Cargando…
BDNF regulates atypical PKC at spinal synapses to initiate and maintain a centralized chronic pain state
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...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2013
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3608966/ https://www.ncbi.nlm.nih.gov/pubmed/23510079 http://dx.doi.org/10.1186/1744-8069-9-12 |
_version_ | 1782264296957280256 |
---|---|
author | Melemedjian, Ohannes K Tillu, Dipti V Asiedu, Marina N Mandell, Edward K Moy, Jamie K Blute, Victoria M Taylor, Caleb J Ghosh, Sourav Price, Theodore J |
author_facet | Melemedjian, Ohannes K Tillu, Dipti V Asiedu, Marina N Mandell, Edward K Moy, Jamie K Blute, Victoria M Taylor, Caleb J Ghosh, Sourav Price, Theodore J |
author_sort | Melemedjian, Ohannes K |
collection | PubMed |
description | 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, PKMζ, but the mechanisms involved in controlling PKMζ in chronic pain are completely unknown. Here we have tested the hypothesis that brain derived neurotrophic factor (BDNF) regulates PKMζ, 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 PKMζ and PKCλ nascent synthesis via mTORC1 and BDNF enhances PKMζ phosphorylaton. Finally, we show that BDNF signaling to PKMζ and PKCλ 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. |
format | Online Article Text |
id | pubmed-3608966 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-36089662013-03-28 BDNF regulates atypical PKC at spinal synapses to initiate and maintain a centralized chronic pain state Melemedjian, Ohannes K Tillu, Dipti V Asiedu, Marina N Mandell, Edward K Moy, Jamie K Blute, Victoria M Taylor, Caleb J Ghosh, Sourav Price, Theodore J Mol Pain Research 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, PKMζ, but the mechanisms involved in controlling PKMζ in chronic pain are completely unknown. Here we have tested the hypothesis that brain derived neurotrophic factor (BDNF) regulates PKMζ, 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 PKMζ and PKCλ nascent synthesis via mTORC1 and BDNF enhances PKMζ phosphorylaton. Finally, we show that BDNF signaling to PKMζ and PKCλ 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. BioMed Central 2013-03-20 /pmc/articles/PMC3608966/ /pubmed/23510079 http://dx.doi.org/10.1186/1744-8069-9-12 Text en Copyright ©2013 Melemedjian et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Melemedjian, Ohannes K Tillu, Dipti V Asiedu, Marina N Mandell, Edward K Moy, Jamie K Blute, Victoria M Taylor, Caleb J Ghosh, Sourav Price, Theodore J BDNF regulates atypical PKC at spinal synapses to initiate and maintain a centralized chronic pain state |
title | BDNF regulates atypical PKC at spinal synapses to initiate and maintain a centralized chronic pain state |
title_full | BDNF regulates atypical PKC at spinal synapses to initiate and maintain a centralized chronic pain state |
title_fullStr | BDNF regulates atypical PKC at spinal synapses to initiate and maintain a centralized chronic pain state |
title_full_unstemmed | BDNF regulates atypical PKC at spinal synapses to initiate and maintain a centralized chronic pain state |
title_short | BDNF regulates atypical PKC at spinal synapses to initiate and maintain a centralized chronic pain state |
title_sort | bdnf regulates atypical pkc at spinal synapses to initiate and maintain a centralized chronic pain state |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3608966/ https://www.ncbi.nlm.nih.gov/pubmed/23510079 http://dx.doi.org/10.1186/1744-8069-9-12 |
work_keys_str_mv | AT melemedjianohannesk bdnfregulatesatypicalpkcatspinalsynapsestoinitiateandmaintainacentralizedchronicpainstate AT tilludiptiv bdnfregulatesatypicalpkcatspinalsynapsestoinitiateandmaintainacentralizedchronicpainstate AT asiedumarinan bdnfregulatesatypicalpkcatspinalsynapsestoinitiateandmaintainacentralizedchronicpainstate AT mandelledwardk bdnfregulatesatypicalpkcatspinalsynapsestoinitiateandmaintainacentralizedchronicpainstate AT moyjamiek bdnfregulatesatypicalpkcatspinalsynapsestoinitiateandmaintainacentralizedchronicpainstate AT blutevictoriam bdnfregulatesatypicalpkcatspinalsynapsestoinitiateandmaintainacentralizedchronicpainstate AT taylorcalebj bdnfregulatesatypicalpkcatspinalsynapsestoinitiateandmaintainacentralizedchronicpainstate AT ghoshsourav bdnfregulatesatypicalpkcatspinalsynapsestoinitiateandmaintainacentralizedchronicpainstate AT pricetheodorej bdnfregulatesatypicalpkcatspinalsynapsestoinitiateandmaintainacentralizedchronicpainstate |