Skin/muscle incision and retraction regulates the persistent postoperative pain in rats by the Epac1/PKC-βII pathway

Qian, Junhong; Lin, Xuezheng; Zhou, Zhili

doi:10.1186/s12871-022-01771-w

Cited by 3 publications

(2 citation statements)

References 44 publications

(35 reference statements)

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“…Activation of EPAC1 in postsurgical pain may induce local postoperative recovery processes and may be an important mechanism for controlling chronic postoperative pain [ 13 ]. Modulation of persistent postoperative pain in rats via the EPAC1/PKC-betaII (protein kinase C, PKC) pathway has been shown in a postoperative tonic pain model [ 14 ]. Furthermore, EPAC1 may act synergistically with other anesthetic drugs such as propofol to co-regulate the spinal GluN2B-p38MAPK pathway to alleviate postoperative pain in animal models of postoperative pain [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Role of EPAC1 in chronic pain

Jiang,

Zhao,

Zhang

et al. 2024

Biochemistry and Biophysics Reports

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Section: Introductionmentioning

confidence: 99%

Role of EPAC1 in chronic pain

Jiang,

Zhao,

Zhang

et al. 2024

Biochemistry and Biophysics Reports

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“…Recently, Epac1, a sensor of cAMP, was reported to display an increase in the DRG that could promote the transition toward chronic pain. This might be a potential pathway for treating chronic pain ( 4 , 23 ). However, the underlying mechanisms are still unclear.…”

Section: Introductionmentioning

confidence: 99%

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

Chen¹,

Qing²,

Liu³

et al. 2022

Ann Transl Med

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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 macrophagederived, 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.

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Inhibition of CXCR2 as a therapeutic target for chronic post-surgical pain: Insights from animal and cell models

Zhao,

Jian,

Chen

et al. 2024

Cytojournal

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Objective: Studies have shown that chemokines can stimulate the migration and activation of microglia to cause chronic post-surgical pain (CPSP). However, the involvement of C-X-C motif chemokine receptor 2 (CXCR2) as a new chemotactic factor in regulating CPSP and its underlying mechanism remains unclear. This study is to investigate the role of CXCR2 in the development of CPSP and reveal the underlying mechanism. Material and Methods: A rat model of skin/muscle incision and retraction was established, and treated with or without SB225002 (a selective inhibitor of CXCR2). In addition, the primary microglia cells induced by lipopolysaccharide were applied as an in vitro model for CPSP and treated individually with si-negative control (NC), si-CXCR2, si-CXCR2+Interleukin (IL)-6 (an agonist of the janus kinase (JAK)/signal transducers and activators of transcription (STAT)3 signaling pathway), si-CXCR2+IL-6+si-NC, or si-CXCR2+IL-6+si-exchange protein 1 directly activated by cAMP (EPAC1). Results: Results from the database analysis showed that CXCR2 and JAK/STAT3 signaling pathway-related genes, including JAK1, STAT3, and EPAC1, were mainly involved in the development of CPSP. Inhibition of CXCR2 expression not only inhibited the reduction of foot pain threshold in CPSP models but also led to a decreased expression of CXCR2 and the phosphorylation levels of JAK and STAT3 in both animal and cell models. Furthermore, inhibition of EPAC1 expression can hinder the regulatory function of CXCR2. Conclusion: This study indicated that the high expression of CXCR2 activates the JAK1/STAT3 signaling pathway, enhances EPAC1 activation in microglial cells, and exacerbates CPSP.

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Skin/muscle incision and retraction regulates the persistent postoperative pain in rats by the Epac1/PKC-βII pathway

Cited by 3 publications

References 44 publications

Role of EPAC1 in chronic pain

Role of EPAC1 in chronic pain

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

Inhibition of CXCR2 as a therapeutic target for chronic post-surgical pain: Insights from animal and cell models

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