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

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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.

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