Bradykinin Receptors Mediate Dynorphin Pronociceptive Action To Produce Persistent Pain

Persistent Link:
http://hdl.handle.net/10150/195460
Title:
Bradykinin Receptors Mediate Dynorphin Pronociceptive Action To Produce Persistent Pain
Author:
Chen, Qingmin
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:
Intrathecal injection of dynorphin or des-Tyr-dynorphin fragments, which do not bind to opioid receptors, produce tactile and thermal hypersensitivity in rodents. The maintenance, but not initiation, of experimental neuropathic pain depends upon pronociceptive effects of elevated levels of spinal dynorphin. Recent findings implicated a direct excitatory action of dynorphin A at bradykinin receptors in vitro. Here, the possibility that the pronociceptive actions of pharmacological dynorphin or of pathological levels of endogenous spinal dynorphin are mediated by interaction with bradykinin receptors was explored.While spinal administration of a wide range of bradykinin did not produce hyperalgesia in rats, intrathecal injection of non-opioid des-tyrosyl-dynorphin A(2-13) produced reversible tactile and thermal hypersensitivities that were reversed by bradykinin receptor antagonists. Dynorphin-induced behavioral hyperesthesias were observed in bradykinin B2 receptor wild-type but not in B2 receptor knockout mice. Spinal administration or infusion of B1, and especially B2, receptor antagonists reversed experimental neuropathic pain behaviors in rats with peripheral nerve injury but only when the antagonists were given at times at which dynorphin was upregulated. After nerve injury, both B1 and B2 receptor mRNA were increased in the dorsal root ganglion, but not in the spinal cord. While a marked increase in mRNA expression for prodynorphin in the lumbar spinal cord was found following nerve injury, expression of mRNA for kininogen was below detection levels. The possible interaction of spinal dynorphin with bradykinin receptors as a basis of the pronociceptive action of this peptide was further tested in the CFA-induced inflammatory pain and DBTC-induced pancreatitis pain. Intrathecal administration of bradykinin receptor antagonists or dynorphin antiserum reversed DBTC-induced abdominal hypersensitivity and CFA-induced hyperalgesia only when spinal dynorphin or prodynorphin is upregulated. The antihyperalgesic effect of the bradykinin receptor antagonists was not due to de novo production of bradykinin.Taken together, our results unravel a novel, non-opioid molecular target of dynorphin, and indicate that dynorphin acts at bradykinin receptors to produce persistent psin in the pathological pain states. This novel pronociceptive mechanism offers new approaches to the development of therapy for pathological pain states.
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
Committee Chair:
Porreca, Frank

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleBradykinin Receptors Mediate Dynorphin Pronociceptive Action To Produce Persistent Painen_US
dc.creatorChen, Qingminen_US
dc.contributor.authorChen, Qingminen_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.abstractIntrathecal injection of dynorphin or des-Tyr-dynorphin fragments, which do not bind to opioid receptors, produce tactile and thermal hypersensitivity in rodents. The maintenance, but not initiation, of experimental neuropathic pain depends upon pronociceptive effects of elevated levels of spinal dynorphin. Recent findings implicated a direct excitatory action of dynorphin A at bradykinin receptors in vitro. Here, the possibility that the pronociceptive actions of pharmacological dynorphin or of pathological levels of endogenous spinal dynorphin are mediated by interaction with bradykinin receptors was explored.While spinal administration of a wide range of bradykinin did not produce hyperalgesia in rats, intrathecal injection of non-opioid des-tyrosyl-dynorphin A(2-13) produced reversible tactile and thermal hypersensitivities that were reversed by bradykinin receptor antagonists. Dynorphin-induced behavioral hyperesthesias were observed in bradykinin B2 receptor wild-type but not in B2 receptor knockout mice. Spinal administration or infusion of B1, and especially B2, receptor antagonists reversed experimental neuropathic pain behaviors in rats with peripheral nerve injury but only when the antagonists were given at times at which dynorphin was upregulated. After nerve injury, both B1 and B2 receptor mRNA were increased in the dorsal root ganglion, but not in the spinal cord. While a marked increase in mRNA expression for prodynorphin in the lumbar spinal cord was found following nerve injury, expression of mRNA for kininogen was below detection levels. The possible interaction of spinal dynorphin with bradykinin receptors as a basis of the pronociceptive action of this peptide was further tested in the CFA-induced inflammatory pain and DBTC-induced pancreatitis pain. Intrathecal administration of bradykinin receptor antagonists or dynorphin antiserum reversed DBTC-induced abdominal hypersensitivity and CFA-induced hyperalgesia only when spinal dynorphin or prodynorphin is upregulated. The antihyperalgesic effect of the bradykinin receptor antagonists was not due to de novo production of bradykinin.Taken together, our results unravel a novel, non-opioid molecular target of dynorphin, and indicate that dynorphin acts at bradykinin receptors to produce persistent psin in the pathological pain states. This novel pronociceptive mechanism offers new approaches to the development of therapy for pathological pain states.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.chairPorreca, Franken_US
dc.contributor.committeememberLai, Josephineen_US
dc.contributor.committeememberVanderah, Todden_US
dc.contributor.committeememberFrench, Edwarden_US
dc.contributor.committeememberSloviter, Roberten_US
dc.identifier.proquest2432en_US
dc.identifier.oclc659748349en_US
All Items in UA Campus Repository are protected by copyright, with all rights reserved, unless otherwise indicated.