Establishment of a mouse model for injury-induced scar formation and the accompanying chronic pain: Comprehensive microarray analysis of molecular expressions in fibrosis and hyperalgesia

Background: Surgery is often accompanied by scar formation, which results in a pathological state called fibrosis. Fibrosis is characterized by the excess deposition of extracellular matrix molecules in the connective tissue, leading to tissue contracture and chronic pain. To understand the molecular mechanisms underlying these processes and their causative relationships, we performed comprehensive analyses of gene expression changes in the hind paw tissue of a mouse model established by generating a scar in the sole. Results: Subcutaneous tissue was extensively stripped from the sole of the operation group mice, while a needle was inserted in the sole of the sham group mice. Pain threshold, as evaluated by mechanical stimulation with von Frey fiber, decreased rapidly in the operated (ipsilateral) paw and a day later in the nonoperated (contralateral) paw. The reductions were maintained for more than three weeks, suggesting that chronic pain spread to the other tissues via the central nervous system. RNA from the paw and the dorsal root ganglion (L3–L5) tissues were subjected to microarray analyses one and two weeks following the operation. The expressions of a number of genes, especially those coding for extracellular matrix molecules and peripheral perceptive nerve receptors, were altered in the operation group mice paw tissues. The expression of few genes was altered in the dorsal root ganglion tissues; distinct upregulation of some nociceptive genes such as cholecystokinin B receptor was observed. Results of real-time polymerase chain reaction and immune and histochemical staining of some of the gene products confirmed the results of the microarray analysis. Conclusion: Analyses using a novel mouse model revealed the extensive involvement of extracellular matrix-related genes and peripheral perceptive nerve receptor genes resulting in scar formation with chronic pain. Future bioinformatics analyses will explore the association between these relationships.