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ResearchIn-Press PreviewGeneticsInflammationNeuroscience Open Access | 10.1172/JCI206667

Neuronal and non-neuronal TRPA1 mediate distinct pain perception mechanisms in Familial Episodic Pain Syndrome models

Matilde Marini,1 Martina Chieca,1 Elisabetta Coppi,2 Marco Montini,3 Lorenzo Bonacchi,1 Lorenzo Landini,1 Irene Scuffi,1 Kelvin Y. Kwan,4 Alice Papini,1 Gaetano De Siena,1 Elisa Bellantoni,1 Lucrezia Timotei,1 Elena Colzi,2 Valentina Albanese,5 Gabriele Ferroni,6 Evelynn D. N. Melo,7 Marie-Christine Birling,8 Romain Lorentz,8 Romina Nassini,1 and Francesco De Logu1

1Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy

2Section of Pharmacology and Toxicology, University of Florence, Florence, Italy

3Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

4Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, United States of America

5Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy

6Clinical Pharmacology and Oncology Section, University of Florence, Italy, Florence, Italy

7Laboratory of Bioactive Products, Federal University of Rio de Janeiro, Macaé, Brazil

8Head associate Genetic engineering and mouse model validation department, Institut Clinique de la Souris (ICS), Illkirch cedex, France

Find articles by Marini, M. in: PubMed | Google Scholar

1Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy

2Section of Pharmacology and Toxicology, University of Florence, Florence, Italy

3Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

4Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, United States of America

5Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy

6Clinical Pharmacology and Oncology Section, University of Florence, Italy, Florence, Italy

7Laboratory of Bioactive Products, Federal University of Rio de Janeiro, Macaé, Brazil

8Head associate Genetic engineering and mouse model validation department, Institut Clinique de la Souris (ICS), Illkirch cedex, France

Find articles by Chieca, M. in: PubMed | Google Scholar

1Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy

2Section of Pharmacology and Toxicology, University of Florence, Florence, Italy

3Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

4Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, United States of America

5Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy

6Clinical Pharmacology and Oncology Section, University of Florence, Italy, Florence, Italy

7Laboratory of Bioactive Products, Federal University of Rio de Janeiro, Macaé, Brazil

8Head associate Genetic engineering and mouse model validation department, Institut Clinique de la Souris (ICS), Illkirch cedex, France

Find articles by Coppi, E. in: PubMed | Google Scholar |

1Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy

2Section of Pharmacology and Toxicology, University of Florence, Florence, Italy

3Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

4Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, United States of America

5Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy

6Clinical Pharmacology and Oncology Section, University of Florence, Italy, Florence, Italy

7Laboratory of Bioactive Products, Federal University of Rio de Janeiro, Macaé, Brazil

8Head associate Genetic engineering and mouse model validation department, Institut Clinique de la Souris (ICS), Illkirch cedex, France

Find articles by Montini, M. in: PubMed | Google Scholar |

1Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy

2Section of Pharmacology and Toxicology, University of Florence, Florence, Italy

3Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

4Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, United States of America

5Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy

6Clinical Pharmacology and Oncology Section, University of Florence, Italy, Florence, Italy

7Laboratory of Bioactive Products, Federal University of Rio de Janeiro, Macaé, Brazil

8Head associate Genetic engineering and mouse model validation department, Institut Clinique de la Souris (ICS), Illkirch cedex, France

Find articles by Bonacchi, L. in: PubMed | Google Scholar

1Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy

2Section of Pharmacology and Toxicology, University of Florence, Florence, Italy

3Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

4Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, United States of America

5Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy

6Clinical Pharmacology and Oncology Section, University of Florence, Italy, Florence, Italy

7Laboratory of Bioactive Products, Federal University of Rio de Janeiro, Macaé, Brazil

8Head associate Genetic engineering and mouse model validation department, Institut Clinique de la Souris (ICS), Illkirch cedex, France

Find articles by Landini, L. in: PubMed | Google Scholar |

1Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy

2Section of Pharmacology and Toxicology, University of Florence, Florence, Italy

3Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

4Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, United States of America

5Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy

6Clinical Pharmacology and Oncology Section, University of Florence, Italy, Florence, Italy

7Laboratory of Bioactive Products, Federal University of Rio de Janeiro, Macaé, Brazil

