Dataset Information

Exchange proteins directly activated by cyclic adenosine monophosphate inhibitor reverses mechanical allodynia via the modification of astrocytes activity in the spinal cord.

ABSTRACT:

Background

Gliosis and inflammation are pivotal in the development of acute and chronic pain. Here, we demonstrated a previously unidentified molecular mechanism in which the activation of exchange proteins directly activated by cyclic adenosine monophosphate (Epac)1 accelerated the activation of astrocytes in the spinal cord, 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 using mechanical withdrawal threshold (MWT) at different times. The lumbosacral enlargement of the spinal cord was isolated to detect the expression of Epac1 and the activity of astrocytes. They were assessed using western blot and immunofluorescence staining.

Results

SMIR induced persistent mechanical hyperalgesia after surgery. This hyperalgesia response was prolonged to more than 21 d after surgery. The time course of spinal Epac1 upregulation was correlated with SMIR-induced pain behaviors. Meanwhile, Epac1 immunoreactivity was colocalized primarily with astrocytes but not with microglial cells or neurons on 7 d after surgery. Intrathecal injection of Epac1 inhibitor CE3F4 significantly suppressed SMIR-induced mechanical allodynia and activation of astrocytes in the spinal cord. This analgesic effect of single-dose administration of CE3F4 lasted up to 6 h and wore off at 12 h after injection.

Conclusions

Spinal Epac1-mediated activation of astrocytes may facilitate CPSP. Inhibition of Epac1 may effectively prevent CPSP.

SUBMITTER: She Q

PROVIDER: S-EPMC8667141 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Publications

Exchange proteins directly activated by cyclic adenosine monophosphate inhibitor reverses mechanical allodynia via the modification of astrocytes activity in the spinal cord.

She Qing Q Chen Junjie J Zhong Chaochao C Huang Saisai S Lu Cui'e C Qin Yibin Y

Annals of translational medicine 20211101 22

<h4>Background</h4>Gliosis and inflammation are pivotal in the development of acute and chronic pain. Here, we demonstrated a previously unidentified molecular mechanism in which the activation of exchange proteins directly activated by cyclic adenosine monophosphate (Epac)1 accelerated the activation of astrocytes in the spinal cord, thereby promoting chronic postsurgical pain (CPSP).<h4>Methods</h4>We established a rat model of CPSP induced by skin/muscle incision and retraction (SMIR). Pain b ...[more]

PMID: 34988165

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Project description:BackgroundThe cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) signaling pathway is closely associated with myocardial infarction (MI). Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) is a key component of this pathway; however, there is currently a lack of clinical evidence linking plasma cGAMP levels to MI.MethodsThis study utilized clinical data from 270 patients diagnosed with coronary heart disease (CHD) at the Second Xiangya Hospital of Central South University. The outcomes included ST-segment elevation and non-ST-segment elevation MI. Univariate and multivariate logistic regression models were used to explore the relationships between plasma cGAMP levels and MI, while restricted cubic spline (RCS) using logistic regression to explore the dose-response relationship.ResultsAmong the 270 patients, the mean plasma cGAMP level was 1352.58 ± 106.02 ng/L and 89 (32.96%) patients were diagnosed with MI. The RCS curves indicated a U-shape association between the cGAMP levels and MI; the risk of MI was negatively correlated with the cGAMP until it hit bottoms at 1352 ng/L. When the cGAMP level exceeded 1352 ng/L, the risk of MI increased significantly (adjusted OR, 1.02; 95% CI: 1.01-1.03). When considering cGAMP as a categorical variable, patients in Tertile 1 and Tertile 3 had a 167% (adjusted OR: 2.67, 95% CI: 1.23-5.78) and 155% (adjusted OR: 2.55, 95% CI: 1.17-5.55) higher risk of MI compared to those in Tertile 2, respectively. These results were consistent across subgroup analyses, notably, a significant interaction by age category was observed in patients with cGAMP ≥ 1352 ng/L, where the positive association was pronounced in the elderly.ConclusionsA U-shaped association exists between cGAMP and MI in the CHD population, with a cutoff point at the cGAMP of 1352 ng/L. Both excessively high and low cGAMP levels are associated with an increased risk of MI, particularly among the elderly with cGAMP ≥ 1352 ng/L. This is the first clinical evidence of the cGAS-cGAMP-STING pathway in metabolic cardiovascular diseases.ClinicaltrialsGov identifierNCT03363035 (Registration date: 2018-01-15).

Dataset Information

Exchange proteins directly activated by cyclic adenosine monophosphate inhibitor reverses mechanical allodynia via the modification of astrocytes activity in the spinal cord.

Background

Methods

Results

Conclusions

Publications

Exchange proteins directly activated by cyclic adenosine monophosphate inhibitor reverses mechanical allodynia via the modification of astrocytes activity in the spinal cord.

Similar Datasets

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