Up-regulation of Cathepsin G in the Development of Chronic Postsurgical Pain: An Experimental and Clinical Genetic Study.
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.
From the Departments of Anaesthesia and Intensive Care (X.L., Y.T., Z.M., Y.C., I.H.T.H., T.G., W.K.K.W., M.T.V.C.) and Obstetrics and Gynaecology (K.W.C.), The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong Special Administrative Region, People's Republic of China; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany (P.L.); Institute of Digestive Disease and State Key Laboratory of Digestive Disease, and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China (S.H.W., J.Y.); and School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China (C.H.K.C.).
Xiaodong
X
Liu
Yuanyuan
Y
Tian
Zhaoyu
Z
Meng
Yan
Y
Chen
Idy H T
IH
Ho
Kwong Wai
KW
Choy
Peter
P
Lichtner
Sunny H
SH
Wong
Jun
J
Yu
Tony
T
Gin
William K K
WK
Wu
Christopher H K
CH
Cheng
Matthew T V
MT
Chan
D000368:Aged; D000818:Animals; D056649:Cathepsin G / Q000096:biosynthesis* / Q000235:genetics; D002478:Cells, Cultured; D059350:Chronic Pain / Q000235:genetics / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010147:Pain Measurement / Q000379:methods; D010149:Postoperative Pain / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000502:physiology
C534094:CTSG protein, human; D056649:Cathepsin G; C534097:Ctsg protein, rat