BDNF regulates atypical PKC at spinal synapses to initiate and maintain a centralized chronic pain state
AffiliationDepartment 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
MetadataShow full item record
CitationMelemedjian et al. Molecular Pain 2013, 9:12 http://www.molecularpain.com/content/9/1/12
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 InformationThis 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 firstname.lastname@example.org.
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.
VersionFinal published version
Except where otherwise noted, this item's license is described as © 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).