TY - JOUR
T1 - Schwann cell endosome CGRP signals elicit periorbital mechanical allodynia in mice
AU - De Logu, Francesco
AU - Nassini, Romina
AU - Hegron, Alan
AU - Landini, Lorenzo
AU - Jensen, Dane D.
AU - Latorre, Rocco
AU - Ding, Julia
AU - Marini, Matilde
AU - Souza Monteiro de Araujo, Daniel
AU - Ramírez-Garcia, Paulina
AU - Whittaker, Michael
AU - Retamal, Jeffri
AU - Titiz, Mustafa
AU - Innocenti, Alessandro
AU - Davis, Thomas P.
AU - Veldhuis, Nicholas
AU - Schmidt, Brian L.
AU - Bunnett, Nigel W.
AU - Geppetti, Pierangelo
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/2/3
Y1 - 2022/2/3
N2 - 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.
AB - 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.
KW - Animals
KW - Calcitonin Gene-Related Peptide/metabolism
KW - Calcitonin Receptor-Like Protein/genetics
KW - Cells, Cultured
KW - Endosomes/metabolism
KW - Female
KW - HEK293 Cells
KW - Humans
KW - Hyperalgesia/diagnosis
KW - Male
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Mice, Transgenic
KW - Middle Aged
KW - Neurons/metabolism
KW - Nitric Oxide/metabolism
KW - Receptor Activity-Modifying Protein 1/genetics
KW - Schwann Cells/metabolism
KW - Signal Transduction/physiology
KW - TRPA1 Cation Channel/genetics
UR - http://www.scopus.com/inward/record.url?scp=85123973251&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85123973251&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-28204-z
DO - 10.1038/s41467-022-28204-z
M3 - Article
C2 - 35115501
AN - SCOPUS:85123973251
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 646
ER -