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Upregulation of cystathionine β-synthetase in the arcuate nucleus produces pain hypersensitivity via PKC upregulation and GluN2B phosphorylation in rats with chronic pancreatitis

ZHENG Hang, ZHU Hong-Yan, ZHANG Xiao-Yu, WANG Meng, XIAO Ying, XU Guang-Yin^*, JIANG Xing-Hong^*

Key Laboratory of Pain Basic Research and Clinical Therapy, Department of Neurobiology &； Physiology, Medical College, Institute of Neuroscience, Soochow University, Suzhou 215123, China

Abstract

Hydrogen sulfide (H2S) contributes to visceral hyperalgesia in primary sensory neurons, but its role in central nervous system remains largely unknown. This study was to investigate the roles and underlying mechanisms of H2S and its endogenous synthesis enzymes in the arcuate nucleus (ARC) in rat pancreatic hyperalgesia. Chronic pancreatitis (CP) was induced in male adult Sprague-Dawley rats by intra-pancreatic ductal injection of trinitrobenzene sulfonic acid (TNBS). Abdominal hyperalgesia was assessed by referred somatic behaviors to mechanical stimulation of rat abdomen. Western blot analysis was performed to detect protein expression in the ARC. CP markedly upregulated cystathionine β-synthetase (CBS) expression but did not alter cystathionine-γ-lyase level in the ARC at 4 weeks after TNBS injection. Although the expression of total GluN2B was not altered, CP greatly enhanced the phosphorylation level of GluN2B in the ARC when compared with age- and sex-matched control rats. CP also significantly increased expression of protein kinase Cγ (PKCγ) in the ARC. Arcuate microinjection of O-(Carboxymethyl) hydroxylamine hemihydrochloride (AOAA, an inhibitor of CBS) significantly attenuated abdominal pain in CP rats in a dose-dependent manner and reversed the CP-induced upregulation of p-GluN2B and PKCγ in the ARC. Furthermore, the GluN2B inhibitor or specific PKC inhibitor chelerythrine significantly attenuated abdominal hyperalgesia in CP rats. The p-GluN2B expression was also suppressed by PKC inhibitor. Taken together, our results suggest that the upregulation of CBS in the ARC leads to an activation of GluN2B via PKCγ, which may play an important role in generation of pain hypersensitivity of CP.

Key words: Arcuate nucleus; chronic pancreatitis; abdominal pain; hydrogen sulfide; NMDA receptor; protein kinase C

Received: 2016-03-25　　Accepted: 2016-06-29

Corresponding author: 徐广银,蒋星红　　E-mail: guangyinxu@suda.edu.cn, jiangxinhong@suda.edu.cn

Citing This Article：

ZHENG Hang, ZHU Hong-Yan, ZHANG Xiao-Yu, WANG Meng, XIAO Ying, XU Guang-Yin, JIANG Xing-Hong. Upregulation of cystathionine β-synthetase in the arcuate nucleus produces pain hypersensitivity via PKC upregulation and GluN2B phosphorylation in rats with chronic pancreatitis. Acta Physiol Sin 2016; 68 (5): 575-584 (in Chinese with English abstract).