0063 Role of Sensory Neurons in Local Inflammation-Induced Hypersomnia

Abstract Introduction Peripheral inflammation often causes sickness symptoms including fever, anorexia, pain, and increased sleep. Circulating cytokines contribute to most of these behaviors, but the mechanisms by which local inflammation increases sleep remain unclear. Recent studies have evidenced a role for sensory neurons in detecting and responding to an infection. Here, we used a model of localized inflammation without fever to investigate the role of sensory neurons and inflammatory mediators in hypersomnia. Methods Adult male and female C57BL6j mice (10-12 weeks.) were instrumented for sleep (EEG/EMG electrodes) and body temperature (telemetry) recordings. To induce local inflammation, we injected Complete Freund’s adjuvant (CFA) intra-knee (5uL) or intraplantarly (5-20uL). We tested the role of peripheral sensory neurons by (1) selectively silencing Na(v)1.8+ neurons using a Cre-dependent tetanus toxin approach and (2) surgically transecting the sciatic nerve and injecting CFA either into the denervated sciatic territory or the (intact) contralateral hind paw. To test the contribution of inflammatory mediators, we administered non-steroidal anti-inflammatory drugs (NSAIDs) at analgesic doses versus vehicle, or a systemic neutralizing anti-TNFα (tumor necrosis factor; 100 ug) antibody versus control IgG. Results CFA-induced local inflammation of the hind paw or knee joint increased both NREM and REM sleep selectively during the dark (active) phase for up to 5 days, compared to saline-injected animals, with no fever. NSAID treatment at doses that alleviated pain did not prevent or attenuate CFA-induced hypersomnia and systemic TNF-α blockade did not reduce CFA-induced hypersomnia relative to IgG controls. In contrast, genetic silencing of Na(v)1.8+ sensory neurons almost completely prevented the CFA-induced increase in sleep. Moreover, sciatic nerve transection markedly reduced the sleep increase when CFA was injected in the denervated paw. Conclusion Together these results suggest that the sleep increase during local inflammation is largely driven by peripheral sensory neurons innervating the inflamed area. These findings identify a direct neural pathway by which inflamed tissue promotes sleep and suggest that sensory–brain communication is a potential target for improving recovery from injury and inflammation. Support (if any) Neurosurgery Pain Research Institute, NIH R01NS112266.