architecture, circadian rhythms, and spinal circadian gene expression.