title: Adrenergic signaling mediates mechanical hyperalgesia through activation of P2X3 receptors in primary sensory neurons of rats with chronic pancreatitis.
abstract: The mechanism of pain in chronic pancreatitis (CP) is poorly understood. The aim of this study was designed to investigate roles of norepinephrine (NE) and P2X receptor (P2XR) signaling pathway in the pathogenesis of hyperalgesia in a rat model of CP. CP was induced in male adult rats by intraductal injection of trinitrobenzene sulfonic acid (TNBS). Mechanical hyperalgesia was assessed by referred somatic behaviors to mechanical stimulation of rat abdomen. P2XR-mediated responses of pancreatic dorsal root ganglion (DRG) neurons were measured utilizing calcium imaging and whole cell patch-clamp-recording techniques. Western blot analysis and immunofluorescence were performed to examine protein expression. TNBS injection produced a significant upregulation of P2X3R expression and an increase in ATP-evoked responses of pancreatic DRG neurons. The sensitization of P2X3Rs was reversed by administration of β-adrenergic receptor antagonist propranolol. Incubation of DRG neurons with NE significantly enhanced ATP-induced intracellular calcium signals, which were abolished by propranolol, and partially blocked by protein kinase A inhibitor H-89. Interestingly, TNBS injection led to a significant elevation of NE concentration in DRGs and the pancreas, an upregulation of β2-adrenergic receptor expression in DRGs, and amplification of the NE-induced potentiation of ATP responses. Importantly, pancreatic hyperalgesia was markedly attenuated by administration of purinergic receptor antagonist suramin or A317491 or β2-adrenergic receptor antagonist butoxamine. Sensitization of P2X3Rs, which was likely mediated by adrenergic signaling in primary sensory neurons, contributes to pancreatic pain, thus identifying a potential target for treating pancreatic pain caused by inflammation.
authors: The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China;
authors: Shusheng
authors: S
authors: Wang
authors: The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China; Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, China;
authors: Hong-Yan
authors: HY
authors: Zhu
authors: Department of Anesthesiology, Nanjing Jinling Hospital, Nanjing, China.
authors: Yi
authors: Y
authors: Jin
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, China;
authors: Youlang
authors: Y
authors: Zhou
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, China;
authors: Shufen
authors: S
authors: Hu
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, China;
authors: Tong
authors: T
authors: Liu
authors: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, China;
authors: Xinghong
authors: X
authors: Jiang
authors: The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, China; Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, China; guangyinxu@suda.edu.cn.
authors: Guang-Yin
authors: GY
authors: Xu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D058672:Adrenergic beta-2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal; D020013:Calcium Signaling / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism*; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D008564:Membrane Potentials; D009043:Motor Activity; D009638:Norepinephrine / Q000378:metabolism*; D017288:Pain Threshold / Q000187:drug effects; D010179:Pancreas / Q000294:innervation*; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D020239:Receptor Cross-Talk; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000378:metabolism; D058477:Receptors, Purinergic P2X3 / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D014302:Trinitrobenzenesulfonic Acid
chemical_list: D058672:Adrenergic beta-2 Receptor Antagonists; D047428:Protein Kinase Inhibitors; D058920:Purinergic P2X Receptor Antagonists; D018343:Receptors, Adrenergic, beta-2; D058477:Receptors, Purinergic P2X3; D000255:Adenosine Triphosphate; D014302:Trinitrobenzenesulfonic Acid; D017868:Cyclic AMP-Dependent Protein Kinases; D009638:Norepinephrine
keywords: chronic pancreatitis; dorsal root ganglion; norepinephrine; protein kinase A; purinergic receptors