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

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

Research output: Contribution to journalArticle

48 Citations (Scopus)

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

Fingerprint

Protein Kinase Inhibitors
Neuropeptides
Pancreatitis
Hypersensitivity
Up-Regulation
Phosphotransferases
Calcitonin Gene-Related Peptide
Pancreas
Acute Necrotizing Pancreatitis
Referred Pain
Nociceptive Pain
Pain
Spinal Ganglia
Substance P
Cyclic AMP-Dependent Protein Kinases
Protein Kinases
Arginine
Spinal Cord
Thorax
Therapeutics

Keywords

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

ASJC Scopus subject areas

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

Cite this

Acute pancreatitis results in referred mechanical hypersensitivity and neuropeptide up-regulation that can be suppressed by the protein kinase inhibitor K252a. / Winston, John; Toma, Hiroki; Shenoy, Mohan; He, Zhi Jun; Zou, Lei; Xiao, Shu Yuan; Micci, Maria; Pasricha, Pankaj Jay.

In: Journal of Pain, Vol. 4, No. 6, 08.2003, p. 329-337.

Research output: Contribution to journalArticle

Winston, John ; Toma, Hiroki ; Shenoy, Mohan ; He, Zhi Jun ; Zou, Lei ; Xiao, Shu Yuan ; Micci, Maria ; Pasricha, Pankaj Jay. / Acute pancreatitis results in referred mechanical hypersensitivity and neuropeptide up-regulation that can be suppressed by the protein kinase inhibitor K252a. In: Journal of Pain. 2003 ; Vol. 4, No. 6. pp. 329-337.
@article{f6facb66bea94ad1a40e6fb69f10ad98,
title = "Acute pancreatitis results in referred mechanical hypersensitivity and neuropeptide up-regulation that can be suppressed by the protein kinase inhibitor K252a",
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.",
keywords = "Dorsal root ganglion, K252a, Nerve growth factor, Pain, Pancreatitis",
author = "John Winston and Hiroki Toma and Mohan Shenoy and He, {Zhi Jun} and Lei Zou and Xiao, {Shu Yuan} and Maria Micci and Pasricha, {Pankaj Jay}",
year = "2003",
month = "8",
doi = "10.1016/S1526-5900(03)00636-9",
language = "English",
volume = "4",
pages = "329--337",
journal = "Journal of Pain",
issn = "1526-5900",
publisher = "Churchill Livingstone",
number = "6",

}

TY - JOUR

T1 - Acute pancreatitis results in referred mechanical hypersensitivity and neuropeptide up-regulation that can be suppressed by the protein kinase inhibitor K252a

AU - Winston, John

AU - Toma, Hiroki

AU - Shenoy, Mohan

AU - He, Zhi Jun

AU - Zou, Lei

AU - Xiao, Shu Yuan

AU - Micci, Maria

AU - Pasricha, Pankaj Jay

PY - 2003/8

Y1 - 2003/8

N2 - 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.

AB - 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.

KW - Dorsal root ganglion

KW - K252a

KW - Nerve growth factor

KW - Pain

KW - Pancreatitis

UR - http://www.scopus.com/inward/record.url?scp=0041469954&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0041469954&partnerID=8YFLogxK

U2 - 10.1016/S1526-5900(03)00636-9

DO - 10.1016/S1526-5900(03)00636-9

M3 - Article

VL - 4

SP - 329

EP - 337

JO - Journal of Pain

JF - Journal of Pain

SN - 1526-5900

IS - 6

ER -