Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/56903
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dc.contributor.authorHutchinson, M.en
dc.contributor.authorRamos, K.en
dc.contributor.authorLoram, L.en
dc.contributor.authorWieseler-Frank, J.en
dc.contributor.authorSholar, P.en
dc.contributor.authorKearney, J.en
dc.contributor.authorLewis, M.en
dc.contributor.authorCrysdale, N.en
dc.contributor.authorZhang, Y.en
dc.contributor.authorHarrison, J.en
dc.contributor.authorMaier, S.en
dc.contributor.authorRice, K.en
dc.contributor.authorWatkins, L.en
dc.date.issued2009en
dc.identifier.citationNeuroscience, 2009; 164(4):1821-1832en
dc.identifier.issn0306-4522en
dc.identifier.issn1873-7544en
dc.identifier.urihttp://hdl.handle.net/2440/56903-
dc.description.abstractSpinal cord microglial toll-like receptor 4 (TLR4) has been implicated in enhancing neuropathic pain and opposing morphine analgesia. The present study was initiated to explore TLR4-mediated pain modulation by intrathecal lipopolysaccharide, a classic TLR4 agonist. However, our initial study revealed that intrathecal lipopolysaccharide failed to induce low-threshold mechanical allodynia in naive rats, suggestive that TLR4 agonism may be insufficient to enhance pain. These studies explore the possibility that a second signal is required; namely, heat shock protein-90 (HSP90). This candidate was chosen for study given its known importance as a regulator of TLR4 signaling. A combination of in vitro TLR4 cell signaling and in vivo behavioral studies of pain modulation suggest that TLR4-enhancement of neuropathic pain and TLR4-suppression of morphine analgesia each likely require HSP90 as a cofactor for the effects observed. In vitro studies revealed that dimethyl sulfoxide (DMSO) enhances HSP90 release, suggestive that this may be a means by which DMSO enhances TLR4 signaling. While 2 and 100 μg lipopolysaccharide intrathecally did not induce mechanical allodynia across the time course tested, co-administration of 1 μg lipopolysaccharide with a drug that enhances HSP90-mediated TLR4 signaling now induced robust allodynia. In support of this allodynia being mediated via a TLR4/HSP90 pathway, it was prevented or reversed by intrathecal co-administration of a HSP90 inhibitor, a TLR4 inhibitor, a microglia/monocyte activation inhibitor (as monocyte-derived cells are the predominant cell type expressing TLR4), and interleukin-1 receptor antagonist (as this proinflammatory cytokine is a downstream consequence of TLR4 activation). Together, these results suggest for the first time that TLR4 activation is necessary but not sufficient to induce spinally mediated pain enhancement. Rather, the data suggest that TLR4-dependent pain phenomena may require contributions by multiple components of the TLR4 receptor complex.en
dc.description.statementofresponsibilityM.R. Hutchinson, K.M. Ramos, L.C. Loram, J. Wieseler, P.W. Sholar, J.J. Kearney, M.T. Lewis, N.Y. Crysdale, Y. Zhang, J.A. Harrison, S.F. Maier, K.C. Rice and L.R. Watkinsen
dc.description.urihttp://www.elsevier.com/wps/find/journaldescription.cws_home/468/description#descriptionen
dc.language.isoenen
dc.publisherPergamon-Elsevier Science Ltden
dc.subjectHEK293-TLR4; lipopolysaccharide; chronic constriction injury; morphine; mechanical allodynia; analgesiaen
dc.titleEvidence for a role of heat shock protein-90 in toll like receptor 4 mediated pain enhancement in ratsen
dc.typeJournal articleen
dc.identifier.rmid0020093621en
dc.identifier.doi10.1016/j.neuroscience.2009.09.046en
dc.identifier.pubid36898-
pubs.library.collectionMedicine publicationsen
pubs.verification-statusVerifieden
pubs.publication-statusPublisheden
Appears in Collections:Medicine publications

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