Persistent Link:
http://hdl.handle.net/10150/195036
Title:
Mechanisms of Pancreatitis-induced Pain
Author:
Vardanyan, Marina
Issue Date:
2007
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Pathogenesis of pain in pancreatitis is multifactorial, however little is known about the mechanisms by which inflammation in the pancreas causes pain. Here, we hypothesized that pancreatitis-induced pain is dependent upon sensitization of primary afferents by inflammatory mediators such as nerve growth factor (NGF) and interleukin-6(IL-6) and that such a pain is mediated through ascending pathways via the nucleus gracilis. Inflammation in the pancreas resulted in a significant increase in the levels of NGF in the pancreas. Pre-treatment with an anti-NGF peptibody delayed the development of pancreatitis-induced pain. Double injection of anti-NGF peptibody completely prevented the development of pancreatitis-induced pain. Post-treatment with anti-NGF peptibody significantly decreased the number of abdominal withdrawals, compared to the placebo group. Treatment with TRPV1 antagonists reversed the referred abdominal hypersensitivity. Intrathecal administration of p38 inhibitor blocked the pancreatitis-induced pain within minutes after administration. The levels of the TRPV1 in the pancreas, DRG and the spinal cord were not significantly different in the animals with pancreatitis compared to the controls. Pancreatic inflammation resulted in a significant increase in the levels of IL-6 in the pancreas. Treatment with an IL-6 receptor antagonist blocked the referred abdominal hypersensitivity in animals with pancreatitis after systemic and oral administration. Intrathecal administration of the antagonist did not reduce the number of abdominal withdrawals. The possibility that IL-6 might sensitize TRPV1 channels was tested. Cultured DRG neurons were stimulated with IL-6, IL-6 antagonist or a combination of IL-6 with an antagonist, followed by stimulation with capsaicin. Stimulation of DRG with IL-6 produced a marked increase in the levels of CGRP release; combination of IL-6 with an antagonist returned the levels of CGRP to the control levels. To determine the role of the nucleus gracilis in the pancreatitis-induced pain bilateral cannulation of the nucleus gracilis was performed. Microinjection of CNQX into the nucleus gracilis produced a reversal of pancreatitis-induced pain, suggesting an important role of ascending pathway to the n.gracilis in pancreatic pain transmission.
Type:
text; Electronic Dissertation
Keywords:
Medical Pharmacology
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Medical Pharmacology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Porreca, Frank

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleMechanisms of Pancreatitis-induced Painen_US
dc.creatorVardanyan, Marinaen_US
dc.contributor.authorVardanyan, Marinaen_US
dc.date.issued2007en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractPathogenesis of pain in pancreatitis is multifactorial, however little is known about the mechanisms by which inflammation in the pancreas causes pain. Here, we hypothesized that pancreatitis-induced pain is dependent upon sensitization of primary afferents by inflammatory mediators such as nerve growth factor (NGF) and interleukin-6(IL-6) and that such a pain is mediated through ascending pathways via the nucleus gracilis. Inflammation in the pancreas resulted in a significant increase in the levels of NGF in the pancreas. Pre-treatment with an anti-NGF peptibody delayed the development of pancreatitis-induced pain. Double injection of anti-NGF peptibody completely prevented the development of pancreatitis-induced pain. Post-treatment with anti-NGF peptibody significantly decreased the number of abdominal withdrawals, compared to the placebo group. Treatment with TRPV1 antagonists reversed the referred abdominal hypersensitivity. Intrathecal administration of p38 inhibitor blocked the pancreatitis-induced pain within minutes after administration. The levels of the TRPV1 in the pancreas, DRG and the spinal cord were not significantly different in the animals with pancreatitis compared to the controls. Pancreatic inflammation resulted in a significant increase in the levels of IL-6 in the pancreas. Treatment with an IL-6 receptor antagonist blocked the referred abdominal hypersensitivity in animals with pancreatitis after systemic and oral administration. Intrathecal administration of the antagonist did not reduce the number of abdominal withdrawals. The possibility that IL-6 might sensitize TRPV1 channels was tested. Cultured DRG neurons were stimulated with IL-6, IL-6 antagonist or a combination of IL-6 with an antagonist, followed by stimulation with capsaicin. Stimulation of DRG with IL-6 produced a marked increase in the levels of CGRP release; combination of IL-6 with an antagonist returned the levels of CGRP to the control levels. To determine the role of the nucleus gracilis in the pancreatitis-induced pain bilateral cannulation of the nucleus gracilis was performed. Microinjection of CNQX into the nucleus gracilis produced a reversal of pancreatitis-induced pain, suggesting an important role of ascending pathway to the n.gracilis in pancreatic pain transmission.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectMedical Pharmacologyen_US
thesis.degree.namePhDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineMedical Pharmacologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorPorreca, Franken_US
dc.contributor.committeememberVanderah, Todd W.en_US
dc.contributor.committeememberFrench, Edwarden_US
dc.contributor.committeememberHruby, Victoren_US
dc.contributor.committeememberOssipov, Michael H.en_US
dc.identifier.proquest2474en_US
dc.identifier.oclc659748391en_US
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