Keratinocytes and PDGF-B/PDGFRβ signaling modulate peripheral opioid tolerance

Area of Science:

• Pharmacology
• Neuroscience
• Dermatology

Background:

• Peripheral opioids offer safer pain management than systemic opioids by avoiding central nervous system side effects.
• Peripheral opioid tolerance, however, limits their clinical efficacy and widespread application.
• Understanding the mechanisms of peripheral tolerance is crucial for improving opioid-based pain therapies.

Purpose of the Study:

• To elucidate the epithelial-neuronal communication mechanisms underlying peripheral opioid tolerance.
• To investigate the role of platelet-derived growth factor B (PDGF-B) and its receptor (PDGFRβ) in peripheral opioid tolerance.
• To identify potential therapeutic targets for mitigating peripheral tolerance and enhancing opioid safety.

Main Methods:

• Repeated intraplantar (i.pl.) morphine injections or keratinocyte photostimulation in mouse models.
• Assessment of peripheral tolerance through behavioral and electrophysiological measures.
• Analysis of PDGF-B expression in keratinocytes and PDGFRβ signaling pathways.

Main Results:

• Repeated morphine or photostimulation induced peripheral tolerance dependent on PDGF-B and PDGFRβ.
• Morphine i.pl. increased PDGF-B in mu-opioid receptor-expressing keratinocytes and altered their electrophysiology.
• PDGFRβ inhibition completely blocked peripheral tolerance in chronic pain models.

Conclusions:

• Keratinocytes and PDGF-B signaling are key mediators of peripheral opioid tolerance.
• PDGFRβ represents a viable therapeutic target to overcome peripheral tolerance.
• Inhibiting PDGFRβ could enable a shift towards safer peripheral opioid delivery for pain management.