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Impairment and restoration of the blood-nerve barrier and its correlation with pain following gradual nerve elongation of the rat sciatic nerve

Abstract Purpose: This study aimed to evaluate the time course of impairment and restoration of the blood-nerve barrier (BNB) following gradual elongation of the sciatic nerve and to clarify its association with nociception. Materials and Methods: The right femur was lengthened at a rate of 1.5 mm/day for 10 days. Von Frey tests were performed until 50 days after lengthening. Compound muscle action potentials (CMAPs) were measured to assess gross dysfunction of the elongated nerve. Evans blue-albumin tracing and immunohistochemistry for endothelial barrier antigen (EBA), rat endothelial cell antigen-1 (RECA-1), and CD68 for qualitative and quantitative analysis of the BNB and macrophage infiltration were performed for up to 50 days after cessation of lengthening in three segments of the sciatic nerves. Results: Paw-withdrawal threshold was significantly decreased at 7 days from initiation and began to recover from day 25 after lengthening. CMAPs showed delayed latency and attenuated amplitude but recovered at day 30 after cessation. On days 10 and 30 after cessation, spotted leakage of Evans blue-albumin in the endoneurium was observed, and the ratio of EBA/RECA-1-positive microvessels was significantly decreased, which subsequently recovered simultaneously in all segments on day 50 after cessation. Macrophages did not infiltrate the BNB at any time point. Conclusion: The restoration of BNB function following gradual nerve elongation was associated with the resolution of mechanical allodynia. Our findings provide insight into the association between nerve stretch injury and chronic nociception in adult male rats, which are potentially relevant to human orthopedic procedures and chronic neuropathic pain.