Mast cell–derived BH4 and serotonin are critical mediators of postoperative pain

Author:

Starkl Philipp1ORCID,Jonsson Gustav234ORCID,Artner Tyler15ORCID,Turnes Bruna Lenfers67ORCID,Gail Laura-Marie89ORCID,Oliveira Tiago23ORCID,Jain Aakanksha67ORCID,Serhan Nadine10ORCID,Stejskal Karel3,Lakovits Karin1,Hladik Anastasiya1,An Meilin11ORCID,Channon Keith M.12ORCID,Kim Hail13ORCID,Köcher Thomas14ORCID,Weninger Wolfgang8ORCID,Stary Georg89ORCID,Knapp Sylvia115ORCID,Klang Victoria16ORCID,Gaudenzio Nicolas1017ORCID,Woolf Clifford J.67ORCID,Tikoo Shweta8ORCID,Jain Rohit8ORCID,Penninger Josef M.231118ORCID,Cronin Shane J. F.23ORCID

Affiliation:

1. Research Division of Infection Biology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

2. Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.

3. Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.

4. Vienna BioCenter PhD Program, Doctoral School of the University of Vienna and Medical University of Vienna, Vienna, Austria.

5. Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.

6. Department of Neurobiology, Harvard Medical School, Boston, MA, USA.

7. F. M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA, USA.

8. Department of Dermatology, Medical University of Vienna, Vienna, Austria.

9. CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

10. Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), Inserm UMR1291 CNRS UMR5051, University of Toulouse III, Toulouse, France.

11. Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, Canada.

12. Radcliffe Department of Medicine, British Heart Foundation Centre of Research Excellence, John Radcliffe Hospital, University of Oxford, Oxford, UK.

13. Korea Advanced Institute of Science and Technology, Daejoen, Republic of Korea.

14. Vienna BioCenter Core Facilities (VBCF), 1030 Vienna, Austria.

15. Ignaz Semmelweis Institute, Interuniversity Institute for Infection Research, Medical University of Vienna, Vienna, Austria.

16. Department of Pharmaceutical Sciences, University of Vienna, Vienna, Austria.

17. Genoskin SAS, Toulouse, France.

18. Helmholtz Centre for Infection Research, Braunschweig, Germany.

Abstract

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 Gch1 , 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 Gch1 or Tph1 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.

Publisher

American Association for the Advancement of Science (AAAS)

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