PXD022106

PXD022106 is an original dataset announced via ProteomeXchange.

Title	Antagonism of the Mu-Delta Opioid Receptor Heterodimer Enhances Opioid Anti-Nociception by Activating Src and CaMKII Signaling
Description	The opioid receptors are important regulators of pain, reward, and addiction. Limited evidence suggests the mu and delta opioid receptors form a heterodimer (MDOR), which may act as a negative feedback brake on opioid-induced analgesia. However, evidence for the MDOR in vivo is indirect and limited, and there are few selective tools available. We recently published the first MDOR-selective antagonist, D24M, allowing us to test the role of the MDOR in mice. We thus co-treated CD-1 mice with D24M and opioids in tail flick, paw incision, and chemotherapy-induced peripheral neuropathy pain models. D24M treatment enhanced oxymorphone anti-nociception in all models by 52.3%-628%. This enhancement could not be replicated with the mu and delta selective antagonists CTAP and naltrindole, and D24M had a mild transient effect in the Rotarod test, suggesting this increase is selective to the MDOR. However, D24M had no effect on morphine or buprenorphine, suggesting that only specific opioids interact with the MDOR. To find a mechanism we performed phosphoproteomic analysis on brainstems of mice. We found that the kinases Src and CaMKII were repressed by oxymorphone, which was restored by D24M. We were able to confirm the role of Src and CaMKII in D24M-enhanced anti-nociception using small molecule inhibitors (KN93, Src-I1). Together these results provide direct in vivo evidence that the MDOR acts as an opioid negative feedback brake, which occurs via the repression of Src and CaMKII signal transduction. These results further suggest that MDOR antagonism could be a means to improve clinical opioid therapy.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:15:30.879.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD022106
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	phosphorylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2020-10-21 02:33:19	ID requested
1	2023-03-10 18:57:26	announced
⏵ 2	2023-11-14 08:15:31	announced	2023-11-14: Updated project metadata.

Keresztes A, Olson K, Nguyen P, Lopez-Pier MA, Hecksel R, Barker NK, Liu Z, Hruby V, Konhilas J, Langlais PR, Streicher JM, Antagonism of the mu-delta opioid receptor heterodimer enhances opioid antinociception by activating Src and calcium/calmodulin-dependent protein kinase II signaling. Pain, 163(1):146-158(2022) [pubmed]

10.6019/PXD022106;

submitter keyword: opiod MDOR oxymorphone nociception

John Streicher
contact affiliation	Department of Pharmacology, University of Arizona College of Medicine, Tucson
contact email	jstreicher@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. PXD022106
     1. Label: PRIDE project
     2. Name: Antagonism of the Mu-Delta Opioid Receptor Heterodimer Enhances Opioid Anti-Nociception by Activating Src and CaMKII Signaling