Persistent Link:
http://hdl.handle.net/10150/196002
Title:
EFFECT OF PERIPHERAL INFLAMMATORY PAIN ON THE BLOOD-BRAIN BARRIER
Author:
Hau, Vincent Sinh
Issue Date:
2005
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:
Currently, there is a growing body of research characterizing the blood-brain barrier (BBB) under normal physiological conditions; however, little is known about BBB regulation under pathophysiological conditions, such as inflammatory pain. This dissertation elucidates peripheral inflammatory pain effects on the BBB both functionally in terms of permeability and structurally via tight junction (TJ) protein expression and regulation.Inflammation was produced by subcutaneous injection of formalin, lambda-carrageenan, or complete Freund's adjuvant (CFA) into the right hind paw of rats. In situ perfusion and Western blot analyses were performed to assess BBB integrity after inflammatory insult. In situ brain perfusion determined that peripheral inflammation significantly increased the uptake of a membrane impermeant marker, sucrose into the cerebral hemispheres in all inflammatory models. Subsequently, a 0-168h time course study of lambda-carrageenan-induced inflammatory pain elicited a biphasic increase in BBB permeability of sucrose with the first phase occurring from 1-6h and the second phase occuring at 48h. Lambda-carrageenan-induced inflammatory pain also increased brain uptake of a commonly used analgesic, codeine at the same time-points. This is the first known observation that peripheral inflammation results in greater analgesic drug uptake to the brain. This uptake also correlated with its antinociceptive profile over a 168h time course. This suggests the presence of inflammatory pain may be an important consideration in therapeutic drug dosing, potential adverse effects and/or neurotoxicity.Western blot analyses showed altered TJ protein expression during peripheral inflammation. Occludin significantly decreased in the lambda-carrageenan- and CFA-treated groups. ZO-1 expression was significantly increased in all pain models. Claudin-1 protein expression was present at the BBB and remained unchanged during inflammation. Actin expression was significantly increased in the lambda-carrageenan- and CFA-treated groups. Over a 72h time period with lambda-carrageenan-induced inflammatory pain, altered TJ protein expression of occludin and ZO-1 correlated with permeability changes in BBB function. This is the first report of peripheral inflammation inducing alterations in TJs and increasing permeability of the BBB. This dissertation demonstrates that changes in the structure of TJs leading to alterations in the BBB may have important clinical ramifications concerning central nervous system homeostasis and therapeutic drug delivery.
Type:
text; Electronic Dissertation
Keywords:
Blood-Brain Barrier; Codeine; Occludin; Inflammation; Pain; Claudin
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Pharmacology & Toxicology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Davis, Thomas P
Committee Chair:
Davis, Thomas P

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleEFFECT OF PERIPHERAL INFLAMMATORY PAIN ON THE BLOOD-BRAIN BARRIERen_US
dc.creatorHau, Vincent Sinhen_US
dc.contributor.authorHau, Vincent Sinhen_US
dc.date.issued2005en_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.abstractCurrently, there is a growing body of research characterizing the blood-brain barrier (BBB) under normal physiological conditions; however, little is known about BBB regulation under pathophysiological conditions, such as inflammatory pain. This dissertation elucidates peripheral inflammatory pain effects on the BBB both functionally in terms of permeability and structurally via tight junction (TJ) protein expression and regulation.Inflammation was produced by subcutaneous injection of formalin, lambda-carrageenan, or complete Freund's adjuvant (CFA) into the right hind paw of rats. In situ perfusion and Western blot analyses were performed to assess BBB integrity after inflammatory insult. In situ brain perfusion determined that peripheral inflammation significantly increased the uptake of a membrane impermeant marker, sucrose into the cerebral hemispheres in all inflammatory models. Subsequently, a 0-168h time course study of lambda-carrageenan-induced inflammatory pain elicited a biphasic increase in BBB permeability of sucrose with the first phase occurring from 1-6h and the second phase occuring at 48h. Lambda-carrageenan-induced inflammatory pain also increased brain uptake of a commonly used analgesic, codeine at the same time-points. This is the first known observation that peripheral inflammation results in greater analgesic drug uptake to the brain. This uptake also correlated with its antinociceptive profile over a 168h time course. This suggests the presence of inflammatory pain may be an important consideration in therapeutic drug dosing, potential adverse effects and/or neurotoxicity.Western blot analyses showed altered TJ protein expression during peripheral inflammation. Occludin significantly decreased in the lambda-carrageenan- and CFA-treated groups. ZO-1 expression was significantly increased in all pain models. Claudin-1 protein expression was present at the BBB and remained unchanged during inflammation. Actin expression was significantly increased in the lambda-carrageenan- and CFA-treated groups. Over a 72h time period with lambda-carrageenan-induced inflammatory pain, altered TJ protein expression of occludin and ZO-1 correlated with permeability changes in BBB function. This is the first report of peripheral inflammation inducing alterations in TJs and increasing permeability of the BBB. This dissertation demonstrates that changes in the structure of TJs leading to alterations in the BBB may have important clinical ramifications concerning central nervous system homeostasis and therapeutic drug delivery.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectBlood-Brain Barrieren_US
dc.subjectCodeineen_US
dc.subjectOccludinen_US
dc.subjectInflammationen_US
dc.subjectPainen_US
dc.subjectClaudinen_US
thesis.degree.namePhDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePharmacology & Toxicologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorDavis, Thomas Pen_US
dc.contributor.chairDavis, Thomas Pen_US
dc.contributor.committeememberYamamura, Henry I.en_US
dc.contributor.committeememberFrench, Edward D.en_US
dc.contributor.committeememberBloom, John W.en_US
dc.contributor.committeememberVanderah, Todd W.en_US
dc.identifier.proquest1071en_US
dc.identifier.oclc137353812en_US
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