Central regulation of Blood Brain Barrier integrity during hyperalgesia

Persistent Link:
http://hdl.handle.net/10150/195377
Title:
Central regulation of Blood Brain Barrier integrity during hyperalgesia
Author:
Campos, Christopher Roman
Issue Date:
2009
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:
The blood-brain barrier (BBB) is located at the level of the cerebral microcapillaries, and functions to maintain environmental homeostasis by allowing the neurons access to the required nutrients and enabling the exchange of metabolic waste. BBB dysfunction has been observed in a number of pathophysiologic statres including peripheral inflammatory pain (Huber et al., 2001b). Using the lamda-carrageenan inflammatory pain (CIP) model, we observed alterations in the tight junction (TJ) proteins paralleled by an increase in BBB permeability to [14C] sucrose. The mechanisms by which these perturbations occurred remain to be elucidated. In the current study, we investigate the central mechanism for the BBB perturbations under CIP. It is our hypothesis that the modulations of the BBB under CIP, are mediated via a central signaling pathway. First, to investigate the involvement of neuronal input from pain activity on alterations in BBB, we developed a method for inhibiting the nociceptive input from the paw. Using a perineural injection of 0.75% bupivacaine into the right hind leg prior to CIP, we were able inhibit development thermal hyperalgesia induced by CIP, as tested by infrared heat stimulus, without effecting edema formation 1 h post CIP. Upon inhibition of nociception under CIP, there was an attenuation of both the changes in permeability and the changes in tight junction protein expression, with both returning to control levels. Next, we investigated intercellular adhesion molecule-1 (ICAM-1), a key signaling protein at the BBB, which in the presence of proinflammatory mediators, increases in expression leading to the activation of signaling pathways as well as morphological changes. We found a region specific increase in ICAM-1 mRNA and protein expression following CIP which directly correlated with increased expression of activated microglia. Finally, we investigated the influence activated microglia had on BBB permeability. Using an 0.150 mg intrathecal bolus injection of minocycline, a potent inhibitor of microglia activation (Klein and Cunha, 1995), we were able to inhibit the increased expression of activated microglia, and saw an attenuation of permeability to control levels. These findings suggest CIP induced BBB disruption is localized and has a central-mediated component independent of peripheral influence.
Type:
text; Electronic Dissertation
Keywords:
blood-brain barrier; ICAM-1; microglia; pain
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Medical Pharmacology; 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.titleCentral regulation of Blood Brain Barrier integrity during hyperalgesiaen_US
dc.creatorCampos, Christopher Romanen_US
dc.contributor.authorCampos, Christopher Romanen_US
dc.date.issued2009en_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.abstractThe blood-brain barrier (BBB) is located at the level of the cerebral microcapillaries, and functions to maintain environmental homeostasis by allowing the neurons access to the required nutrients and enabling the exchange of metabolic waste. BBB dysfunction has been observed in a number of pathophysiologic statres including peripheral inflammatory pain (Huber et al., 2001b). Using the lamda-carrageenan inflammatory pain (CIP) model, we observed alterations in the tight junction (TJ) proteins paralleled by an increase in BBB permeability to [14C] sucrose. The mechanisms by which these perturbations occurred remain to be elucidated. In the current study, we investigate the central mechanism for the BBB perturbations under CIP. It is our hypothesis that the modulations of the BBB under CIP, are mediated via a central signaling pathway. First, to investigate the involvement of neuronal input from pain activity on alterations in BBB, we developed a method for inhibiting the nociceptive input from the paw. Using a perineural injection of 0.75% bupivacaine into the right hind leg prior to CIP, we were able inhibit development thermal hyperalgesia induced by CIP, as tested by infrared heat stimulus, without effecting edema formation 1 h post CIP. Upon inhibition of nociception under CIP, there was an attenuation of both the changes in permeability and the changes in tight junction protein expression, with both returning to control levels. Next, we investigated intercellular adhesion molecule-1 (ICAM-1), a key signaling protein at the BBB, which in the presence of proinflammatory mediators, increases in expression leading to the activation of signaling pathways as well as morphological changes. We found a region specific increase in ICAM-1 mRNA and protein expression following CIP which directly correlated with increased expression of activated microglia. Finally, we investigated the influence activated microglia had on BBB permeability. Using an 0.150 mg intrathecal bolus injection of minocycline, a potent inhibitor of microglia activation (Klein and Cunha, 1995), we were able to inhibit the increased expression of activated microglia, and saw an attenuation of permeability to control levels. These findings suggest CIP induced BBB disruption is localized and has a central-mediated component independent of peripheral influence.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectblood-brain barrieren_US
dc.subjectICAM-1en_US
dc.subjectmicrogliaen_US
dc.subjectpainen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineMedical Pharmacologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorDavis, Thomas P.en_US
dc.contributor.chairDavis, Thomas P.en_US
dc.contributor.committeememberBloom, Johnen_US
dc.contributor.committeememberFrench, Edwarden_US
dc.contributor.committeememberStamer, William Danen_US
dc.contributor.committeememberVanderah, Todden_US
dc.identifier.proquest10292en_US
dc.identifier.oclc659750912en_US
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