The Role of Sleep and Cytokines in the Development of Mechanical Hypersensitivity in a Mouse Model of Musculoskeletal Sensitization.

[摘要] Disordered sleep impacts more than 30% of the American population and an estimated 70 million patients with a diagnosed sleep disorder.Chronic pain also affects approximately 100 million Americans. Sleep and pain have a bi-directional link such that pain disrupts sleep and poor sleep enhances pain.Cytokines, small signaling molecules of the immune system, serve a regulatory role in physiological sleep and contribute to pain.Musculoskeletal sensitization is a pre-clinical model of the musculoskeletal pain associated with chronic diseases, including fibromyalgia, and causes mechanical hypersensitivity. This dissertation investigates the relationship between sleep and pain during musculoskeletal sensitization with a mechanistic focus on the role of cytokines.The quantification of sleep/wake behavior for 3 weeks after musculoskeletal sensitization demonstrates an increase in the number of sleep state transitions during the light period without altering sleep duration. During musculoskeletal sensitization the inflammatory cytokines interleukin (IL)-1 and IL-6 are significantly elevated in muscle tissue.Pharmacological manipulation to block the nuclear translocation of NF-κB intramuscularly prevents mechanical hypersensitivity following musculoskeletal sensitization. Genetic knockout of either IL-1 receptor 1 (R1) or IL-6, but not tumor necrosis factor-alpha receptor 1, inhibits the development of mechanical hypersensitivity following musculoskeletal sensitization.Fragmenting the sleep of mice for 5 days prior to musculoskeletal sensitization alters behavioral outcomes including mechanical hypersensitivity and subsequent sleep.Sleep fragmentation combined with musculoskeletal sensitization significantly increases state transitions of subsequent sleep, alters NREM sleep, alters delta power during NREM sleep, and increases mechanical hypersensitivity. Collectively, data in this dissertation demonstrate that musculoskeletal sensitization fragments sleep, intramuscular cytokines serve a mechanistic role in the development of mechanical hypersensitivity following musculoskeletal sensitization, and sleep fragmentation combined with musculoskeletal sensitization exacerbates the behavioral outcomes of sensitized mice including mechanical hypersensitivity and subsequent sleep.Musculoskeletal pain and sleep interactions represent a significant public health problem and the combined treatment costs are estimated in the trillions of dollars annually for the United States.Mechanistic understanding of the interactions between sleep and musculoskeletal pain can help to reduce the economic costs and improve patient quality of life.

[发布机构] University of Michigan

[效力级别] Sleep

[关键词] Chronic Pain;Sleep;Mouse;Sleep Fragmentation;Cytokines;Science (General);Science;Neuroscience