Nociceptive Sensitization by Activation of Protease-Activated Receptor 2 in a Rat Model of Incisional Pain

Kanta Kido,Shigekazu Sugino,Masanori Yamauchi,Hiromasa Kawana,Eiji Masaki,Norika Katagiri

doi:10.3390/brainsci11020144

Abstract

Postoperative pain and consequent inflammatory responses after tissue incision adversely affects many surgical patients due to complicated mechanisms. In this study, we examined whether activation of protease-activated receptor 2 (PAR-2), which is stimulated by tryptase from mast cells, elicits nociception and whether the PAR-2 antagonist could reduce incisional nociceptive responses in vivo and in vitro. The effects of a selective PAR-2 antagonist, N3-methylbutyryl-N-6-aminohexanoyl-piperazine (ENMD-1068), pretreatment on pain behaviors were assessed after plantar incision in rats. The effects of a PAR-2 agonist, SLIGRL-NH2, on nociception was assessed after the injection into the hind paw. Furthermore, the responses of C-mechanosensitive nociceptors to the PAR-2 agonist were observed using an in vitro skin–nerve preparation as well. Intraplantar injection of SLIGRL-NH2 elicited spontaneous nociceptive behavior and hyperalgesia. Local administration of ENMD-1068 suppressed guarding behaviors, mechanical and heat hyperalgesia only within the first few hours after incision. SLIGRL-NH2 caused ongoing activity in 47% of C-mechanonociceptors in vitro. This study suggests that PAR-2 may support early nociception after incision by direct or indirect sensitization of C-fibers in rats. Moreover, PAR-2 may play a regulatory role in the early period of postoperative pain together with other co-factors to that contribute to postoperative pain.

Highlights

Postoperative pain is caused by multiple processes including inflammatory, neuropathic and ischemic components [1,2,3,4]
We examined rats and we tested whether the selective protease-activated receptor 2 (PAR-2) antagonist N3-methylbutyryl-N-6-aminohexanoyl-piperazine (ENMD-1068) could reduce incisional nociception, and whether the injection of a PAR-2 agonist SLIGRL-NH2 elicited pain in vivo
There was a greater effect after injection of 1 mM 100 μL of SLIGRL-NH2, which produced nociceptive behavior from 5 min to 10 min compared with phosphate buffered saline (PBS)-vehicle (0.6 ± 0.2 vs. 13.7 ± 3.1, p < 0.001; n = 8 per group)

Summary

Introduction

Postoperative pain is caused by multiple processes including inflammatory, neuropathic and ischemic components [1,2,3,4]. Various mechanisms of postoperative pain have been investigated, including excitation, sensitization and inhibition of the peripheral and central nervous system [1,7,8]. Many inflammatory mediators from immune cells or resident cells involving neutrophils, platelets, macrophages and mast cells, contribute to peripheral nociceptive sensitization after tissue injury [9,10]. Oliveira et al described that preventing degranulation of mast cells reduced spontaneous pain and mechanical allodynia after plantar incision in mice [16,17], and we previously reported that mast cell stabilization by cromoglycate promoted antinociceptive effects in mice [18]. The antagonism of typical mediators like serotonin and histamine has shown weak efficacy in a surgery-induced pain in rodents [16,19,20], suggesting that other mediators could participate in the pain process

Results

Discussion

Conclusion