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.

Schwann cell endosome CGRP signals elicit periorbital mechanical allodynia in mice / De Logu F.; Nassini R.; Hegron A.; Landini L.; Jensen D.D.; Latorre R.; Ding J.; Marini M.; Souza Monteiro de Araujo D.; Ramirez-Garcia P.; Whittaker M.; Retamal J.; Titiz M.; Innocenti A.; Davis T.P.; Veldhuis N.; Schmidt B.L.; Bunnett N.W.; Geppetti P.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - ELETTRONICO. - 13:(2022), pp. 0-0. [10.1038/s41467-022-28204-z]

Schwann cell endosome CGRP signals elicit periorbital mechanical allodynia in mice

De Logu F.;Nassini R.;Landini L.;Marini M.;Souza Monteiro de Araujo D.;Titiz M.;Innocenti A.;Geppetti P.
2022

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.
2022
13
0
0
De Logu F.; Nassini R.; Hegron A.; Landini L.; Jensen D.D.; Latorre R.; Ding J.; Marini M.; Souza Monteiro de Araujo D.; Ramirez-Garcia P.; Whittaker M.; Retamal J.; Titiz M.; Innocenti A.; Davis T.P.; Veldhuis N.; Schmidt B.L.; Bunnett N.W.; Geppetti P.
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1261583
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