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, Pierangelo Geppetti

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number646
JournalNature communications
Issue number1
StatePublished - Feb 3 2022


  • Animals
  • Calcitonin Gene-Related Peptide/metabolism
  • Calcitonin Receptor-Like Protein/genetics
  • Cells, Cultured
  • Endosomes/metabolism
  • Female
  • HEK293 Cells
  • Humans
  • Hyperalgesia/diagnosis
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Middle Aged
  • Neurons/metabolism
  • Nitric Oxide/metabolism
  • Receptor Activity-Modifying Protein 1/genetics
  • Schwann Cells/metabolism
  • Signal Transduction/physiology
  • TRPA1 Cation Channel/genetics

ASJC Scopus subject areas

  • General Physics and Astronomy
  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology


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