HSP90 inhibition in the mouse spinal cord enhances opioid signaling by suppressing an AMPK-mediated negative feedback loop

被引:5
作者
Gabriel, Katherin A. [1 ]
Streicher, John M. [1 ,2 ]
机构
[1] Univ Arizona, Coll Med, Dept Pharmacol, Tucson, AZ 85721 USA
[2] Univ Arizona, Comprehens Pain & Addict Ctr, Tucson, AZ 85721 USA
基金
美国国家卫生研究院;
关键词
ACTIVATED PROTEIN-KINASE; PAIN; SPECIFICITY; NOCICEPTION; TOLERANCE; NEURONS; PATHWAY;
D O I
10.1126/scisignal.ade2438
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Opioids and other agonists of the mu-opioid receptor are effective at managing acute pain, but their chronic use can lead to tolerance that limits their efficacy. We previously reported that inhibiting the chaperone protein HSP90 in the spinal cords of mice promotes the antinociceptive effects of opioids in a manner that involved increased activation of the kinase ERK. Here, we found that the underlying mechanism involves the relief of a negative feedback loop mediated by the kinase AMPK. Intrathecal treatment of male and female mice with the HSP90 inhibitor 17-AAG decreased the abundance of the beta 1 subunit of AMPK in the spinal cord. The antinoci-ceptive effects of 17-AAG with morphine were suppressed by intrathecal administration of AMPK activators and enhanced by an AMPK inhibitor. Opioid treatment increased the abundance of phosphorylated AMPK in the dorsal horn of the spinal cord, where it colocalized with a neuronal marker and the neuropeptide CGRP. Knock-ing down AMPK in CGRP-positive neurons enhanced the antinociceptive effects of morphine and demonstrated that AMPK mediated the signal transduction between HSP90 inhibition and ERK activation. These data suggest that AMPK mediates an opioid-induced negative feedback loop in CGRP neurons of the spinal cord and that this loop can be disabled by HSP90 inhibition to enhance the efficacy of opioids.
引用
收藏
页数:11
相关论文
共 48 条
[1]   Molecular Mechanisms of Opioid Receptor-dependent Signaling and Behavior [J].
Al-Hasani, Ream ;
Bruchas, Michael R. .
ANESTHESIOLOGY, 2011, 115 (06) :1363-1381
[2]   IB4(+) nociceptors mediate persistent muscle pain induced by GDNF [J].
Alvarez, Pedro ;
Chen, Xiaojie ;
Bogen, Oliver ;
Green, Paul G. ;
Levine, Jon D. .
JOURNAL OF NEUROPHYSIOLOGY, 2012, 108 (09) :2545-2553
[3]  
Argoff CE., 2009, Pain Management Secrets, VThird, P19, DOI DOI 10.1016/B978-0-323-04019-8.00003-2
[4]  
Asiedu MN, 2016, EXPERIENTIA SUPPL, V107, P257, DOI 10.1007/978-3-319-43589-3_11
[5]   CGRP receptors in the control of pain and inflammation [J].
Benemei, Silvia ;
Nicoletti, Paola ;
Capone, Jay G. ;
Geppetti, Pierangelo .
CURRENT OPINION IN PHARMACOLOGY, 2009, 9 (01) :9-14
[6]   Strong opioids for noncancer pain due to musculoskeletal diseases: Not more effective than acetaminophen or NSAIDs [J].
Berthelot, Jean-Marie ;
Darrieutort-Lafitte, Christelle ;
Le Goff, Benoit ;
Maugars, Yves .
JOINT BONE SPINE, 2015, 82 (06) :397-401
[7]   Depolarization-Dependent C-Raf Signaling Promotes Hyperexcitability and Reduces Opioid Sensitivity of Isolated Nociceptors after Spinal Cord Injury [J].
Carbajal, Anibal Garza ;
Bavencoffe, Alexis ;
Walters, Edgar T. ;
Dessauer, Carmen W. .
JOURNAL OF NEUROSCIENCE, 2020, 40 (34) :6522-6535
[8]   QUANTITATIVE ASSESSMENT OF TACTILE ALLODYNIA IN THE RAT PAW [J].
CHAPLAN, SR ;
BACH, FW ;
POGREL, JW ;
CHUNG, JM ;
YAKSH, TL .
JOURNAL OF NEUROSCIENCE METHODS, 1994, 53 (01) :55-63
[9]   Diabetes-induced mechanical hyperalgesia involves spinal mitogen-activated protein kinase activation in neurons and microglia via N-methyl-D-aspartate-dependent mechanisms [J].
Daulhac, Laurence ;
Mallet, Christophe ;
Courteix, Christine ;
Etienne, Monique ;
Duroux, Eliane ;
Privat, Anne-Marie ;
Eschalier, Alain ;
Fialip, Joseph .
MOLECULAR PHARMACOLOGY, 2006, 70 (04) :1246-1254
[10]   Inhibition of Hsp90 in the spinal cord enhances the antinociceptive effects of morphine by activating an ERK-RSK pathway [J].
Duron, David, I ;
Lei, Wei ;
Barker, Natalie K. ;
Stine, Carrie ;
Mishra, Sanket ;
Blagg, Brian S. J. ;
Langlais, Paul R. ;
Streicher, John M. .
SCIENCE SIGNALING, 2020, 13 (630)