Spinal Opioid Tolerance Depends upon Platelet-Derived Growth Factor Receptor-β Signaling, Not μ-Opioid Receptor Internalization

Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics..

Opioids are some of the most potent analgesics available. However, their effectiveness is limited by the development of analgesic tolerance. Traditionally, tolerance was thought to occur by termination of μ-opioid receptor (MOR) signaling via desensitization and internalization. Contradictory findings led to a more recent proposal that sustained MOR signaling caused analgesic tolerance. However, this view has also been called into question. We recently discovered that the platelet-derived growth factor receptor(PDGFR)-β signaling system is both necessary and sufficient to cause opioid tolerance. We therefore propose a completely new hypothesis: that opioid tolerance is mediated by selective cellular signals and is independent of MOR internalization. To test this hypothesis, we developed an automated software-based method to perform unbiased analyses of opioid-induced MOR internalization in the rat substantia gelatinosa. We induced tolerance with either morphine, which did not cause MOR internalization, or fentanyl, which did. We also blocked tolerance by administering morphine or fentanyl with the PDGFR-β inhibitor imatinib. We found that imatinib blocked tolerance without altering receptor internalization induced by either morphine or fentanyl. We also showed that imatinib blocked tolerance to other clinically used opioids. Our findings indicate that opioid tolerance is not dependent upon MOR internalization and support the novel hypothesis that opioid tolerance is mediated by intracellular signaling that can be selectively targeted. This suggests the exciting possibility that undesirable opioid side effects can be selectively eliminated, dramatically improving the safety and efficacy of opioids. SIGNIFICANCE STATEMENT: Classically, it was thought that analgesic tolerance to opioids was caused by desensitization and internalization of μ-opioid receptors (MORs). More recently, it was proposed that sustained, rather than reduced, MOR signaling caused tolerance. Here, we present conclusive evidence that opioid tolerance occurs independently of MOR internalization and that it is selectively mediated by platelet-derived growth factor receptor signaling. This novel hypothesis suggests that dangerous opioid side effects can be selectively targeted and blocked, improving the safety and efficacy of opioids.

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - volume:98

Enthalten in:

Molecular pharmacology - 98(2020), 4 vom: 11. Okt., Seite 487-496

Sprache:

Englisch

Beteiligte Personen:

Puig, S [VerfasserIn]
Barker, K E [VerfasserIn]
Szott, S R [VerfasserIn]
Kann, P T [VerfasserIn]
Morris, J S [VerfasserIn]
Gutstein, H B [VerfasserIn]

Links:

Volltext

Themen:

76I7G6D29C
8A1O1M485B
Analgesics, Opioid
EC 2.7.10.1
Fentanyl
Imatinib Mesylate
Journal Article
Morphine
Receptor, Platelet-Derived Growth Factor beta
Receptors, Opioid, mu
Research Support, N.I.H., Extramural
UF599785JZ

Anmerkungen:

Date Completed 06.11.2020

Date Revised 02.10.2021

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1124/mol.120.119552

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM312995032