Chronic pain and its prevention by physical exercise: cellular signaling mechanisms involving muscular, immunological and nervous system

Abstract

Despite the clinical relevance of chronic muscle pain, the mechanisms underlying its chronification are not fully elucidated. Recent experiments of our laboratory demonstrate that acute and chronic inflammatory muscle pain are characterized by an increase in macrophages with a pro-inflammatory phenotype and that in the acute phase, but not in the chronic, there is an increase in IL-1² cytokine. We also demonstrated that both regular physical exercise through swimming and the activation of PPAR³ receptors through its 15dPGJ2 agonist prevented these increases and/or induced an increase in macrophages with an anti-inflammatory phenotype. Exercise also increased the tissue concentration of IL-10 in both the acute and chronic phases of muscle pain, but only in the chronic phase, through PPAR³ receptors. Considering these findings, the present study aims to advance the investigation of the mechanisms involved in the process of chronic muscle inflammation as well as the mechanisms involved in its prevention by physical exercise. We will evaluate the following mechanisms: 1) signaling between myocytes and macrophages in the development and maintenance of acute and chronic muscle pain as well as in their prevention by physical exercise: Involvement of the signaling pathway PGC-1±/ PPAR³; 2) the involvement of the inflammatory cytokine IL-1² released in the muscle tissue and the dorsal horn of the spinal cord in maintaining the chronicity of muscle pain and its prevention by physical exercise; and 3) the role of astrocytes and microglia in the development and maintenance of chronic muscle pain and its prevention by physical exercise. To this end, we will use behavioral pharmacology, transgenic animals, and different molecular biology techniques, such as immunofluorescence, cell culture, western blot, RTqPCR, ELISA, overexpression, and knockout of genes through plasmids and CRISPR, respectively. Finally, all in vivo experiments will be evaluated in male and female animals and, in this case, the analysis of the estrous cycle will be performed. (AU)