Schwann cell endosome CGRP signals elicit periorbital mechanical allodynia in mice

Francesco De Logu, Romina Nassini, Alan Hegron, Lorenzo Landini, Dane D. Jensen, Rocco Latorre, Julia Ding, Matilde Marini, Daniel Souza Monteiro de Araujo, Paulina Ramírez-Garcia, Michael Whittaker, Jeffri Retamal, Mustafa Titiz, Alessandro Innocenti, Thomas P. Davis, Nicholas Veldhuis, Brian L. Schmidt, Nigel W. Bunnett () and Pierangelo Geppetti ()
Additional contact information
Francesco De Logu: University of Florence
Romina Nassini: University of Florence
Alan Hegron: New York University
Lorenzo Landini: University of Florence
Dane D. Jensen: New York University
Rocco Latorre: New York University
Julia Ding: Columbia University
Matilde Marini: University of Florence
Daniel Souza Monteiro de Araujo: University of Florence
Paulina Ramírez-Garcia: Monash University
Michael Whittaker: Monash University
Jeffri Retamal: Monash University
Mustafa Titiz: University of Florence
Alessandro Innocenti: Plastic and Reconstructive Microsurgery - Careggi University Hospital
Thomas P. Davis: Monash University
Nicholas Veldhuis: Monash University
Brian L. Schmidt: New York University
Nigel W. Bunnett: New York University
Pierangelo Geppetti: University of Florence

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-28204-z

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