World journal of gastroenterology · 2025
NMDAR2B/PKA/CREB signaling pathway contributes to esophageal neuropathic pain in gastroesophageal reflux disease.
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Wang Yi, Li Guan-Wu, Zhu Sheng-Liang, Xu Ting-Ting, Qin Yi-Wen, Cheng Chuan-Qi, Zheng Qin-Wei, He Cong, Zhou Bing-Duo, Fang Sheng-Quan
Аннотация
BACKGROUND: Esophageal hypersensitivity is an important cause of refractory gastroesophageal reflux disease, in which patients do not respond to standard acid-suppressive therapy and suffer from continuous noncardiac chest pain and regurgitation. The N-methyl-D-aspartate receptor (NMDAR) may play a crucial role in the development of visceral hypersensitivity in functional gastrointestinal disorders. However, the specific mechanisms of visceral hypersensitivity in upper digestive tract diseases remain poorly understood.
AIM: To investigate the role of the NMDAR2B/protein kinase A (PKA)/cAMP-response element binding protein (CREB) signaling pathway in the development of esophageal neuropathic pain associated with gastroesophageal reflux disease (GERD).
METHODS: Thirty-six 6-week-old specific pathogen free rats were randomly assigned to six groups: the control, model, model + NMDAR agonist, model + NMDAR antagonist, model + PKA antagonist, and model + NMDAR antagonist + PKA agonist groups, with six rats in each group. The model was induced via an intraperitoneal injection of ovalbumin for sensitization along with local esophageal stimulation. Immunohistochemistry and Western blotting were utilized to assess the expression levels of NMDAR2B signaling pathway-related proteins in the cingulate gyrus, dorsal thalamus, spinal dorsal horn, and peripheral esophageal tissues. RT-PCR was used to measure the corresponding mRNA expression, and ELISA was used to determine the serum brain-derived neurotrophic factor (BDNF) concentration. Behavioral scoring was performed during balloon distention and acid perfusion of the lower esophagus.
RESULTS: Compared with the control group, the model group presented significantly increased expression levels of the NMDAR2B, PKA, CREB, BDNF, substance P, and calcitonin gene-related peptide proteins and mRNAs in the cingulate gyrus, dorsal thalamus, spinal dorsal horn, and lower esophagus (P < 0.05). Compared with the model group, the model + NMDAR agonist group exhibited even higher expression levels of these proteins and mRNAs (P < 0.05), whereas the model + NMDAR antagonist and model + PKA antagonist groups presented lower expression levels (P < 0.05). The model + NMDAR antagonist + PKA agonist group presented higher expression levels than did the model + NMDAR antagonist group (P < 0.05). The changes in the serum BDNF concentration and behavioral score during balloon distention and acid perfusion were consistent with these changes in expression.
CONCLUSION: The NMDAR2B signaling pathway plays a critical role in the development of neuropathic pain in GERD through the PKA/CREB/BDNF pathway.
AIM: To investigate the role of the NMDAR2B/protein kinase A (PKA)/cAMP-response element binding protein (CREB) signaling pathway in the development of esophageal neuropathic pain associated with gastroesophageal reflux disease (GERD).
METHODS: Thirty-six 6-week-old specific pathogen free rats were randomly assigned to six groups: the control, model, model + NMDAR agonist, model + NMDAR antagonist, model + PKA antagonist, and model + NMDAR antagonist + PKA agonist groups, with six rats in each group. The model was induced via an intraperitoneal injection of ovalbumin for sensitization along with local esophageal stimulation. Immunohistochemistry and Western blotting were utilized to assess the expression levels of NMDAR2B signaling pathway-related proteins in the cingulate gyrus, dorsal thalamus, spinal dorsal horn, and peripheral esophageal tissues. RT-PCR was used to measure the corresponding mRNA expression, and ELISA was used to determine the serum brain-derived neurotrophic factor (BDNF) concentration. Behavioral scoring was performed during balloon distention and acid perfusion of the lower esophagus.
RESULTS: Compared with the control group, the model group presented significantly increased expression levels of the NMDAR2B, PKA, CREB, BDNF, substance P, and calcitonin gene-related peptide proteins and mRNAs in the cingulate gyrus, dorsal thalamus, spinal dorsal horn, and lower esophagus (P < 0.05). Compared with the model group, the model + NMDAR agonist group exhibited even higher expression levels of these proteins and mRNAs (P < 0.05), whereas the model + NMDAR antagonist and model + PKA antagonist groups presented lower expression levels (P < 0.05). The model + NMDAR antagonist + PKA agonist group presented higher expression levels than did the model + NMDAR antagonist group (P < 0.05). The changes in the serum BDNF concentration and behavioral score during balloon distention and acid perfusion were consistent with these changes in expression.
CONCLUSION: The NMDAR2B signaling pathway plays a critical role in the development of neuropathic pain in GERD through the PKA/CREB/BDNF pathway.