Acute increases in intramuscular inflammatory cytokines are necessary for the development of mechanical hypersensitivity in a mouse model of musculoskeletal sensitization.

Abstract

Musculoskeletal pain is a widespread health problem in the United States. Back pain, neck pain, and facial pain are three of the most prevalent types of chronic pain, and each is characterized as musculoskeletal in origin. Despite its prevalence, preclinical research investigating musculoskeletal pain is limited. Musculoskeletal sensitization is a preclinical model of muscle pain that produces mechanical hypersensitivity. In a rodent model of musculoskeletal sensitization, mechanical hypersensitivity develops at the hind paws after injection of acidified saline (pH 4.0) into the gastrocnemius muscle. Inflammatory cytokines contribute to pain during a variety of pathologies, and in this study we investigate the role of local, intramuscular cytokines in the development of mechanical hypersensitivity after musculoskeletal sensitization in mice. Local intramuscular concentrations of interleukin-1β (IL-1), IL-6 and tumor necrosis factor-α (TNF) were quantified following injection of normal (pH 7.2) or acidified saline into the gastrocnemius muscle. A cell-permeable inhibitor was used to determine the impact on mechanical hypersensitivity of inhibiting nuclear translocation of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) prior to musculoskeletal sensitization. The role of individual cytokines in mechanical hypersensitivity following musculoskeletal sensitization was assessed using knockout mice lacking components of the IL-1, IL-6 or TNF systems. Collectively, our data demonstrate that acidified saline injection increases intramuscular IL-1 and IL-6, but not TNF; that intramuscular pre-treatment with an NF-κB inhibitor blocks mechanical hypersensitivity; and that genetic manipulation of the IL-1 and IL-6, but not TNF systems, prevents mechanical hypersensitivity following musculoskeletal sensitization. These data establish that actions of IL-1 and IL-6 in local muscle tissue play an acute regulatory role in the development of mechanical hypersensitivity following musculoskeletal sensitization.