Schwann cell endosome CGRP signals elicit periorbital mechanical allodynia in mice.

Autor: De Logu F; Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence, 50139, Italy., Nassini R; Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence, 50139, Italy.; Headache Center, Careggi University Hospital, Florence, 50139, Italy., Hegron A; Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY, 10010, USA., Landini L; Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence, 50139, Italy., Jensen DD; Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY, 10010, USA.; Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY, 10010, USA., Latorre R; Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY, 10010, USA., Ding J; Department of Anesthesiology, Columbia University, New York, NY, 10010, USA., Marini M; Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence, 50139, Italy., Souza Monteiro de Araujo D; Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence, 50139, Italy., Ramírez-Garcia P; Drug Discovery Biology Theme and Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia., Whittaker M; Drug Discovery Biology Theme and Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia., Retamal J; Drug Discovery Biology Theme and Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia., Titiz M; Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence, 50139, Italy., Innocenti A; Plastic and Reconstructive Microsurgery - Careggi University Hospital, Florence, 50139, Italy., Davis TP; Drug Discovery Biology Theme and Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia.; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, 4072, Australia., Veldhuis N; Drug Discovery Biology Theme and Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, 3052, Australia., Schmidt BL; Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY, 10010, USA.; Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY, 10010, USA.; Department of Neuroscience and Physiology and Neuroscience Institute, School of Medicine, New York University, New York, NY, 10010, USA., Bunnett NW; Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY, 10010, USA. nwb2@nyu.edu.; Department of Neuroscience and Physiology and Neuroscience Institute, School of Medicine, New York University, New York, NY, 10010, USA. nwb2@nyu.edu., Geppetti P; Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Florence, 50139, Italy. pierangelo.geppetti@unifi.it.; Headache Center, Careggi University Hospital, Florence, 50139, Italy. pierangelo.geppetti@unifi.it.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Feb 03; Vol. 13 (1), pp. 646. Date of Electronic Publication: 2022 Feb 03.
DOI: 10.1038/s41467-022-28204-z
Abstrakt: Efficacy of monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor (calcitonin receptor-like receptor/receptor activity modifying protein-1, CLR/RAMP1) implicates peripherally-released CGRP in migraine pain. However, the site and mechanism of CGRP-evoked peripheral pain remain unclear. By cell-selective RAMP1 gene deletion, we reveal that CGRP released from mouse cutaneous trigeminal fibers targets CLR/RAMP1 on surrounding Schwann cells to evoke periorbital mechanical allodynia. CLR/RAMP1 activation in human and mouse Schwann cells generates long-lasting signals from endosomes that evoke cAMP-dependent formation of NO. NO, by gating Schwann cell transient receptor potential ankyrin 1 (TRPA1), releases ROS, which in a feed-forward manner sustain allodynia via nociceptor TRPA1. When encapsulated into nanoparticles that release cargo in acidified endosomes, a CLR/RAMP1 antagonist provides superior inhibition of CGRP signaling and allodynia in mice. Our data suggest that the CGRP-mediated neuronal/Schwann cell pathway mediates allodynia associated with neurogenic inflammation, contributing to the algesic action of CGRP in mice.
(© 2022. The Author(s).)
Databáze: MEDLINE
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