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Keresztes A, Olson K, Nguyen P, et al. Antagonism of the mu-delta opioid receptor heterodimer enhances opioid antinociception by activating Src and calcium/calmodulin-dependent protein kinase II signaling. Pain. 2022;163(1):146-158doi: 10.1097/j.pain.0000000000002320.
Keresztes, A., Olson, K., Nguyen, P., Lopez-Pier, M. A., Hecksel, R., Barker, N. K., Liu, Z., Hruby, V., Konhilas, J., Langlais, P. R., & Streicher, J. M. (2022). 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. https://doi.org/10.1097/j.pain.0000000000002320
Keresztes, Attila, et al. "Antagonism of the mu-delta opioid receptor heterodimer enhances opioid antinociception by activating Src and calcium/calmodulin-dependent protein kinase II signaling." Pain vol. 163,1 (2022): 146-158. doi: https://doi.org/10.1097/j.pain.0000000000002320
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. 2022 Jan 01;163(1):146-158. doi: 10.1097/j.pain.0000000000002320. PMID: 34252907; PMCID: PMC8688156.
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Pain. 2022 Jan 01;163(1):146-158. doi: 10.1097/j.pain.0000000000002320.

Antagonism of the mu-delta opioid receptor heterodimer enhances opioid antinociception by activating Src and calcium/calmodulin-dependent protein kinase II signaling.

Pain

Attila Keresztes, Keith Olson, Paul Nguyen, Marissa A Lopez-Pier, Ryan Hecksel, Natalie K Barker, Zekun Liu, Victor Hruby, John Konhilas, Paul R Langlais, John M Streicher

Affiliations

  1. Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, United States.
  2. Department of Chemistry and Biochemistry, College of Science, University of Arizona, Tucson, AZ, United States.
  3. Medicine, College of Medicine, University of Arizona, Tucson, AZ, United States.
  4. Departments of Physiology and.

PMID: 34252907 PMCID: PMC8688156 DOI: 10.1097/j.pain.0000000000002320

Abstract

ABSTRACT: 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 cotreated CD-1 mice with D24M and opioids in tail flick, paw incision, and chemotherapy-induced peripheral neuropathy pain models. D24M treatment enhanced oxymorphone antinociception in all models by 54.7% to 628%. This enhancement could not be replicated with the mu and delta selective antagonists CTAP, naltrindole, and naloxonazine, 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 antinociception using small molecule inhibitors (KN93 and Src-I1). Together, these results provide direct in vivo evidence that the MDOR acts as an opioid negative feedback brake, which occurs through the repression of Src and CaMKII signal transduction. These results further suggest that MDOR antagonism could be a means to improve clinical opioid therapy.

Copyright © 2021 International Association for the Study of Pain.

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