PMID- 26270583
OWN - NLM
STAT- MEDLINE
DCOM- 20160913
LR  - 20221005
IS  - 1872-6623 (Electronic)
IS  - 0304-3959 (Print)
IS  - 0304-3959 (Linking)
VI  - 156
IP  - 12
DP  - 2015 Dec
TI  - Protein kinase C gamma-mediated phosphorylation of GluA1 in the postsynaptic 
      density of spinal dorsal horn neurons accompanies neuropathic pain, and 
      dephosphorylation by calcineurin is associated with prolonged analgesia.
PG  - 2514-2520
LID - 10.1097/j.pain.0000000000000323 [doi]
AB  - Loss of calcineurin (protein phosphatase 3) activity and protein content in the 
      postsynaptic density (PSD) of spinal dorsal horn neurons was associated with pain 
      behavior after chronic constriction injury (CCI) of the rat sciatic nerve, and 
      intrathecal administration of the phosphatase provided prolonged analgesia 
      (Miletic et al. 2013). In this study, we examined whether one consequence of the 
      loss of calcineurin was the persistent phosphorylation of the GluA1 subunit of 
      alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropioinic acid (AMPAR) receptors in the 
      PSD. This would allow continual activation of AMPAR receptors at the synapse to 
      help maintain a long-lasting enhancement of synaptic function, ie, neuropathic 
      pain. We also investigated if the phosphorylation was mediated by protein kinase 
      A (PKA), protein kinase C gamma (PKCgamma), or calcium-calmodulin dependent kinase II 
      (CaMKII), and if the prolonged calcineurin analgesia was associated with GluA1 
      dephosphorylation. Mechanical thresholds and thermal latencies were obtained 
      before CCI. Seven days later, the behavioral testing was repeated before saline, 
      calcineurin, or the specific peptide inhibitors of PKA (PKI-tide), PKCgamma (PKC 
      19-31), or CaMKII (autocamtide-2-related inhibitory peptide) were injected 
      intrathecally. The behavior was retested before the animals were euthanized and 
      their PSD isolated. All CCI animals developed mechanical and thermal 
      hypersensitivity. This was associated with phosphorylation of GluA1 in the 
      ipsilateral PSD at Ser831 (but not Ser845) by PKCgamma and not by PKA or CaMKII. 
      Intrathecal treatment with calcineurin provided prolonged analgesia, and this was 
      accompanied by GluA1 dephosphorylation. Therapy with calcineurin may prove useful 
      in the prolonged clinical management of well-established neuropathic pain.
FAU - Miletic, Gordana
AU  - Miletic G
AD  - Department of Anesthesiology, School of Medicine and Public Health, University of 
      Wisconsin, Madison, WI, USA.
FAU - Hermes, Jessie L
AU  - Hermes JL
FAU - Bosscher, Georgia L
AU  - Bosscher GL
FAU - Meier, Brenton M
AU  - Meier BM
FAU - Miletic, Vjekoslav
AU  - Miletic V
LA  - eng
GR  - R01 NS075917/NS/NINDS NIH HHS/United States
GR  - NS075917/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Pain
JT  - Pain
JID - 7508686
RN  - 0 (Receptors, AMPA)
RN  - EC 2.7.1.- (protein kinase C gamma)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein 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 3.1.3.16 (Calcineurin)
RN  - TFZ3H25BS1 (glutamate receptor ionotropic, AMPA 1)
SB  - IM
MH  - *Analgesia
MH  - Animals
MH  - Behavior, Animal/drug effects
MH  - Calcineurin/*pharmacology
MH  - Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & 
      inhibitors/*metabolism
MH  - Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors/*metabolism
MH  - Injections, Spinal
MH  - Male
MH  - Neuralgia/*metabolism
MH  - Phosphorylation
MH  - Post-Synaptic Density/*drug effects/metabolism
MH  - Posterior Horn Cells/*drug effects/metabolism
MH  - Protein Kinase C/antagonists & inhibitors/*metabolism
MH  - Rats
MH  - Receptors, AMPA/*metabolism
MH  - Sciatic Nerve/injuries
PMC - PMC4653070
MID - NIHMS713297
EDAT- 2015/08/14 06:00
MHDA- 2016/09/14 06:00
PMCR- 2016/12/01
CRDT- 2015/08/14 06:00
PHST- 2015/08/14 06:00 [entrez]
PHST- 2015/08/14 06:00 [pubmed]
PHST- 2016/09/14 06:00 [medline]
PHST- 2016/12/01 00:00 [pmc-release]
AID - 00006396-201512000-00016 [pii]
AID - 10.1097/j.pain.0000000000000323 [doi]
PST - ppublish
SO  - Pain. 2015 Dec;156(12):2514-2520. doi: 10.1097/j.pain.0000000000000323.