The potent, indirect adenosine monophosphate- activated protein kinase activator R419 attenuates mitogen-activated protein kinase signaling, inhibits nociceptor excitability, and reduces pain hypersensitivity in mice.
There is a great need for new therapeutics for the treatment of pain. A possible avenue to development of such therapeutics is to interfere with signaling pathways engaged in peripheral nociceptors that cause these neurons to become hyperexcitable. There is strong evidence that mitogen activated protein kinases (MAPKs) and phosphoinositide 3-kinase (PI3K) / mechanistic target of rapamycin (mTOR) signaling pathways are key modulators of nociceptor excitabilityin vitroandin vivo. Activation of adenosine monophosphate activated protein kinase (AMPK) can inhibit signaling in both of these pathways and AMPK activators have been shown to inhibit nociceptor excitability and pain hypersensitivity in rodents. R419 is one of, if not the most potent AMPK activator described to date. We tested whether R419 activates AMPK in dorsal root ganglion (DRG) neurons and if this leads to decreased pain hypersensitivity in mice. We find that R419 activates AMPK in DRG neurons resulting in decreased MAPK signaling, decreased nascent protein synthesis and enhanced P body formation. R419 attenuates nerve growth factor-(NGF) induced changes in excitability in DRG neurons and blocks NGF-induced mechanical pain amplificationin vivo. Moreover, locally applied R419 attenuates pain hypersensitivity in a model of post-surgical pain and blocks the development of hyperalgesic priming to both NGF and incision. We conclude that R419 is a promising lead candidate compound for the development of potent and specific AMPK activation to inhibit pain hypersensitivity as a result of injury.
School of Behavioral and Brain Sciences, The University of Texas at Dallas, 800 W Campbell Rd, Richardson, TX 75080, USA.
Galo L
GL
Mejia
School of Behavioral and Brain Sciences, The University of Texas at Dallas, 800 W Campbell Rd, Richardson, TX 75080, USA.
Marina N
MN
Asiedu
Rigel Pharmaceuticals Inc, 1180 Veterans Blvd, South San Francisco, CA 94080, USA.
Yasumichi
Y
Hitoshi
School of Behavioral and Brain Sciences, The University of Texas at Dallas, 800 W Campbell Rd, Richardson, TX 75080, USA.
Gregory
G
Dussor
School of Behavioral and Brain Sciences, The University of Texas at Dallas, 800 W Campbell Rd, Richardson, TX 75080, USA.
Theodore J
TJ
Price
Br J Clin Pharmacol. 1981 Aug;12(2):235-46
7306436
Mol Pain. 2015 Sep 17;11:58
26376783
Lancet. 2006 May 13;367(9522):1618-25
16698416
Pain. 2006 Mar;121(1-2):105-14
16472913
Xenobiotica. 1994 Jan;24(1):49-57
8165821
Mol Pain. 2011 Sep 21;7:70
21936900
Prog Mol Biol Transl Sci. 2015;131:409-34
25744681
Pain. 2006 Jun;122(3):245-57
16530964
Neurosci Lett. 2013 Dec 17;557 Pt A:9-18
23831352
Science. 2005 Dec 9;310(5754):1642-6
16308421
J Pain. 2004 Apr;5(3):157-63
15106128
PLoS One. 2014 Jun 23;9(6):e100701
24955774
Curr Drug Targets. 2016;17(8):908-20
26521775
PLoS One. 2013 Dec 05;8(12):e81870
24339975
Pain. 2013 Dec;154 Suppl 1:S2-9
23711480
Cell Metab. 2014 Dec 2;20(6):939-52
25448702
Mol Biol Cell. 2008 Oct;19(10):4154-66
18653466
Sci Signal. 2011 Mar 29;4(166):pe16
21447797
Eur J Neurosci. 2009 Jun;29(12):2253-63
19490023
J Neurosci. 2008 Mar 19;28(12):3190-201
18354022
PLoS One. 2008 Apr 09;3(4):e1961
18398477
Brain. 2012 Jun;135(Pt 6):1751-66
22561641
J Neurosci. 2009 Nov 25;29(47):15017-27
19940197
J Clin Invest. 2008 Sep;118(9):3065-74
18725988
Handb Exp Pharmacol. 2015;227:15-37
25846612
Biochim Biophys Acta. 2015 Jul;1852(7):1257-67
25779083
Brain Res Rev. 2009 Apr;60(1):135-48
19150373
Anesthesiology. 2006 Dec;105(6):1246-53
17122588
Pain. 2012 Mar;153(3):704-9
22244441
J Neurosci Methods. 1994 Jul;53(1):55-63
7990513
Curr Opin Cell Biol. 2015 Apr;33:1-7
25259783
Pain. 2013 Jul;154(7):1080-91
23607966
Philos Trans R Soc Lond B Biol Sci. 1996 Mar 29;351(1338):431-40
8730782
Cell. 2009 Oct 16;139(2):267-84
19837031
Anesthesiology. 2003 Oct;99(4):1023-7
14508341
Science. 2016 Jan 15;351(6270):275-281
26816379
J Pain. 2013 Nov;14(11):1330-40
23916727
Nature. 2014 Jun 26;510(7506):542-6
24847880
J Pain. 2015 Oct;16(10):981-94
26142652
J Neurosci. 2010 Nov 10;30(45):15113-23
21068317
Pain. 2005 Sep;117(1-2):68-76
16061324
Nat Rev Mol Cell Biol. 2012 Mar 22;13(4):251-62
22436748
Mol Metab. 2015 Jun 15;4(9):643-51
26413470
Clin Pharmacol Ther. 2015 Nov;98(5):551-9
26108785
J Neurosci. 2007 Dec 19;27(51):13958-67
18094233
J Pain Res. 2013 Dec 09;6:755-63
24357937
Neurosci Lett. 2014 Mar 20;563:169-74
24080374
Nat Neurosci. 2014 Feb;17(2):153-63
24473263
Nat Rev Neurol. 2014 Jun;10(6):326-36
24840972
Biochem J. 2000 Jun 15;348 Pt 3:607-14
10839993
Nature. 2013 Feb 14;494(7436):256-60
23292513
Anesthesiology. 2015 Nov;123(5):1170-85
26378398
Anesthesiology. 2007 Jul;107(1):128-35
17585224
J Neurosci. 2010 Feb 3;30(5):1637-47
20130174
Eur J Pharmacol. 2015 Oct 5;764:599-606
26054810
Mol Pain. 2012 Jan 23;8:5
22269797
Prog Mol Biol Transl Sci. 2015;131:119-46
25744672
J Biol Chem. 2011 Jan 7;286(1):1-11
21059655
Xenobiotica. 2010 Dec;40(12):817-25
20863201
Nat Methods. 2009 Apr;6(4):275-7
19305406
Trends Neurosci. 2009 Dec;32(12):611-8
19781793
Cell Metab. 2015 Nov 3;22(5):922-35
26437602
Cell Metab. 2006 Jun;3(6):403-16
16753576