Abstract
BACKGROUND: Postoperative sleep disturbances are common and have been shown to exacerbate incisional pain by enhancing the central nervous system's excitability. However, the specific neural circuit mechanisms underlying the pain chronification induced by postoperative sleep deprivation remain largely elusive. METHODS: We established a model of postoperative pain by plantar incision with perioperative sleep deprivation 6 h/day for 3 consecutive days in male mice. The activity of the neurons in the paraventricular thalamus nucleus (PVT) and the locus coeruleus (LC) was assessed using immunofluorescence and fiber photometry. Viral tracing, immunofluorescence staining, chemogenetics, optogenetics, and fiber photometry were utilized to investigate the anatomical and functional connections of the neural circuit. Furthermore, chemogenetic and optogenetic manipulations, combined with behavioral tests, were employed to investigate the roles of various nuclei or neural circuits in the perioperative sleep deprivation-induced prolongation of postsurgical pain. RESULTS: Sleep deprivation prolonged the duration of postsurgical pain and increased the excitability of glutamatergic neurons in the PVT (PVT(Glu)) and tyrosine hydroxylase-positive neurons in the LC (LC(TH)). Viral tracing revealed a direct projection from LC(TH) neurons to PVT(Glu) neurons. Selective chemogenetic activation of the LC(TH)-PVT(Glu) pathway reduced sleep duration and replicated the pain-prolonging effects of sleep deprivation. Furthermore, viral tracing and morphology indicate that GABAergic neurons in the medial prefrontal cortex (mPFC(GABA)) receive projections from the LC(TH)-PVT(Glu) pathway. We found that hypersensitivity was sustained by the activation of the LC(TH)-PVT(Glu)-mPFC after incision, while its chemogenetic inhibition reversed sleep deprivation mediated pain prolongation. CONCLUSION: These findings indicate that brainstem-thalamocortical pathway mediates the sleep deprivation-induced prolongation of postoperative pain. This circuit may serve as a mechanistic link between disrupted arousal states and pain duration, representing a potential therapeutic target for managing postsurgical pain.