Schwann cell endosome CGRP signals elicit periorbital mechanical allodynia in mice
De Logu F, Nassini R, Hegron A, Landini L, Jensen DD, Latorre R, Ding J, Marini M, Souza Monteiro de Araujo D, Ramírez-Garcia P, Whittaker M, Retamal J, Titiz M, Innocenti A, Davis TP, Veldhuis N, Schmidt BL, Bunnett NW, Geppetti P. Schwann cell endosome CGRP signals elicit periorbital mechanical allodynia in mice. Nat Commun. 2022 Feb 3;13(1):646. doi: 10.1038/s41467-022-28204-z.
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.
