BDNF regulates atypical PKC at spinal synapses to initiate and maintain a centralized chronic pain state

Persistent Link:
http://hdl.handle.net/10150/610217
Title:
BDNF regulates atypical PKC at spinal synapses to initiate and maintain a centralized chronic pain state
Author:
Melemedjian, Ohannes; Tillu, Dipti; Asiedu, Marina; Mandell, Edward; Moy, Jamie; Blute, Victoria; Taylor, Caleb; Ghosh, Sourav; Price, Theodore
Affiliation:
Department of Pharmacology, The University of Arizona School of Medicine, Tucson, USA; Department of Cellular and Molecular Medicine, The University of Arizona School of Medicine, Tucson, USA; Bio5 Institute, University of Arizona, Tucson, USA; Graduate Interdisciplinary Program in Neuroscience, University of Arizona, Tucson, USA
Issue Date:
2013
Publisher:
BioMed Central
Citation:
Melemedjian et al. Molecular Pain 2013, 9:12 http://www.molecularpain.com/content/9/1/12
Journal:
Molecular Pain
Rights:
© 2013 Melemedjian et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0)
Collection Information:
This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.
Abstract:
BACKGROUND:Chronic pain is an important medical problem affecting hundreds of millions of people worldwide. Mechanisms underlying the maintenance of chronic pain states are poorly understood but the elucidation of such mechanisms have the potential to reveal novel therapeutics capable of reversing a chronic pain state. We have recently shown that the maintenance of a chronic pain state is dependent on an atypical PKC, PKMzeta, but the mechanisms involved in controlling PKMzeta in chronic pain are completely unknown. Here we have tested the hypothesis that brain derived neurotrophic factor (BDNF) regulates PKMzeta, and possibly other aPKCs, to maintain a centralized chronic pain state.RESULTS:We first demonstrate that although other kinases play a role in the initiation of persistent nociceptive sensitization, they are not involved in the maintenance of this chronic pain state indicating that a ZIP-reversible process is responsible for the maintenance of persistent sensitization. We further show that BDNF plays a critical role in initiating and maintaining persistent nociceptive sensitization and that this occurs via a ZIP-reversible process. Moreover, at spinal synapses, BDNF controls PKMzeta and PKClambda nascent synthesis via mTORC1 and BDNF enhances PKMzeta phosphorylaton. Finally, we show that BDNF signaling to PKMzeta and PKClambda is conserved across CNS synapses demonstrating molecular links between pain and memory mechanisms.CONCLUSIONS:Hence, BDNF is a key regulator of aPKC synthesis and phosphorylation and an essential mediator of the maintenance of a centralized chronic pain state. These findings point to BDNF regulation of aPKC as a potential therapeutic target for the permanent reversal of a chronic pain state.
EISSN:
1744-8069
DOI:
10.1186/1744-8069-9-12
Version:
Final published version
Additional Links:
http://mpx.sagepub.com/content/9/1744-8069-9-12.full

Full metadata record

DC FieldValue Language
dc.contributor.authorMelemedjian, Ohannesen
dc.contributor.authorTillu, Diptien
dc.contributor.authorAsiedu, Marinaen
dc.contributor.authorMandell, Edwarden
dc.contributor.authorMoy, Jamieen
dc.contributor.authorBlute, Victoriaen
dc.contributor.authorTaylor, Caleben
dc.contributor.authorGhosh, Souraven
dc.contributor.authorPrice, Theodoreen
dc.date.accessioned2016-05-20T09:01:22Z-
dc.date.available2016-05-20T09:01:22Z-
dc.date.issued2013en
dc.identifier.citationMelemedjian et al. Molecular Pain 2013, 9:12 http://www.molecularpain.com/content/9/1/12en
dc.identifier.doi10.1186/1744-8069-9-12en
dc.identifier.urihttp://hdl.handle.net/10150/610217-
dc.description.abstractBACKGROUND:Chronic pain is an important medical problem affecting hundreds of millions of people worldwide. Mechanisms underlying the maintenance of chronic pain states are poorly understood but the elucidation of such mechanisms have the potential to reveal novel therapeutics capable of reversing a chronic pain state. We have recently shown that the maintenance of a chronic pain state is dependent on an atypical PKC, PKMzeta, but the mechanisms involved in controlling PKMzeta in chronic pain are completely unknown. Here we have tested the hypothesis that brain derived neurotrophic factor (BDNF) regulates PKMzeta, and possibly other aPKCs, to maintain a centralized chronic pain state.RESULTS:We first demonstrate that although other kinases play a role in the initiation of persistent nociceptive sensitization, they are not involved in the maintenance of this chronic pain state indicating that a ZIP-reversible process is responsible for the maintenance of persistent sensitization. We further show that BDNF plays a critical role in initiating and maintaining persistent nociceptive sensitization and that this occurs via a ZIP-reversible process. Moreover, at spinal synapses, BDNF controls PKMzeta and PKClambda nascent synthesis via mTORC1 and BDNF enhances PKMzeta phosphorylaton. Finally, we show that BDNF signaling to PKMzeta and PKClambda is conserved across CNS synapses demonstrating molecular links between pain and memory mechanisms.CONCLUSIONS:Hence, BDNF is a key regulator of aPKC synthesis and phosphorylation and an essential mediator of the maintenance of a centralized chronic pain state. These findings point to BDNF regulation of aPKC as a potential therapeutic target for the permanent reversal of a chronic pain state.en
dc.language.isoenen
dc.publisherBioMed Centralen
dc.relation.urlhttp://mpx.sagepub.com/content/9/1744-8069-9-12.fullen
dc.rights© 2013 Melemedjian et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0)en
dc.titleBDNF regulates atypical PKC at spinal synapses to initiate and maintain a centralized chronic pain stateen
dc.typeArticleen
dc.identifier.eissn1744-8069en
dc.contributor.departmentDepartment of Pharmacology, The University of Arizona School of Medicine, Tucson, USAen
dc.contributor.departmentDepartment of Cellular and Molecular Medicine, The University of Arizona School of Medicine, Tucson, USAen
dc.contributor.departmentBio5 Institute, University of Arizona, Tucson, USAen
dc.contributor.departmentGraduate Interdisciplinary Program in Neuroscience, University of Arizona, Tucson, USAen
dc.identifier.journalMolecular Painen
dc.description.collectioninformationThis item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
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