Mammalian target of rapamycin signaling in the spinal cord is required for neuronal plasticity and behavioral hypersensitivity associated with neuropathy in the rat.
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.


CONCLUSIONS
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.
Asante
Curtis O
CO
Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK. curtisasante@gmail.com
Wallace
Victoria C
VC
Dickenson
Anthony H
AH
D000818:Animals; D001522:Behavior, Animal; D004594:Electrophysiology; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D009437:Neuralgia / Q000378:metabolism* / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D010523:Peripheral Nervous System Diseases / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D013127:Spinal Nerves / Q000187:drug effects / Q000293:injuries / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; C401859:temsirolimus; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
J Neurosci. 2008 Apr 16;28(16):4261-70
18417706
Pain. 1992 Sep;50(3):355-363
1333581
Science. 1997 Oct 10;278(5336):279-83
9323205
Anesth Analg. 2006 Sep;103(3):714-20
16931686
Methods. 1999 Aug;18(4):459-64
10491275
J Neurosci. 2007 Dec 19;27(51):13958-67
18094233
Mol Pain. 2009 Jun 07;5:27
19500426
Brain Res Brain Res Protoc. 2003 Aug;12(1):26-34
12928042
Cell. 1996 Aug 23;86(4):517-20
8752206
J Histochem Cytochem. 1996 Dec;44(12):1353-62
8985127
Eur J Neurosci. 2001 Jun;13(11):2105-14
11422451
Brain Res. 1999 Jun 26;833(1):71-80
10375678
J Histochem Cytochem. 2002 Apr;50(4):575-82
11897811
Nat Neurosci. 2002 Dec;5(12):1319-26
12402039
Eur J Neurosci. 2009 Jun;29(12):2253-63
19490023
J Neurosci. 2008 Aug 6;28(32):7936-44
18685019
PLoS One. 2008 Apr 09;3(4):e1961
18398477
J Neurosci. 2005 Jun 15;25(24):5833-43
15958750
J Physiol. 2008 Sep 1;586(17):4165-77
18635648
J Neurosci. 2009 Nov 25;29(47):15017-27
19940197
Biochim Biophys Acta. 2008 Jan;1784(1):116-32
17913600
Eur J Neurol. 2006 Nov;13(11):1153-69
17038030
Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10320-5
11504907
Neuropharmacology. 1998 Aug;37(8):1091-3
9833638
Pain. 2005 Oct;117(3):292-303
16150546
Genes Chromosomes Cancer. 2006 Oct;45(10):933-44
16845661
Genes Dev. 2004 Aug 15;18(16):1926-45
15314020
Br J Pharmacol. 2001 Apr;132(7):1615-23
11264257
Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14368-73
14623952
Neuron. 1998 Apr;20(4):629-32
9581756
Pain. 1983 Jun;16(2):109-110
6877845
J Neurosci. 2004 Nov 10;24(45):10211-22
15537893
Mol Neurobiol. 2006 Dec;34(3):205-19
17308353
J Neurosci. 2004 Nov 3;24(44):9760-9
15525761
Pain. 2000 Apr;85(3):493-502
10781924
Eur J Neurosci. 2006 Jan;23(2):365-73
16420444
J Neurosci. 2006 Dec 13;26(50):12977-83
17167087
Exp Neurol. 2000 Jun;163(2):408-13
10833315
J Neurosci. 2004 Nov 17;24(46):10393-401
15548654
J Neurophysiol. 2003 Mar;89(3):1588-602
12612024
J Neurosci. 2009 Jan 28;29(4):1093-104
19176818