PMID- 23510079
OWN - NLM
STAT- MEDLINE
DCOM- 20130716
LR  - 20220321
IS  - 1744-8069 (Electronic)
IS  - 1744-8069 (Linking)
VI  - 9
DP  - 2013 Mar 20
TI  - BDNF regulates atypical PKC at spinal synapses to initiate and maintain a 
      centralized chronic pain state.
PG  - 12
LID - 10.1186/1744-8069-9-12 [doi]
AB  - 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.
FAU - Melemedjian, Ohannes K
AU  - Melemedjian OK
AD  - Department of Pharmacology, The University of Arizona School of Medicine, Tucson, 
      AZ, USA.
FAU - Tillu, Dipti V
AU  - Tillu DV
FAU - Asiedu, Marina N
AU  - Asiedu MN
FAU - Mandell, Edward K
AU  - Mandell EK
FAU - Moy, Jamie K
AU  - Moy JK
FAU - Blute, Victoria M
AU  - Blute VM
FAU - Taylor, Caleb J
AU  - Taylor CJ
FAU - Ghosh, Sourav
AU  - Ghosh S
FAU - Price, Theodore J
AU  - Price TJ
LA  - eng
GR  - R25 GM062584/GM/NIGMS NIH HHS/United States
GR  - T35HL007479/HL/NHLBI NIH HHS/United States
GR  - R01NS065926/NS/NINDS NIH HHS/United States
GR  - R01CA149258/CA/NCI NIH HHS/United States
GR  - R01 CA149258/CA/NCI NIH HHS/United States
GR  - R01GM102575/GM/NIGMS NIH HHS/United States
GR  - CA009213/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130320
PL  - United States
TA  - Mol Pain
JT  - Molecular pain
JID - 101242662
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Eukaryotic Initiation Factor-4F)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
SB  - IM
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/*pharmacology
MH  - Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism
MH  - Cerebral Cortex/pathology
MH  - Chronic Pain/*enzymology/pathology
MH  - Eukaryotic Initiation Factor-4F/metabolism
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - MAP Kinase Signaling System/drug effects
MH  - Male
MH  - Mice
MH  - Mice, Inbred ICR
MH  - Mitogen-Activated Protein Kinase Kinases/metabolism
MH  - Models, Biological
MH  - Phosphorylation/drug effects
MH  - Posterior Horn Cells/drug effects/enzymology
MH  - Protein Biosynthesis/drug effects
MH  - Protein Kinase C/antagonists & inhibitors/*metabolism
MH  - Protein Transport/drug effects
MH  - Synapses/drug effects/*enzymology
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Time Factors
PMC - PMC3608966
EDAT- 2013/03/21 06:00
MHDA- 2013/07/17 06:00
PMCR- 2013/03/20
CRDT- 2013/03/21 06:00
PHST- 2013/01/29 00:00 [received]
PHST- 2013/03/18 00:00 [accepted]
PHST- 2013/03/21 06:00 [entrez]
PHST- 2013/03/21 06:00 [pubmed]
PHST- 2013/07/17 06:00 [medline]
PHST- 2013/03/20 00:00 [pmc-release]
AID - 1744-8069-9-12 [pii]
AID - 10.1186/1744-8069-9-12 [doi]
PST - epublish
SO  - Mol Pain. 2013 Mar 20;9:12. doi: 10.1186/1744-8069-9-12.