HSP90 inhibition in the mouse spinal cord enhances opioid signaling by suppressing an AMPK-mediated negative feedback loop
Name:
Streicher_Manuscript&Sup.Mat..pdf
Size:
923.1Kb
Format:
PDF
Description:
Final Accepted Manuscript
Affiliation
Department of Pharmacology, College of Medicine, University of ArizonaComprehensive Pain and Addiction Center, University of Arizona
Issue Date
2023-04-11
Metadata
Show full item recordCitation
Katherin A. Gabriel, John M. Streicher ,HSP90 inhibition in the mouse spinal cord enhances opioid signaling by suppressing an AMPK-mediated negative feedback loop.Sci. Signal.16, eade2438 (2023). DOI:10.1126/scisignal.ade2438Journal
Science signalingRights
© 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
Opioids and other agonists of the μ-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 β1 subunit of AMPK in the spinal cord. The antinociceptive 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. Knocking 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.Note
Immediate accessEISSN
1937-9145PubMed ID
37040443Version
Final accepted manuscriptae974a485f413a2113503eed53cd6c53
10.1126/scisignal.ade2438
Scopus Count
Collections
Related articles
- Inhibition of Hsp90 in the spinal cord enhances the antinociceptive effects of morphine by activating an ERK-RSK pathway.
- Authors: Duron DI, Lei W, Barker NK, Stine C, Mishra S, Blagg BSJ, Langlais PR, Streicher JM
- Issue date: 2020 May 5
- Inhibiting spinal cord-specific hsp90 isoforms reveals a novel strategy to improve the therapeutic index of opioid treatment.
- Authors: Duron DI, Tanguturi P, Campbell CS, Chou K, Bejarano P, Gabriel KA, Bowden JL, Mishra S, Brackett C, Barlow D, Houseknecht KL, Blagg BSJ, Streicher JM
- Issue date: 2024 Jun 26
- Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation.
- Authors: Pan Y, Sun X, Jiang L, Hu L, Kong H, Han Y, Qian C, Song C, Qian Y, Liu W
- Issue date: 2016 Nov 17
- Mitochondrial-Derived Peptide MOTS-c Ameliorates Spared Nerve Injury-Induced Neuropathic Pain in Mice by Inhibiting Microglia Activation and Neuronal Oxidative Damage in the Spinal Cord via the AMPK Pathway.
- Authors: Jiang J, Xu L, Yang L, Liu S, Wang Z
- Issue date: 2023 Jun 21
- Spinal modulation of calcitonin gene-related peptide by endocannabinoids in the development of opioid physical dependence.
- Authors: Trang T, Ma W, Chabot JG, Quirion R, Jhamandas K
- Issue date: 2006 Dec 15