Acute pancreatitis results in referred mechanical hypersensitivity and neuropeptide up-regulation that can be suppressed by the protein kinase inhibitor k252a.
Although pain is a cardinal feature of pancreatitis, its pathogenesis is poorly understood and treatment remains difficult. Nociceptive sensitization in several somatic pain models has been associated with activation of protein kinases including trkA, protein kinase C, and protein kinase A. We therefore tested the hypothesis that systemic treatment with a kinase inhibitor, k252a, known to inhibit all of these kinases would alleviate pain in an animal model of pancreatitis. Von Frey filament testing of somatic referral regions was evaluated as a method to measure referred pain in a rat model of acute necrotizing pancreatitis induced by L-arginine. Rats with pancreatitis showed increased sensitivity to abdominal stimulation with Von Frey filament. This referred mechanical sensitivity was associated with an 8-fold increase in levels of phosphorylated trkA in the pancreas and with significant up-regulation of both calcitonin gene-related peptide and preprotachykinin mRNA expression in thoracic dorsal root ganglia and with increased calcitonin gene-related peptide and substance P immunoreactivity in spinal cord segment T10. Treatment with the kinase inhibitor k252a suppressed the phosphorylation of trkA in the pancreas as well as reversed both the behavioral changes and the increase in neuropeptide expression associated with pancreatitis.
Winston
John H
JH
Enteric Neuromuscular Disorders and Pain Group, Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Toma
Hiroki
H
Shenoy
Mohan
M
He
Zhi-Jun
ZJ
Zou
Lei
L
Xiao
Shu-Yuan
SY
Micci
Maria-Adelaide
MA
Pasricha
Pankaj J
PJ
D000818:Animals; D001120:Arginine; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D026121:Indole Alkaloids; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D019283:Pancreatitis, Acute Necrotizing / Q000150:complications / Q000503:physiopathology*; D010766:Phosphorylation / Q000187:drug effects; D010812:Physical Stimulation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011498:Protein Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000037:antagonists & inhibitors / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D013373:Substance P / Q000378:metabolism; D015320:Tachykinins / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D011498:Protein Precursors; D012333:RNA, Messenger; D015320:Tachykinins; C044206:preprotachykinin; D013373:Substance P; D001120:Arginine; C049985:staurosporine aglycone; D020917:Receptor, trkA; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D015740:Calcitonin Gene-Related Peptide