Up-regulation of Cathepsin G in the Development of Chronic Postsurgical Pain: An Experimental and Clinical Genetic Study

• Published in: Anesthesiology (Philadelphia) 2015-10, Vol.123 (4), p.838-850
• Main Authors: Liu, Xiaodong, Tian, Yuanyuan, Meng, Zhaoyu, Chen, Yan, Ho, Idy H T, Choy, Kwong Wai, Lichtner, Peter, Wong, Sunny H, Yu, Jun, Gin, Tony, Wu, William K K, Cheng, Christopher H K, Chan, Matthew T V
• Format: Article
• Language: English
• Subjects: Aged; Animals; Cathepsin G - biosynthesis; Cathepsin G - genetics; Cells, Cultured; Chronic Pain - genetics; Chronic Pain - metabolism; Cohort Studies; Female; Humans; Male; Middle Aged; Pain Measurement - methods; Pain, Postoperative - genetics; Pain, Postoperative - metabolism; Rats; Rats, Sprague-Dawley; Up-Regulation - physiology
• ISSN: 0003-3022; 1528-1175
• DOI: 10.1097/ALN.0000000000000828

BACKGROUND:Proteases have been shown to modulate pain signaling in the spinal cord and may contribute to the development of chronic postsurgical pain. By using peripheral inflammation in rats as a chronic pain model, the authors identified the deregulation of proteases and their inhibitors as a hallmark of chronic pain development using a genome-wide screening approach. METHODS:A microarray analysis was performed and identified spinal cathepsin G (CTSG) as the most up-regulated gene in rats with persistent hyperalgesia after intraplantar injection of complete Freund’s adjuvant (n = 4). Further experiments were performed to elucidate the mechanisms of CTSG-induced hyperalgesia by intrathecally applying specific CTSG inhibitor (n = 10). The authors also evaluated the association between CTSG gene polymorphisms and the risk of chronic postsurgical pain in 1,152 surgical patients. RESULTS:CTSG blockade reduced heat hyperalgesia, accompanied by a reduction in neutrophil infiltration and interleukin 1β levels in the dorsal horns. In the gene association study, 246 patients (21.4%) reported chronic postsurgical pain at 12-month follow-up. Patients with AA genotypes at polymorphisms rs2070697 (AA-15.3%, GA-24.1%, and GG-22.3%) or rs2236742 (AA-6.4%, GA-20.4%, and GG-22.6%) in the CTSG gene had lower risk for chronic postsurgical pain compared with wild-types. The adjusted odds ratios were 0.67 (95% CI, 0.26 to 0.99) and 0.34 (95% CI, 0.21 to 0.98), respectively. CONCLUSIONS:This study demonstrated that CTSG is a pronociceptive mediator in both animal model and human study. CTSG represents a new target for pain control and a potential marker to predict patients who are prone to develop chronic pain after surgery.