title: BDNF regulates atypical PKC at spinal synapses to initiate and maintain a centralized chronic pain state.
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, 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.
authors.affiliation: Department of Pharmacology, The University of Arizona School of Medicine, Tucson, AZ, USA.
authors.forename: Ohannes K
authors.initials: OK
authors.lastname: Melemedjian
authors.forename: Dipti V
authors.initials: DV
authors.lastname: Tillu
authors.forename: Marina N
authors.initials: MN
authors.lastname: Asiedu
authors.forename: Edward K
authors.initials: EK
authors.lastname: Mandell
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Moy
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Blute
authors.forename: Caleb J
authors.initials: CJ
authors.lastname: Taylor
authors.forename: Sourav
authors.initials: S
authors.lastname: Ghosh
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Price
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002540:Cerebral Cortex / Q000473:pathology; D059350:Chronic Pain / Q000201:enzymology* / Q000473:pathology; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D020671:Posterior Horn Cells / Q000187:drug effects / Q000201:enzymology; D014176:Protein Biosynthesis / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000201:enzymology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D039562:Eukaryotic Initiation Factor-4F; D058570:TOR Serine-Threonine Kinases; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases