The peripheral Epac1/p-Cav-1 pathway underlies the disruption of the vascular endothelial barrier following skin/muscle incision and retraction-induced chronic postsurgical pain.

Abstract

Background:

Vascular endothelial barrier disruption is pivotal in the development of acute and chronic pain. Here, we demonstrate a previously unidentified molecular mechanism in which activation of the peripheral Epac1/p-Cav-1 pathway accelerated the disruption of the vascular endothelial barrier, thereby promoting chronic postsurgical pain (CPSP).

Methods:

We established a rat model of CPSP induced by skin/muscle incision and retraction (SMIR). Pain behaviors were assessed by the mechanical withdrawal threshold (MWT) at different times. Local muscle tissues around the incision were isolated to detect the vascular permeability and the expression of Epac1 and Cav-1. They were assessed by western blot and immunofluorescence staining.

Results:

SMIR increased vascular endothelial permeability and the number of macrophages and endothelial cells in the muscle tissues around the incision. The peripheral upregulation of Epac1 was macrophage-derived, whereas that of p-Cav-1 was both macrophage and endothelial cell-derived in the SMIR model. Moreover, the Epac1 agonist 8-pCPT could induce mechanical sensitivity, increase the expression of p-Cav-1, and disrupt vascular endothelial barrier in normal rats. The Epac1 inhibitor CE3F4 attenuated established SMIR-induced mechanical hyperalgesia, the upregulation of p-Cav-1 and vascular endothelial barrier. Finally, we showed that intrathecal injection of Cav-1siRNA relieved SMIR-induced mechanical allodynia, but had no effects of the expression of Epac1.

Conclusions:

Collectively, these results revealed a molecular mechanism for modulating CPSP through the peripheral Epac1/Cav-1 pathway. Importantly, targeting Epac1/Cav-1 signaling might be a potential treatment for CPSP.

• Authors: Hongsheng Chen, Qing She, Yanfang Liu, Junjie Chen, Yibin Qin, Cui'e Lu
• Journal: Annals of translational medicine (Ann Transl Med) Vol. 10 Issue 24 Pg. 1377 (Dec 2022) ISSN: 2305-5839 [Print] China
• PMID: 36660643 (Publication Type: Journal Article)
• Copyright: 2022 Annals of Translational Medicine. All rights reserved.