Acute pancreatitis results in referred mechanical hypersensitivity and neuropeptide up-regulation that can be suppressed by the protein kinase inhibitor K252a

John H. Winston, Hiroki Toma, Mohan Shenoy, Zhi Jun He, Lei Zou, Shu Yuan Xiao, Maria Adelaide Micci, Pankaj Jay Pasricha

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)329-337
Number of pages9
JournalJournal of Pain
Volume4
Issue number6
DOIs
StatePublished - Aug 2003

Keywords

  • Dorsal root ganglion
  • K252a
  • Nerve growth factor
  • Pain
  • Pancreatitis

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine
  • Clinical Neurology
  • Neurology
  • Nursing(all)

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