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

Abstract

Peripheral opioids are safer than systemic opioids by avoiding central side effects. However, peripheral tolerance hampers their clinical use. We highlight an epithelial-neuronal communication mechanism for peripheral opioid tolerance. We discovered that both repeated intraplantar (i.pl.) morphine injections or repeated keratinocyte photostimulation in mice cause peripheral tolerance in a platelet-derived growth factor type B (PDGF-B) and PDGF receptor beta (PDGFRβ)-dependent manner. We also find that morphine i.pl. increases PDGF-B in mu-opioid receptor-expressing keratinocytes and alters the electrophysiological properties of keratinocytes. This underscores the importance of keratinocytes and the necessity for PDGF-B release for peripheral tolerance, though the source of PDGF-B remains undetermined. Nevertheless, we show that PDGFRβ inhibition completely blocks peripheral tolerance in peripheral chronic pain models, highlighting the translational relevance of our findings. Overall, we highlight that keratinocytes and PDGFRβ are promising targets to reduce peripheral tolerance, which could allow shifting from systemic to peripheral opioid delivery and increase opioid safety.

Spartina anglica extract attenuates TNF-α/IFN-γ-induced inflammatory responses in HaCaT keratinocytes through suppression of the MAPK, NF-κB, and STAT1 signaling pathways
Yuna Ha, Yewon Kim, Jeong-In Park +3
Frontiers in Pharmacology30 Oct 2026Peer-reviewedCC BY 4.0Pharmacology & toxicologyFrontiersCrossref
Substance P–NK1R signaling of keratinocytes initiates the skin inflammatory environment required for allergic contact dermatitis
Sumeet Manandhar, Mohna Bandyopadhyay, Olga A. Tkacheva +5
JCI Insight1 Sep 2026Peer-reviewedCC BY 4.0Full textGeneral medicinePMC
Bioactive compounds from Perilla frutescens modulate multiple cell death pathways and signaling networks in cancer therapy
Hai Xu, Jingyi Liu, Huikun Wu +5
Frontiers in pharmacology16 Oct 2026Peer-reviewedCC BYFull textPharmacology & toxicologyEurope PMC
The RNA-binding protein Psc1 functions downstream of the NDR/LATS kinase Cbk1 to modulate CO2 tolerance in Cryptococcus neoformans
Emma E. Blackburn, Laura C. Ristow, Xiaofeng Xie +2
mBio21 Sep 2026Peer-reviewedCC BY 4.0Full textEpidemiology & public healthPMC
Metabolites derived from cell signaling pathways modulate AMPK-dependent autophagic flux in disease-relevant cell models under cellular stress conditions
Shifaa O. Alshammari
Scientific Reports1 Aug 2026Peer-reviewedCC BYFull textEpidemiology & public healthDOAJ

Cite

BibTeX RIS

BibTeX

@article{posa2026keratinocytes,
  title = {{Keratinocytes and PDGF-B/PDGFRβ signaling modulate peripheral opioid tolerance}},
  author = {Luca Posa and Angelique Buton and Anita Khasnavis and Sophia Miracle and Kathryn Albers and Matthew Fanelli and Timmy Le and Mackenzie Gamble and Ashley Mcdonald and Gilles Martin and Salomé Fabri‐ruiz and Zachary Freyberg and Ryan Logan and Stephanie Puig},
  journal = {iScience},
  year = {2026},
  month = oct,
  doi = {10.1016/j.isci.2026.116634},
  url = {https://hal.inrae.fr/hal-05797435v1},
  note = {CC BY},
}

RIS

TY  - JOUR
TI  - Keratinocytes and PDGF-B/PDGFRβ signaling modulate peripheral opioid tolerance
AU  - Luca Posa
AU  - Angelique Buton
AU  - Anita Khasnavis
AU  - Sophia Miracle
AU  - Kathryn Albers
AU  - Matthew Fanelli
AU  - Timmy Le
AU  - Mackenzie Gamble
AU  - Ashley Mcdonald
AU  - Gilles Martin
AU  - Salomé Fabri‐ruiz
AU  - Zachary Freyberg
AU  - Ryan Logan
AU  - Stephanie Puig
PY  - 2026
DA  - 2026/10/13
JO  - iScience
DO  - 10.1016/j.isci.2026.116634
UR  - https://hal.inrae.fr/hal-05797435v1
AB  - Peripheral opioids are safer than systemic opioids by avoiding central side effects. However, peripheral tolerance hampers their clinical use. We highlight an epithelial-neuronal communication mechanism for peripheral opioid tolerance. We discovered that both repeated intraplantar (i.pl.) morphine injections or repeated keratinocyte photostimulation in mice cause peripheral tolerance in a platelet-derived growth factor type B (PDGF-B) and PDGF receptor beta (PDGFRβ)-dependent manner. We also find that morphine i.pl. increases PDGF-B in mu-opioid receptor-expressing keratinocytes and alters the electrophysiological properties of keratinocytes. This underscores the importance of keratinocytes and the necessity for PDGF-B release for peripheral tolerance, though the source of PDGF-B remains undetermined. Nevertheless, we show that PDGFRβ inhibition completely blocks peripheral tolerance in peripheral chronic pain models, highlighting the translational relevance of our findings. Overall, we highlight that keratinocytes and PDGFRβ are promising targets to reduce peripheral tolerance, which could allow shifting from systemic to peripheral opioid delivery and increase opioid safety.
SN  - 2589-0042
ER  -

Abstract

Related

Cite