Mast cell–derived BH4 and serotonin are critical mediators of postoperative pain
Postoperative pain affects most patients after major surgery and can transition to chronic pain. The considerable side effects and limited efficacy of current treatments underline the need for new therapeutic options. We observed increased amounts of the metabolites BH4 and serotonin after skin injury. Mast cells were primary postoperative sources of <i>Gch1</i>, the rate-limiting enzyme in BH4 synthesis, itself an obligate cofactor in serotonin production by tryptophan hydroxylase (Tph1). Mice deficient in mast cells or in mast cell-specific <i>Gch1</i> or <i>Tph1</i> showed drastically decreased postoperative pain. We found that injury induced the nociceptive neuropeptide substance P, mast cell degranulation, and granule nerve colocalization. Substance P triggered serotonin release in mouse and human mast cells, and substance P receptor blockade substantially ameliorated pain hypersensitivity. Our findings highlight the importance of mast cells at the neuroimmune interface and substance P-driven mast cell BH4 and serotonin production as a therapeutic target for postoperative pain treatment.
Authors
- Bruna Lenfers Turnes (ORCID: https://orcid.org/0000-0002-3989-8394)
- Nicolas Gaudenzio (ORCID: https://orcid.org/0000-0002-5648-509X)
- Hail Kim (ORCID: https://orcid.org/0000-0002-6652-1349)
- Gustav Jonsson (ORCID: https://orcid.org/0000-0001-6692-8395)
- Keith M. Channon (ORCID: https://orcid.org/0000-0002-1043-4342)
- Shane J. F. Cronin (ORCID: https://orcid.org/0000-0003-4222-5315)
- Clifford J. Woolf (ORCID: https://orcid.org/0000-0002-6636-3897)
- Georg Stary (ORCID: https://orcid.org/0000-0003-1746-4250)
- Philipp Starkl (ORCID: https://orcid.org/0000-0001-7521-129X)
- Rohit Jain (ORCID: https://orcid.org/0000-0002-4905-462X)
- Karel Stejskal (ORCID: https://orcid.org/0000-0001-7835-8123)
- Karin Lakovits
- Sylvia Knapp (ORCID: https://orcid.org/0000-0001-9016-5244)
- Nadine Serhan (ORCID: https://orcid.org/0000-0001-9870-9875)
- Shweta Tikoo (ORCID: https://orcid.org/0000-0001-5850-8075)
- Josef Penninger (ORCID: https://orcid.org/0000-0002-8194-3777)
- Tiago Oliveira (ORCID: https://orcid.org/0000-0003-4759-1728)
- Tyler Artner (ORCID: https://orcid.org/0000-0003-3421-3453)
- Meilin An (ORCID: https://orcid.org/0000-0003-3498-2674)
- Thomas Köcher
- Aakanksha Jain (ORCID: https://orcid.org/0000-0001-9602-4987)
- Wolfgang Weninger (ORCID: https://orcid.org/0000-0003-3133-8699)
- Laura Marie Gail (ORCID: https://orcid.org/0000-0002-2525-9399)
- Victoria Klang (ORCID: https://orcid.org/0000-0003-2561-4378)
- Anastasiya Hladik
Institutions
- Institute of Molecular Biotechnology (AT)
- Boston Children's Hospital (US)
- Centre National de la Recherche Scientifique (FR)
- University of Vienna (AT)
- Université Toulouse III - Paul Sabatier (FR)
- Harvard University (US)
- Austrian Academy of Sciences (AT)
- University of British Columbia (CA)
- Inserm (FR)
- Korea Advanced Institute of Science and Technology (KR)
- Université Fédérale de Toulouse Midi-Pyrénées (FR)
- John Radcliffe Hospital (GB)
- Helmholtz Centre for Infection Research (DE)
- CeMM Research Center for Molecular Medicine (AT)
- Vienna Biocenter (AT)
- Vienna BioCenter Core Facilities (AT)
- Medical University of Vienna (AT)
Publication Details
- Journal
- Science Immunology
- Published
- 2024-08-23
- DOI
- https://doi.org/10.1126/sciimmunol.adh0545
- Citations
- 14
- Primary Topic
- Pain Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 4.57