PMID- 20452291
OWN - NLM
STAT- MEDLINE
DCOM- 20110321
LR  - 20230526
IS  - 1528-8447 (Electronic)
IS  - 1526-5900 (Print)
IS  - 1526-5900 (Linking)
VI  - 11
IP  - 12
DP  - 2010 Dec
TI  - Mammalian target of rapamycin signaling in the spinal cord is required for 
      neuronal plasticity and behavioral hypersensitivity associated with neuropathy in 
      the rat.
PG  - 1356-67
LID - 10.1016/j.jpain.2010.03.013 [doi]
AB  - The protein kinase mammalian target of rapamycin (mTOR) regulates mRNA 
      translation and is inhibited by rapamycin. Signaling pathways involving mTOR are 
      implicated in physiological and pathophysiological processes. We determined the 
      spinal effects of the rapamycin analogue cell cycle inhibitor (CCI)-779 on 
      neuronal responses and behavioral hypersensitivity in a model of persistent 
      neuropathic pain. We also assessed the anatomical distribution of spinal mTOR 
      signaling pathways. Specifically, we ligated rat spinal nerves L5 and L6 to 
      produce a model of neuropathic pain. After confirming neuropathy with behavioral 
      testing, we obtained in vivo single-unit extracellular stimulus-evoked recordings 
      from deep dorsal horn spinal neurons. We applied CCI-779 spinally in 
      electrophysiological and behavioral studies and assessed its effects accordingly. 
      We also used immunohistochemistry to probe for mTOR signaling pathways in dorsal 
      root ganglia (DRG) and the spinal cord. We found that spinally administered 
      CCI-779 rapidly attenuated calibrated mechanically but not thermally evoked 
      neuronal responses and mechanically evoked behavioral responses. 
      Immunohistochemistry showed presence of mTOR signaling pathways in 
      nociceptive-specific C-fiber DRG and in neurons of inner lamina II of the spinal 
      cord. We conclude that alterations in the activity of spinal mTOR signaling 
      pathways are crucial to the full establishment of spinal neuronal plasticity and 
      behavioral hypersensitivity associated with nerve injury. PERSPECTIVE: This study 
      is consistent with growing evidence implicating mTOR signaling pathways as 
      important modulators of persistent pain, providing novel insights into the 
      molecular mechanisms of pain maintenance and potential for novel approaches into 
      treating chronic pain.
CI  - Copyright (c) 2010 American Pain Society. Published by Elsevier Inc. All rights 
      reserved.
FAU - Asante, Curtis O
AU  - Asante CO
AD  - Department of Neuroscience, Physiology and Pharmacology, University College 
      London, London, UK. curtisasante@gmail.com
FAU - Wallace, Victoria C
AU  - Wallace VC
FAU - Dickenson, Anthony H
AU  - Dickenson AH
LA  - eng
GR  - WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100508
PL  - United States
TA  - J Pain
JT  - The journal of pain
JID - 100898657
RN  - 0 (Protein Kinase Inhibitors)
RN  - 624KN6GM2T (temsirolimus)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Behavior, Animal
MH  - Electrophysiology
MH  - Hyperalgesia/metabolism/physiopathology
MH  - Immunohistochemistry
MH  - Male
MH  - Neuralgia/*metabolism/physiopathology
MH  - Neuronal Plasticity/drug effects/*physiology
MH  - Peripheral Nervous System Diseases/*metabolism
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction/drug effects/*physiology
MH  - Sirolimus/analogs & derivatives/pharmacology
MH  - Spinal Cord/drug effects/*metabolism/physiopathology
MH  - Spinal Nerves/drug effects/injuries/*metabolism
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC3000494
EDAT- 2010/05/11 06:00
MHDA- 2011/03/22 06:00
PMCR- 2010/12/01
CRDT- 2010/05/11 06:00
PHST- 2009/10/27 00:00 [received]
PHST- 2010/03/04 00:00 [revised]
PHST- 2010/03/16 00:00 [accepted]
PHST- 2010/05/11 06:00 [entrez]
PHST- 2010/05/11 06:00 [pubmed]
PHST- 2011/03/22 06:00 [medline]
PHST- 2010/12/01 00:00 [pmc-release]
AID - S1526-5900(10)00428-1 [pii]
AID - 10.1016/j.jpain.2010.03.013 [doi]
PST - ppublish
SO  - J Pain. 2010 Dec;11(12):1356-67. doi: 10.1016/j.jpain.2010.03.013. Epub 2010 May 
      8.