8Head associate Genetic engineering and mouse model validation department, Institut Clinique de la Souris (ICS), Illkirch cedex, France

Find articles by Scuffi, I. in: PubMed | Google Scholar

1Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy

2Section of Pharmacology and Toxicology, University of Florence, Florence, Italy

3Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

4Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, United States of America

5Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy

6Clinical Pharmacology and Oncology Section, University of Florence, Italy, Florence, Italy

7Laboratory of Bioactive Products, Federal University of Rio de Janeiro, Macaé, Brazil

8Head associate Genetic engineering and mouse model validation department, Institut Clinique de la Souris (ICS), Illkirch cedex, France

Find articles by Kwan, K. in: PubMed | Google Scholar

1Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy

2Section of Pharmacology and Toxicology, University of Florence, Florence, Italy

3Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

4Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, United States of America

5Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy

6Clinical Pharmacology and Oncology Section, University of Florence, Italy, Florence, Italy

7Laboratory of Bioactive Products, Federal University of Rio de Janeiro, Macaé, Brazil

8Head associate Genetic engineering and mouse model validation department, Institut Clinique de la Souris (ICS), Illkirch cedex, France

Find articles by Papini, A. in: PubMed | Google Scholar

1Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy

2Section of Pharmacology and Toxicology, University of Florence, Florence, Italy

3Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

4Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, United States of America

5Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy

6Clinical Pharmacology and Oncology Section, University of Florence, Italy, Florence, Italy

7Laboratory of Bioactive Products, Federal University of Rio de Janeiro, Macaé, Brazil

8Head associate Genetic engineering and mouse model validation department, Institut Clinique de la Souris (ICS), Illkirch cedex, France

Find articles by De Siena, G. in: PubMed | Google Scholar

1Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy

2Section of Pharmacology and Toxicology, University of Florence, Florence, Italy

3Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

4Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, United States of America

5Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy

6Clinical Pharmacology and Oncology Section, University of Florence, Italy, Florence, Italy

7Laboratory of Bioactive Products, Federal University of Rio de Janeiro, Macaé, Brazil

8Head associate Genetic engineering and mouse model validation department, Institut Clinique de la Souris (ICS), Illkirch cedex, France

Find articles by Bellantoni, E. in: PubMed | Google Scholar

1Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy

2Section of Pharmacology and Toxicology, University of Florence, Florence, Italy

3Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

4Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, United States of America

5Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy

6Clinical Pharmacology and Oncology Section, University of Florence, Italy, Florence, Italy

7Laboratory of Bioactive Products, Federal University of Rio de Janeiro, Macaé, Brazil

8Head associate Genetic engineering and mouse model validation department, Institut Clinique de la Souris (ICS), Illkirch cedex, France

Find articles by Timotei, L. in: PubMed | Google Scholar

1Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy

2Section of Pharmacology and Toxicology, University of Florence, Florence, Italy

3Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

4Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, United States of America

5Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy

6Clinical Pharmacology and Oncology Section, University of Florence, Italy, Florence, Italy

7Laboratory of Bioactive Products, Federal University of Rio de Janeiro, Macaé, Brazil

8Head associate Genetic engineering and mouse model validation department, Institut Clinique de la Souris (ICS), Illkirch cedex, France

Find articles by Colzi, E. in: PubMed | Google Scholar

1Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy

2Section of Pharmacology and Toxicology, University of Florence, Florence, Italy

3Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

4Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, United States of America

5Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy

6Clinical Pharmacology and Oncology Section, University of Florence, Italy, Florence, Italy

7Laboratory of Bioactive Products, Federal University of Rio de Janeiro, Macaé, Brazil

8Head associate Genetic engineering and mouse model validation department, Institut Clinique de la Souris (ICS), Illkirch cedex, France

Find articles by Albanese, V. in: PubMed | Google Scholar

1Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy

2Section of Pharmacology and Toxicology, University of Florence, Florence, Italy

3Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

4Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, United States of America

5Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy

6Clinical Pharmacology and Oncology Section, University of Florence, Italy, Florence, Italy

7Laboratory of Bioactive Products, Federal University of Rio de Janeiro, Macaé, Brazil

8Head associate Genetic engineering and mouse model validation department, Institut Clinique de la Souris (ICS), Illkirch cedex, France

