Evidence Based on Sleep Disorder Exacerbating Postoperative Pain via Kynureninase

Background: Surgery is a frequently employed intervention for patients; however, 30-80% of patients report moderate to severe pain after surgery. Postoperative pain is affected by a variety of factors, with sleep disturbance being a critical modulating factor that exacerbates postoperative pain intensity. Kynureninase (KYNU), a key hydrolase in the kynurenine pathway that produces quinolinic acid, may link sleep disturbances to pain sensitization; however, the underlying mechanisms remain unclear. Methods: We obtained skin and blood samples from 40 abdominal surgery patients and performed whole-transcriptome sequencing. Through analysis of the intersecting gene sets between patients with adequate and inadequate analgesia, as well as between those with sleep disorder and normal sleep, we identified genes significantly linked to both sleep disorders and postoperative pain. We established an animal model by making a hind paw plantar incision in mice subjected to chronic sleep deprivation. We then performed behavioral tests, including the tail flick test and von Frey filaments, measured the expression of differentially expressed genes via real-time quantitative polymerase chain reaction and immunofluorescence, and validated the results using pharmacological and calcium imaging methods. Results: We found that sleep deprivation greatly exacerbated postoperative pain, and KYNU was notably higher in the skin, blood, and dorsal root ganglion (DRG). Repeated intraperitoneal injections of carbidopa, a KYNU modulator, reduced the severity of pain induced by sleep deprivation and abnormal excitability of DRG neurons. Furthermore, in preclinical models, carbidopa treatment effectively reduced both inflammatory and neuropathic pain. Conclusion: We conclude that the upregulated expression of KYNU is associated with the exacerbation of postoperative pain due to sleep deprivation and identified the compound carbidopa as possessing significant analgesic potential.