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Schwann cell endosome CGRP signals elicit periorbital mechanical allodynia in mice

Author

Listed:
  • Francesco De Logu

    (University of Florence)

  • Romina Nassini

    (University of Florence
    Careggi University Hospital)

  • Alan Hegron

    (New York University)

  • Lorenzo Landini

    (University of Florence)

  • Dane D. Jensen

    (New York University
    New York University College of Dentistry)

  • 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
    The University of Queensland)

  • Nicholas Veldhuis

    (Monash University)

  • Brian L. Schmidt

    (New York University
    New York University College of Dentistry
    New York University)

  • Nigel W. Bunnett

    (New York University
    New York University)

  • Pierangelo Geppetti

    (University of Florence
    Careggi University Hospital)

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.

Suggested Citation

  • 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 W, 2022. "Schwann cell endosome CGRP signals elicit periorbital mechanical allodynia in mice," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28204-z
    DOI: 10.1038/s41467-022-28204-z
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    Cited by:

    1. Mustafa Titiz & Lorenzo Landini & Daniel Souza Monteiro de Araujo & Matilde Marini & Viola Seravalli & Martina Chieca & Pasquale Pensieri & Marco Montini & Gaetano De Siena & Benedetta Pasquini & Silv, 2024. "Schwann cell C5aR1 co-opts inflammasome NLRP1 to sustain pain in a mouse model of endometriosis," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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