Abstract SNACC-33

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Cathepsin G – a novel protease in the regulation of chronic pain

Liu X, Tian Y, Meng A, Gin T, Cheng C, Chan M
The Chinese University of Hong Kong, Hong Kong SAR, , China

Introduction: Proteases have been shown to modulate pain signaling in central sensitization. In a series of rat experiments, we aimed to identify the protease network during the development of chronic pain using a genome-wide screening approach. We then determined the role of cathepsin G (CTSG) as a novel protease in the modulation of spinal pain signaling. Finally, we evaluated the clinical relevance of our animal experiments by determining the association between CTSG gene polymorphisms and the risk of chronic postsurgical pain in a cohort of surgical patients.

Methods: We conducted a microarray analysis of spinal dorsal horn in rats with chronic inflammatory pain after intraplantar injection of complete Freund's adjuvant (CFA). Using an intrathecal catheter, we injected twice daily specific CTSG inhibitor (CatGI) or saline vehicle to rats with CFA induced chronic inflammatory pain. Heat hyperalgesia was determined by using the plantar analgesia meter.
In order to determine the role of CTSG in the development of chronic pain in humans, we genotyped variants in the CTSG gene of 1,152 patients undergoing a wide variety of surgery. Patients were contacted at 12 months after index surgery and were asked to rate their experience of pain over the surgical site using the brief pain inventory. A multivariable logistic regression was performed to determine the association of CTSG gene polymorphism on chronic postsurgical pain. The animal experimentation and clinical research ethics committee approved our animal and human gene association studies, respectively. All patients gave written informed consents.

Results: In the microarray analysis, we found that the expression of CTSG was the most up-regulated candidate gene (4.7 fold, p = 0.0003) in CFA rats (n = 4) compared with control (n = 4). Inhibition of CTSG reduced heat hyperalgesia (Figure 1). This was contributed by the reduction in neutrophil infiltration and a decrease of IL 1β levels in the spinal dorsal horn. In patients undergoing surgery, polymorphisms of two CTSG genes were associated with a lower risk of chronic postsurgical pain [rs2070697, odds ratios (95%CI): 0.57 (0.23-1.42); rs2236742, odds ratio (95%CI): 0.24 (0.13-0.45)].

Conclusions: Our study demonstrated that CTSG is a pro-nociceptive 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.

Figure 1: (A) CTSG inhibition with intrathecal inhibitor (CatGI) reduced heat hyperalgesia as indicated with higher paw withdrawal latency (PWL), n=8 in each group, ANOVA p < 0.001. *p < 0.05, **p < 0.01, unpaired t test. (B and C) Spinal cord sections showed an increase in myeloperoxidase positive cells (green), 4 days after CFA injection. (D) Intrathecal injection of CatGI reduced IL1β expression. High CatGI=100 μM in 10 μL, Low CatGI=10 μM in 10 μL, n=6 in each group.

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