OSCR

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

Overview

Authors: Luca Posa1, Angelique J. Buton2,3,4, Anita M. Khasnavis2,3,4,5, Sophia A. Miracle1, Kathryn M. Albers6, Matthew J. Fanelli2,3,4,5, Timmy Le3,4,5, Mackenzie Gamble2,3,4,7, Ashley K. McDonald1, Gilles Martin3,4, Salome Fabri-Ruiz8, Zachary Freyberg9,10, Ryan W. Logan2,3,4, Stephanie Puig2,3,4
ORCID iDs: Timmy Le, Stephanie Puig
  1. Department of Pharmacology, Physiology and Biophysics, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA
  2. Department of Psychiatry and Behavioral Sciences, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
  3. Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
  4. Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
  5. Graduate Program of Neuroscience, Morningside Graduate School of Biological Sciences, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
  6. Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA
  7. Molecular and Translational Medicine, Department of Medicine, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA
  8. DECOD, L’Institut Agro, IFREMER, INRAE, Nantes 44311, France
  9. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA
  10. Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA
Institutions: Boston University (United States); University of Massachusetts Chan Medical School (United States); University of Pittsburgh (United States); Ifremer (France); Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (France); Dynamique et durabilité des écosystèmes : de la source à l'océan (France)
Journal: iScience, volume 29, issue 7, article 116634
Dates: received 28 May 2025; accepted 15 June 2026; published online 30 June 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1016/j.isci.2026.116634 · PMID 42491735 · PMCID PMC13378143 · OpenAlex W7166685814
Open access: gold, a free copy (OpenAlex)
Status: code on request
Categories: pain (population), cellular / molecular (subfield)
Methods: Statistics, fMRI & imaging
Keywords: opioid analgesia, Peripheral opioid tolerance, Keratinocytes, growth factors
Topic: Pain Mechanisms and Treatments (Physiology, Medicine), according to OpenAlex
Funding: University of Pittsburgh; Morningside Graduate School; UMass Chan; NIH (R21DA051636, R01AR0777341, R01DK124955, R01DA051390, R01DA06124, R21AA028800, R01ES034037, R01DA061243); Pittsburgh Foundation (FPG00043); Commonwealth of Pennsylvania (PA-HEALTH)
Citations: not cited yet (Europe PMC); 108 references in the paper
Research resources: Y1021-PDGFRβ rabbit polyclonal antibody RRID:AB_10856220, PDGFRβ rabbit polyclonal antibody RRID:AB_10985851, HRP conjugated goat anti-rabbit antibody RRID:AB_2099233, HRP conjugated anti β-actin mAb RRID:AB_262011, IgG2a kappa Isotype Control antibody RRID:AB_410156, PDGFRβ monoclonal neutralizing antibody RRID:AB_469070

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.

The paper's code and data availability statement is in the Data section.

Tracing map

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Data

No dataset and no data link were found in the paper.

Data and code availability

Data: • All data reported in this paper will be shared by the lead contact upon request.

Code: • This paper does not report original code.

Additional information: • Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 2, 28 September 2026

  • Authors: added Stephanie Puig (0000-0001-7200-1094); removed Stephanie Puig

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 14 authors, 4 keywords, 6 funders, 104 references, 6 RRIDs.

Cite

This paper

Posa, L., Buton, A. J., Khasnavis, A. M., Miracle, S. A., Albers, K. M., Fanelli, M. J., Le, T., Gamble, M., McDonald, A. K., Martin, G., Fabri-Ruiz, S., Freyberg, Z., Logan, R. W., & Puig, S. (2026). Keratinocytes and PDGF-B/PDGFRβ signaling modulate peripheral opioid tolerance. iScience, 29(7), 116634. https://doi.org/10.1016/j.isci.2026.116634

BibTeX

@article{posa2026keratinocytes,
author = {Posa, Luca and Buton, Angelique J. and Khasnavis, Anita M. and Miracle, Sophia A. and Albers, Kathryn M. and Fanelli, Matthew J. and Le, Timmy and Gamble, Mackenzie and McDonald, Ashley K. and Martin, Gilles and Fabri-Ruiz, Salome and Freyberg, Zachary and Logan, Ryan W. and Puig, Stephanie},
title = {{Keratinocytes and PDGF-B/PDGFRβ signaling modulate peripheral opioid tolerance}},
journal = {iScience},
year = {2026},
month = jun,
volume = {29},
number = {7},
pages = {116634},
publisher = {Elsevier},
issn = {2589-0042},
doi = {10.1016/j.isci.2026.116634},
url = {https://doi.org/10.1016/j.isci.2026.116634},
pmid = {42491735},
pmcid = {PMC13378143}
}

RIS

TY - JOUR
AU - Posa, Luca
AU - Buton, Angelique J.
AU - Khasnavis, Anita M.
AU - Miracle, Sophia A.
AU - Albers, Kathryn M.
AU - Fanelli, Matthew J.
AU - Le, Timmy
AU - Gamble, Mackenzie
AU - McDonald, Ashley K.
AU - Martin, Gilles
AU - Fabri-Ruiz, Salome
AU - Freyberg, Zachary
AU - Logan, Ryan W.
AU - Puig, Stephanie
TI - Keratinocytes and PDGF-B/PDGFRβ signaling modulate peripheral opioid tolerance
T2 - iScience
J2 - iScience
PY - 2026
DA - 2026/06/30
VL - 29
IS - 7
SP - 116634
SN - 2589-0042
PB - Elsevier
DO - 10.1016/j.isci.2026.116634
UR - https://doi.org/10.1016/j.isci.2026.116634
LA - en
ER -

CSL-JSON

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