PMID- 22341316
OWN - NLM
STAT- MEDLINE
DCOM- 20130118
LR  - 20211203
IS  - 1528-8447 (Electronic)
IS  - 1526-5900 (Print)
IS  - 1526-5900 (Linking)
VI  - 13
IP  - 4
DP  - 2012 Apr
TI  - Spinal cord NMDA receptor-mediated activation of mammalian target of rapamycin is 
      required for the development and maintenance of bone cancer-induced pain 
      hypersensitivities in rats.
PG  - 338-49
LID - 10.1016/j.jpain.2011.12.006 [doi]
AB  - Mammalian target of rapamycin (mTOR) controls mRNA translation and is critical 
      for neuronal plasticity. However, how it participates in central sensitization 
      underlying chronic pain is unclear. Here, we show that NMDA receptors are 
      required for the functional role of spinal cord mTOR in bone cancer pain induced 
      by injecting prostate cancer cells (PCCs) into the tibia. Intrathecal rapamycin, 
      a specific mTOR inhibitor, dose dependently attenuated the development and 
      maintenance of PCC-induced mechanical allodynia and thermal hyperalgesia. 
      Rapamycin alone did not affect locomotor activity and acute responses to thermal 
      or mechanical stimuli. Phosphorylation of mTOR and p70S6K (a downstream effector) 
      was increased time dependently in L(4-5) dorsal horn and transiently in L(4-5) 
      dorsal root ganglions on the ipsilateral side after PCC injection, although total 
      expression of mTOR or p70S6K was not changed in these regions. The increases in 
      dorsal horn were abolished by intrathecal infusion of DL-AP5, an NMDA receptor 
      antagonist. Moreover, NMDA receptor subunit NR1 colocalized with mTOR and p70S6K 
      in dorsal horn neurons. These findings suggest that PCC-induced dorsal horn 
      activation of the mTOR pathway participates in NMDA receptor-triggered dorsal 
      central sensitization under cancer pain conditions. PERSPECTIVE: The present 
      study shows that inhibition of spinal mTOR blocks cancer-related pain without 
      affecting acute pain and locomotor function. Given that mTOR inhibitors are 
      FDA-approved drugs, mTOR in spinal cord may represent a potential new target for 
      preventing and/or treating cancer-related pain.
CI  - Copyright (c) 2012 American Pain Society. Published by Elsevier Inc. All rights 
      reserved.
FAU - Shih, Ming-Hung
AU  - Shih MH
AD  - Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University 
      School of Medicine, Baltimore, MD, USA.
FAU - Kao, Sheng-Chin
AU  - Kao SC
FAU - Wang, Wei
AU  - Wang W
FAU - Yaster, Myron
AU  - Yaster M
FAU - Tao, Yuan-Xiang
AU  - Tao YX
LA  - eng
GR  - R01 NS058886-04/NS/NINDS NIH HHS/United States
GR  - NS058886/NS/NINDS NIH HHS/United States
GR  - NS072206/NS/NINDS NIH HHS/United States
GR  - R01 NS058886/NS/NINDS NIH HHS/United States
GR  - R01 NS058886-03/NS/NINDS NIH HHS/United States
GR  - R01 NS072206/NS/NINDS NIH HHS/United States
GR  - R01 NS072206-01A1/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120215
PL  - United States
TA  - J Pain
JT  - The journal of pain
JID - 100898657
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Bone Neoplasms/complications/*physiopathology
MH  - Disease Models, Animal
MH  - Hyperalgesia/drug therapy/etiology/*physiopathology
MH  - Male
MH  - Neoplasms, Experimental/complications/physiopathology
MH  - Pain, Intractable/drug therapy/etiology/physiopathology
MH  - Rats
MH  - Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/*physiology
MH  - Spinal Cord/drug effects/metabolism/*physiopathology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*metabolism
MH  - Tumor Cells, Cultured
PMC - PMC3321092
MID - NIHMS347732
EDAT- 2012/02/22 06:00
MHDA- 2013/01/19 06:00
PMCR- 2013/04/01
CRDT- 2012/02/21 06:00
PHST- 2011/10/22 00:00 [received]
PHST- 2011/12/08 00:00 [revised]
PHST- 2011/12/19 00:00 [accepted]
PHST- 2012/02/21 06:00 [entrez]
PHST- 2012/02/22 06:00 [pubmed]
PHST- 2013/01/19 06:00 [medline]
PHST- 2013/04/01 00:00 [pmc-release]
AID - S1526-5900(11)00953-9 [pii]
AID - 10.1016/j.jpain.2011.12.006 [doi]
PST - ppublish
SO  - J Pain. 2012 Apr;13(4):338-49. doi: 10.1016/j.jpain.2011.12.006. Epub 2012 Feb 
      15.