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.
Highlights
Efficacy of monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor implicates peripherally-released CGRP in migraine pain
In PlpCreERT+;Ramp1fl/fl mice 4-OHT treatment down-regulated receptor activity-modifying protein 1 (RAMP1) immunoreactivity in S100 + ve cells surrounding trigeminal but not sciatic nerve fibers (Fig. 1d) and did not prevent paw mechanical allodynia evoked by intraplantar CGRP, which was prevented by intraplantar 4-OHT (Supplementary Fig. 1f)
The major findings of the present study are that CGRP causes periorbital mechanical allodynia (PMA) by activating calcitonin receptor-like receptor (CLR)/RAMP1 of Schwann cells, CLR/ RAMP1 signals from endosomes of Schwann cells to activate pain pathways, and endosomal CLR/RAMP1 can be targeted using nanoparticles and endocytosis inhibitors to relieve CGRP-evoked PMA
Summary
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. Noxious stimuli such as capsaicin, a pungent agonist of the transient receptor potential vanilloid 1 (TRPV1) channel[4], evoke the peripheral release of CGRP which induces arteriolar vasodilatation[2] and of SP which elicits plasma protein extravasation[5], and produce sensory responses, which encompasses acute nociception and prolonged mechanical allodynia[6]. The CGRP receptor is a heterodimer of calcitonin receptor-like receptor (CLR), a G protein-coupled receptor (GPCR), and receptor activity-modifying protein 1 (RAMP1), a single transmembrane domain CLR chaperone[24] These two components coexist in cells that mediate the actions of CGRP, for example, vascular myocytes[2]. Persistent endosomal signaling of GPCRs, including CLR/RAMP1, underlies sustained neuronal activation and nociception in the CNS33–35
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