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Activation of microglial GLP-1R in the trigeminal nucleus caudalis suppresses central sensitization of chronic migraine after recurrent nitroglycerin stimulation.
- Source :
-
Journal of Headache & Pain . 7/29/2021, Vol. 22 Issue 1, p1-18. 18p. - Publication Year :
- 2021
-
Abstract
- Background: Central sensitization is considered a critical pathogenic mechanism of chronic migraine (CM). Activation of microglia in the trigeminal nucleus caudalis (TNC) contributes to this progression. Microglial glucagon-like peptide-1 receptor (GLP-1R) activation can alleviate pain; however, whether it is involved in the mechanism of CM has not been determined. Thus, this study aims to investigate the precise role of GLP-1R in the central sensitization of CM. Methods: Repeated nitroglycerin injection-treated mice were used as a CM animal model in the experiment. To identify the distribution and cell localization of GLP-1R in the TNC, we performed immunofluorescence staining. Changes in the expression of GLP-1R, Iba-1, PI3K and p-Akt in the TNC were examined by western blotting. To confirm the effect of GLP-1R and PI3K/Akt in CM, a GLP-1R selective agonist (liraglutide) and antagonist (exendin(9–39)) and a PI3K selective antagonist (LY294002) were administered. Mechanical hypersensitivity was measured through von Frey filaments. To investigate the role of GLP-1R in central sensitization, calcitonin gene-related peptide (CGRP) and c-fos were determined using western blotting and immunofluorescence. To determine the changes in microglial activation, IL-1β and TNF-α were examined by western blotting, and the number and morphology of microglia were measured by immunofluorescence. We also confirmed the effect of GLP-1R on microglial activation in lipopolysaccharide-treated BV-2 microglia. Results: The protein expression of GLP-1R was increased in the TNC after nitroglycerin injection. GLP-1R was colocalized with microglia and astrocytes in the TNC and was fully expressed in BV-2 microglia. The GLP-1R agonist liraglutide alleviated basal allodynia and suppressed the upregulation of CGRP, c-fos and PI3K/p-Akt in the TNC. Similarly, the PI3K inhibitor LY294002 prevented nitroglycerin-induced hyperalgesia. In addition, activating GLP-1R reduced Iba-1, IL-1β and TNF-α release and inhibited TNC microglial number and morphological changes (process retraction) following nitroglycerin administration. In vitro, the protein levels of IL-1β and TNF-α in lipopolysaccharide-stimulated BV-2 microglia were also decreased by liraglutide. Conclusions: These findings suggest that microglial GLP-1R activation in the TNC may suppress the central sensitization of CM by regulating TNC microglial activation via the PI3K/Akt pathway. [ABSTRACT FROM AUTHOR]
- Subjects :
- *BRAIN stem physiology
*CHRONIC disease treatment
*NEURAL physiology
*BIOLOGICAL models
*INTERLEUKINS
*LIPOPOLYSACCHARIDES
*INJECTIONS
*STAINS & staining (Microscopy)
*MIGRAINE
*GLUCAGON-like peptide 1
*ANIMAL experimentation
*NITROGLYCERIN
*FLUOROIMMUNOASSAY
*WESTERN immunoblotting
*CELL receptors
*CELL physiology
*TRIGEMINAL nerve
*SENSORY stimulation
*GENE expression
*ELECTRIC stimulation
*TUMOR necrosis factors
*COMBINED modality therapy
*ALLERGIES
*GLUCAGON-like peptide-1 agonists
*MICE
*ALLODYNIA
*HYPERALGESIA
THERAPEUTIC use of nitroglycerin
Subjects
Details
- Language :
- English
- ISSN :
- 11292369
- Volume :
- 22
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Journal of Headache & Pain
- Publication Type :
- Academic Journal
- Accession number :
- 151648962
- Full Text :
- https://doi.org/10.1186/s10194-021-01302-x