Trypsin mediates nociception via the proteinase-activated receptor 2: a potentially novel role in pancreatic pain |
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Authors: | Hoogerwerf Willemijntje A Shenoy Mohan Winston John H Xiao Shu-Yuan He Zhijun Pasricha Pankaj J |
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Affiliation: | Enteric Neuromuscular Disorders and Pain Laboratory, Division of Gastroenterology and Hepatology, University of Texas Medical Branch, Galveston, Texas, USA. |
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Abstract: | BACKGROUND & AIMS: The pathogenesis of pain in pancreatitis remains poorly understood. We hypothesized that trypsin, a key inflammatory mediator in this condition, can also activate nociceptive neurons via the proteinase-activated receptor 2. METHODS: Double immunohistochemical staining of T8 to T12 dorsal root ganglia sections was performed with antibodies against proteinase-activated receptor 2 and vanilloid receptor 1, a marker for primary nociceptive neurons. In vivo nociceptive activity was measured by FOS immunoreactivity in thoracic spinal dorsal horn segments after intrapancreatic administration of proteinase-activated receptor 2 agonists. Pain behavior was assessed by visceromotor reflex activity in response to noxious stimulation of the pancreas with proteinase-activated receptor 2 agonists. RESULTS: Proteinase-activated receptor 2 was expressed by virtually all nociceptive neurons in thoracic dorsal root ganglia. Intraductal trypsin, in subinflammatory concentrations, activated spinal dorsal horn neurons in a dose-dependent manner, as measured by FOS expression. Both trypsin and a proteinase-activated receptor 2-specific peptide agonist induced a behavioral pain response when infused into the pancreatic duct of awake rats. Preinfusion of the pancreatic duct with proteinase-activated receptor 2-specific activating peptide desensitized the response to trypsin. CONCLUSIONS: Our findings suggest a novel proteinase-activated receptor 2-mediated role for trypsin in the pathogenesis of pancreatic pain and one that is independent of its inflammatory effect. |
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Keywords: | AcPep, activating peptide AUC, area under the curve BTRP, boiled trypsin CoPep, control peptide DRG, dorsal root ganglia EMG, electromyographic IR, immunoreactive PAR-2, proteinase-activated receptor 2 TRPV-1, vanilloid receptor 1 VMR, visceromotor reflex. |
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