PMID- 27296621
OWN - NLM
STAT- MEDLINE
DCOM- 20161226
LR  - 20220331
IS  - 1744-8069 (Electronic)
IS  - 1744-8069 (Linking)
VI  - 12
DP  - 2016
TI  - Intact subepidermal nerve fibers mediate mechanical hypersensitivity via the 
      activation of protein kinase C gamma in spared nerve injury.
LID - 10.1177/1744806916656189 [doi]
LID - 1744806916656189
AB  - BACKGROUND: Spared nerve injury is an important neuropathic pain model for 
      investigating the role of intact primary afferents in the skin on pain 
      hypersensitivity. However, potential cellular mechanisms remain poorly 
      understood. In phosphoinositide-3 kinase pathway, pyruvate dehydrogenase kinase 1 
      (PDK1) participates in the regulation of neuronal plasticity for central 
      sensitization. The downstream cascades of PDK1 include: (1) protein kinase C 
      gamma (PKCg) controls the trafficking and phosphorylation of ionotropic glutamate 
      receptor; (2) protein kinase B (Akt)/the mammalian target of rapamycin (mTOR) 
      signaling is responsible for local protein synthesis. Under these statements, we 
      therefore hypothesized that an increase of PKCg activation and mTOR-dependent 
      PKCg synthesis in intact primary afferents after SNI might contribute to pain 
      hypersensitivity. RESULTS: The variants of spared nerve injury were performed in 
      Sprague-Dawley rats by transecting any two of the three branches of the sciatic 
      nerve, leaving only one branch intact. Following SNIt (spared tibial branch), 
      mechanical hyperalgesia and mechanical allodynia, but not thermal hyperalgesia, 
      were significantly induced. In the first footpad, normal epidermal innervations 
      were verified by the protein gene product 9.5 (PGP9.5)- and growth-associated 
      protein 43 (GAP43)-immunoreactive (IR) intraepidermal nerve fibers (IENFs) 
      densities. Furthermore, the rapid increases of phospho-PKCg- and phosphomTOR-IR 
      subepidermal nerve fibers (SENFs) areas were distinct gathered from the results 
      of PGP9.5-, GAP43-, and neurofilament 200 (NF200)-IR SENFs areas. The efficacy of 
      PKC inhibitor (GF 109203X) or mTOR complex 1 inhibitor (rapamycin) for 
      attenuating mechanical hyperalgesia and mechanical allodynia by intraplantar 
      injection was dose-dependent. CONCLUSIONS: From results obtained in this study, 
      we strongly recommend that the intact SENFs persistently increase PKCg activation 
      and mTOR-dependent PKCg synthesis participate in the initiation and maintenance 
      of mechanical hypersensitivity in spared nerve injury, which represents as a 
      novel insight into the therapeutic strategy of pain in the periphery.
FAU - Ko, Miau-Hwa
AU  - Ko MH
FAU - Yang, Ming-Ling
AU  - Yang ML
FAU - Youn, Su-Chung
AU  - Youn SC
FAU - Lan, Chyn-Tair
AU  - Lan CT
FAU - Tseng, To-Jung
AU  - Tseng TJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160613
PL  - United States
TA  - Mol Pain
JT  - Molecular pain
JID - 101242662
RN  - EC 2.7.1.- (protein kinase C gamma)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.13 (Protein Kinase C)
SB  - IM
MH  - Animals
MH  - Behavior, Animal
MH  - Dermis/pathology
MH  - Enzyme Activation
MH  - Epidermis/*innervation/surgery
MH  - Hyperalgesia/*enzymology/*pathology
MH  - Male
MH  - Merkel Cells/pathology
MH  - Nerve Fibers/*pathology
MH  - Pain/complications/pathology
MH  - Protein Kinase C/*metabolism
MH  - Rats, Sprague-Dawley
MH  - Sciatic Nerve/*enzymology/*injuries/pathology
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC4956387
EDAT- 2016/06/15 06:00
MHDA- 2016/12/27 06:00
PMCR- 2016/06/13
CRDT- 2016/06/15 06:00
PHST- 2016/06/15 06:00 [entrez]
PHST- 2016/06/15 06:00 [pubmed]
PHST- 2016/12/27 06:00 [medline]
PHST- 2016/06/13 00:00 [pmc-release]
AID - 12/0/1744806916656189 [pii]
AID - 10.1177_1744806916656189 [pii]
AID - 10.1177/1744806916656189 [doi]
PST - epublish
SO  - Mol Pain. 2016 Jun 13;12:1744806916656189. doi: 10.1177/1744806916656189. Print 
      2016.