PXD015060

PXD015060 is an original dataset announced via ProteomeXchange.

Title	Inhibition of spinal cord Hsp90 enhances morphine anti-nociception by activating an ERK/RSK pathway
Description	Morphine and other opioids continue to be commonly utilized as clinical analgesics, despite their numerous adverse side effects, including respiratory depression, addiction, and tolerance. The modulation of µ-opioid receptor (MOR) signaling and subsequent behavioral output is one viable approach to improve opioid therapy. Heat shock protein 90 (Hsp90) is a molecular chaperone protein that has recently been implicated in downstream MOR signaling within the brain in mice. Here we identify a context-dependent impact on MOR signaling in which the inhibition of Hsp90 within the spinal cord promotes morphine induced anti-nociception. We show that intrathecal and not systemic administration of the Hsp90 inhibitors 17-AAG or KU-32 amplifies morphine-induced anti-nociception in both thermal and mechanical pain models. Further, we demonstrate that the inhibition of Hsp90 allows for ERK phosphorylation after opioid treatment. ERK activation was localized within the dorsal horns of the spinal cord, which are heavily populated with primary afferents responsible for nociception. The behavioral effects observed with Hsp90 inhibitors were abolished upon intrathecal U0126 (ERK inhibitor) and cycloheximide (translation inhibitor) treatment, suggesting that downstream ERK phosphorylation and rapid protein translation are responsible for the observed amplification of anti-nociception. Quantitative proteomic analysis identified upregulated RSK with spinal cord Hsp90 inhibition, which we further found was necessary for the observed enhancement of anti-nociception. Taken together, we have uncovered a novel downstream MOR ERK/RSK cascade, localized to the spinal cord and repressed by Hsp90, whose modulation may allow for enhanced efficacy and decreased side effects during opioid therapy.
HostingRepository	PRIDE
AnnounceDate	2020-04-24
AnnouncementXML	Submission_2020-06-12_04:50:18.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD015060
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Paul Langlais
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	Ammonia-loss; Phospho; Dehydrated; Oxidation; Acetyl
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2019-08-16 05:35:30	ID requested
1	2020-04-24 02:15:51	announced
⏵ 2	2020-06-12 04:50:19	announced	2020-06-12: Updated publication reference for PubMed record(s): 32371496.

Duron DI, Lei W, Barker NK, Stine C, Mishra S, Blagg BSJ, Langlais PR, Streicher JM, Inhibition of Hsp90 in the spinal cord enhances the antinociceptive effects of morphine by activating an ERK-RSK pathway. Sci Signal, 13(630):(2020) [pubmed]

submitter keyword: Hsp90, anti-nociception, ERK, spinal cord

Paul R. Langlais
contact affiliation	University of Arizona College of Medicine, Department of Medicine, Division of Endocrinology
contact email	langlais@deptofmed.arizona.edu
lab head
Paul Langlais
contact affiliation	University of Arizona
contact email	langlais@deptofmed.arizona.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD015060
     1. Label: PRIDE project
     2. Name: Inhibition of spinal cord Hsp90 enhances morphine anti-nociception by activating an ERK/RSK pathway