Trypsin mediates nociception via the proteinase-activated receptor 2: a potentially novel role in pancreatic pain.
OBJECTIVE
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.
Hoogerwerf
Willemijntje A
WA
Enteric Neuromuscular Disorders and Pain Laboratory, Division of Gastroenterology and Hepatology, University of Texas Medical Branch, Galveston, Texas, USA.
Shenoy
Mohan
M
Winston
John H
JH
Xiao
Shu-Yuan
SY
He
Zhijun
Z
Pasricha
Pankaj J
PJ
D000818:Animals; D005727:Ganglia, Spinal / Q000378:metabolism; D008297:Male; D023421:Models, Animal; D009619:Nociceptors / Q000378:metabolism*; D010146:Pain / Q000209:etiology / Q000378:metabolism*; D010147:Pain Measurement; D010179:Pancreas / Q000378:metabolism / Q000503:physiopathology; D010195:Pancreatitis / Q000150:complications / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044464:Receptor, PAR-2 / Q000378:metabolism*; D011955:Receptors, Drug / Q000378:metabolism; D050916:TRPV Cation Channels; D014357:Trypsin / Q000378:metabolism*
D016760:Proto-Oncogene Proteins c-fos; D044464:Receptor, PAR-2; D011955:Receptors, Drug; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D014357:Trypsin