PMID- 36660643
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230121
IS  - 2305-5839 (Print)
IS  - 2305-5847 (Electronic)
IS  - 2305-5839 (Linking)
VI  - 10
IP  - 24
DP  - 2022 Dec
TI  - 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.
PG  - 1377
LID - 10.21037/atm-22-6069 [doi]
LID - 1377
AB  - 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.
CI  - 2022 Annals of Translational Medicine. All rights reserved.
FAU - Chen, Hongsheng
AU  - Chen H
AD  - Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, 
      China.
FAU - She, Qing
AU  - She Q
AD  - Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, 
      China.
FAU - Liu, Yanfang
AU  - Liu Y
AD  - Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, 
      China.
FAU - Chen, Junjie
AU  - Chen J
AD  - Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, 
      China.
FAU - Qin, Yibin
AU  - Qin Y
AD  - Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, 
      China.
FAU - Lu, Cui'e
AU  - Lu C
AD  - Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, 
      China.
LA  - eng
PT  - Journal Article
PL  - China
TA  - Ann Transl Med
JT  - Annals of translational medicine
JID - 101617978
PMC - PMC9843368
OTO - NOTNLM
OT  - Cav-1
OT  - Epac1
OT  - chronic postsurgical pain (CPSP)
OT  - vascular endothelial barrier
COIS- Conflicts of Interest: All authors have completed the ICMJE uniform disclosure 
      form (available at 
      https://atm.amegroups.com/article/view/10.21037/atm-22-6069/coif). All authors 
      report that this research was supported by National Natural Science Foundation of 
      China (No. 81701106). The authors have no other conflicts of interest to declare.
EDAT- 2023/01/21 06:00
MHDA- 2023/01/21 06:01
PMCR- 2022/12/01
CRDT- 2023/01/20 02:16
PHST- 2022/11/02 00:00 [received]
PHST- 2022/12/20 00:00 [accepted]
PHST- 2023/01/20 02:16 [entrez]
PHST- 2023/01/21 06:00 [pubmed]
PHST- 2023/01/21 06:01 [medline]
PHST- 2022/12/01 00:00 [pmc-release]
AID - atm-10-24-1377 [pii]
AID - 10.21037/atm-22-6069 [doi]
PST - ppublish
SO  - Ann Transl Med. 2022 Dec;10(24):1377. doi: 10.21037/atm-22-6069.