Schwann cell endosome CGRP signals elicit periorbital mechanical allodynia in mice

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.

Grape seed extract suppresses calcitonin gene-related peptide secretion and upregulates expression of GAD 65/67 and GABAB receptor in primary trigeminal ganglion cultures

“…Increasing the GABAergic response in satellite glial cells would be expected to suppress peripheral sensitization and activation of trigeminal neurons and the formation of gap junctions between the neuronal cell body and satellite glial cells, which is implicated in the transition from acute to chronic pain ( Garrett and Durham, 2009 , Durham and Garrett, 2010 ). Similarly, GSE promoted upregulation of GABAB1 and GABAB2 receptor subunits in the cell body and processes of Schwann cells, which were recently implicated in the underlying pathology of migraine ( De Logu et al, 2022 ). In that study, CGRP binding to its receptor on Schwann cells led to the production of nitric oxide and modulation of ligand-gated ion channels on Aδ and C fiber neurons to cause cellular changes associated with allodynic pain signaling.…”

“…GSE inhibition of basal CGRP release from trigeminal ganglion neurons may have important implications since CGRP is known to promote peripheral sensitization of nociceptive neurons via an increase in proinflammatory cytokines and stimulation of nitric oxide release ( Durham, 2016 , Messlinger et al, 2020 ). Further, elevated CGRP levels are implicated in TMD and migraine pathology and results from a recent preclinical migraine model provided evidence that CGRP causes cellular changes in the ganglion that mediate allodynia ( De Logu et al, 2022 ). Results from this study are in agreement with our prior finding that dietary inclusion of GSE suppressed basal CGRP expression in the medullary horn of spinal cord tissue ( Cady et al, 2010 ).…”

Deep Learning-Based Grimace Scoring Is Comparable to Human Scoring in a Mouse Migraine Model

“…In a previous work, we utilized the MGS in a mouse migraine model induced by repeated intermittent NTG injections [ 22 ]. In this model, both paw allodynia [ 27 ] and orbital allodynia [ 28 , 29 , 30 ] were found due to TGVS activation. This model can be employed as a platform for developing abortive and preventive treatments for migraine since mechanical allodynic responses induced by acute and chronic NTG treatments are sensitive to sumatriptan and topiramate, the abortive and preventive medicines of migraine, respectively [ 31 ].…”

CGRP-induced migraine-like headache in persistent post-traumatic headache attributed to mild traumatic brain injury

“…Although these findings do not exclude involvement of the intracranial vasculature in the genesis of migraine-like headache, it seems reasonable to further explore whether CGRP mediates its pro-nociceptive effects via direct receptor-binding on primary afferents of the trigeminal ganglion and (upper cervical dorsal root ganglia). It should also be noted that some intriguing evidence suggest that CGRP-mediated nociceptive signals might be mediated via Schwann cells [ 38 ].…”