Find articles by Ferroni, G. in: PubMed | Google Scholar

1Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy

2Section of Pharmacology and Toxicology, University of Florence, Florence, Italy

3Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

4Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, United States of America

5Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy

6Clinical Pharmacology and Oncology Section, University of Florence, Italy, Florence, Italy

7Laboratory of Bioactive Products, Federal University of Rio de Janeiro, Macaé, Brazil

8Head associate Genetic engineering and mouse model validation department, Institut Clinique de la Souris (ICS), Illkirch cedex, France

Find articles by Melo, E. in: PubMed | Google Scholar

1Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy

2Section of Pharmacology and Toxicology, University of Florence, Florence, Italy

3Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

4Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, United States of America

5Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy

6Clinical Pharmacology and Oncology Section, University of Florence, Italy, Florence, Italy

7Laboratory of Bioactive Products, Federal University of Rio de Janeiro, Macaé, Brazil

8Head associate Genetic engineering and mouse model validation department, Institut Clinique de la Souris (ICS), Illkirch cedex, France

Find articles by Birling, M. in: PubMed | Google Scholar |

1Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy

2Section of Pharmacology and Toxicology, University of Florence, Florence, Italy

3Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

4Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, United States of America

5Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy

6Clinical Pharmacology and Oncology Section, University of Florence, Italy, Florence, Italy

7Laboratory of Bioactive Products, Federal University of Rio de Janeiro, Macaé, Brazil

8Head associate Genetic engineering and mouse model validation department, Institut Clinique de la Souris (ICS), Illkirch cedex, France

Find articles by Lorentz, R. in: PubMed | Google Scholar

1Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy

2Section of Pharmacology and Toxicology, University of Florence, Florence, Italy

3Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

4Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, United States of America

5Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy

6Clinical Pharmacology and Oncology Section, University of Florence, Italy, Florence, Italy

7Laboratory of Bioactive Products, Federal University of Rio de Janeiro, Macaé, Brazil

8Head associate Genetic engineering and mouse model validation department, Institut Clinique de la Souris (ICS), Illkirch cedex, France

Find articles by Nassini, R. in: PubMed | Google Scholar |

1Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy

2Section of Pharmacology and Toxicology, University of Florence, Florence, Italy

3Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy

4Department of Cell Biology & Neuroscience, Rutgers University, Piscataway, United States of America

5Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy

6Clinical Pharmacology and Oncology Section, University of Florence, Italy, Florence, Italy

7Laboratory of Bioactive Products, Federal University of Rio de Janeiro, Macaé, Brazil

8Head associate Genetic engineering and mouse model validation department, Institut Clinique de la Souris (ICS), Illkirch cedex, France

Find articles by De Logu, F. in: PubMed | Google Scholar |

Published October 1, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI206667.
Copyright © 2026, Marini et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 1, 2026 - Version history
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Abstract

Familial Episodic Pain Syndrome (FEPS) is a rare inherited disorder characterized by recurrent episodes of severe upper-body pain triggered by stimuli such as cold, stress, or fasting. A gain-of-function mutation (N855S) in the Transient Receptor Potential Ankyrin 1 (TRPA1) ion channel has been identified in affected individuals, yet the cellular mechanisms driving FEPS pain remain poorly defined. Although TRPA1 has been primarily studied in sensory neurons, emerging evidence suggests that non-neuronal cells may contribute to pain signaling. To define the cell-specific role of mutant TRPA1 (TRPA1mut), we generated mouse models selectively expressing TRPA1mut in Schwann cells or sensory neurons, using CRISPR-based and Cre-loxP strategies. Patch-clamp recordings confirmed enhanced agonist-evoked currents in TRPA1mut compared with wild-type channels. Behavioral analyses revealed that neuronal TRPA1mut mediates acute nociceptive responses, whereas Schwann cell TRPA1mut drives mechanical allodynia induced by subthreshold TRPA1 agonists and physiological triggers relevant to FEPS, including fasting, cold exposure, and restraint stress. These responses were associated with increased reactive oxygen species and accumulation of 4-hydroxynonenal in sciatic nerves and were attenuated by antioxidant treatment. These findings uncover a previously unrecognized Schwann cell-dependent mechanism of TRPA1-driven pain and identify non-neuronal TRPA1 signaling as a potential therapeutic target in FEPS and related pain channelopathies.

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