Expression of Sensory Neuropeptides in Tendon is Associated with Failed Healing and Activity-Related Tendon Pain in Collagenase-Induced Tendon Injury

Abstract

Background Increase in expression of substance P (SP) and calcitonin gene-related peptide (CGRP) has been reported in clinical samples of tendinopathy. Purpose To examine the spatial-temporal expression of these neuropeptides as well as their association with activity-related tendon pain, matrix degeneration, failed healing, and pathologic calcification in an established collagenase-induced tendon injury rat model. Study Design Controlled laboratory study. Methods Collagenase or saline was injected into the patellar tendon of rats. At weeks 2, 4, 8, 12, and 16, just before the rats were sacrificed, the double-stance duration of rats was examined by gait analysis method. After sacrifice, the patellar tendons were harvested for histologic analysis and immunohistochemical staining of SP and CGRP. Results There was an increase of SP and CGRP immunopositivity in tendon fibroblasts at week 2. The immunopositive signals decreased at weeks 4 and 8 and were observed in chondrocyte-like cells. At weeks 12 and 16, the immunopositive staining increased again and was observed in cells embedded in calcific deposits in addition to tendon fibroblasts and chondrocyte-like cells. The expression pattern was consistent with matrix degeneration, calcification, and failed healing in the animal model. There were significant positive correlations of immunopositivity of SP (rho = .502, P = .002) and CGRP (rho = .483, P = .003) with double-stance duration after collagenase injection. Conclusion There was increased expression of SP and CGRP after collagenase-induced tendon injury, and their expression was positively associated with double-stance duration. Clinical Relevance Substance P and CGRP might be involved in the pathogenesis and origin of pain of tendinopathy and could be the targets for future intervention.