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Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
Published on: July 29, 2014
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Spinal Opioid Tolerance Depends upon Platelet-Derived Growth Factor Receptor-β Signaling, Not μ-Opioid Receptor
S Puig1, K E Barker1, S R Szott1
1Anesthesiology Institute, Allegheny Health Network, Pittsburgh, Pennsylvania (H.B.G.); University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (S.P., S.R.S., P.T.K.); MD Anderson Cancer Center, Houston, Texas (K.E.B.); and Biostatistics Division, Perelman School of Medicine, Philadelphia, Pennsylvania (J.S.M.).
Molecular Pharmacology
|July 30, 2020
Summary
Opioid tolerance develops independently of mu-opioid receptor internalization. Platelet-derived growth factor receptor-beta signaling selectively mediates tolerance, offering new therapeutic targets to improve opioid safety and efficacy.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Opioid analgesics are potent pain relievers, but their efficacy is limited by analgesic tolerance.
- Previous theories proposed tolerance resulted from mu-opioid receptor (MOR) signaling termination or sustained signaling, but evidence was contradictory.
Purpose of the Study:
- To investigate a novel hypothesis that opioid tolerance is mediated by selective intracellular signaling pathways, independent of MOR internalization.
- To determine the role of platelet-derived growth factor receptor-beta (PDGFR-β) signaling in opioid tolerance.
Main Methods:
- Developed an automated software method for unbiased analysis of opioid-induced MOR internalization in rat substantia gelatinosa.
- Induced tolerance using morphine or fentanyl and assessed the effect of imatinib, a PDGFR-β inhibitor, on tolerance and MOR internalization.
Main Results:
- Morphine did not induce MOR internalization, while fentanyl did, yet both led to tolerance.
- Imatinib blocked opioid tolerance to both morphine and fentanyl without affecting MOR internalization.
- Imatinib demonstrated efficacy in blocking tolerance to other clinically used opioids.
Conclusions:
- Opioid tolerance is not dependent on MOR internalization, challenging traditional and recent views.
- PDGFR-β signaling selectively mediates opioid tolerance, providing a novel therapeutic target.
- Targeting intracellular signaling pathways offers a promising strategy to selectively eliminate opioid side effects, enhancing safety and efficacy.
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