CGRP Signals from Endosomes of Schwann Cells to Elicit Migraine Pain

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 migraine pain remain unknown. 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. The CGRP-mediated neuronal/Schwann cell pathway is critical to mediate allodynia associated with neurogenic inflammation, thus contributing to the pro-migraine action of CGRP.

Non‐neuronal TRPA1 encodes mechanical allodynia associated with neurogenic inflammation and partial nerve injury in rats

“…Exposure to CGRP elicited a delayed calcium response in rat Schwann cells (but not in DRG neurons) that was attenuated by olcegepant, A-967079 and calcium-free medium (Figure 4f,g). The delayed response to CGRP confirms previous results observed in human Schwann cells that the activation of a series of intracellular mediators is required to elicit a TRPA1-dependent calcium response (De Logu et al, 2022). Activation of the rat Schwann cell CT receptor/RAMP1 by CGRP increased cAMP and induced a PKA-dependent activation of endothelial NOS (eNOS) and the resulting increase in NO eventually targeted TRPA1.…”

“…From these findings, the hypothesis was advanced that the pro-algesic role of TRPA1 is confined to mice and it cannot be replicated in another rodent species and possibly in other species (Reese et al, 2020). Here, based on recent findings obtained in mice (De Logu et al, 2022), we explored in rats the role of TRPA1 in mechanical allodynia associated with neurogenic inflammation or neuropathic pain models. Logu et al, 2022).…”

“…Here, based on recent findings obtained in mice (De Logu et al, 2022), we explored in rats the role of TRPA1 in mechanical allodynia associated with neurogenic inflammation or neuropathic pain models. Logu et al, 2022). The underlying mechanism of the capsaicin-evoked hind paw mechanical allodynia (HPMA) in rats and periorbital mechanical allodynia in mice is apparently identical.…”

“…Capsaicin, acting on TRPV1, is the prototypical agent that evokes sensory neuropeptide release and neurogenic inflammation (Szallasi & Blumberg, 1999). Capsaicin injection in the mouse and human skin also elicits an acute and transient nociceptive response or pain respectively, and in both species a sustained mechanical hypersensitivity (De Logu et al, 2022;LaMotte et al, 1992) that in mice is mediated by CGRP (De Logu et al, 2022).…”

“…In recent years, the role of TRPA1 in sustaining mechanical allodynia has been identified in mouse models of inflammatory, neuropathic, cancer and migraine pain. These include intra-articular injection of monosodium urate (Trevisan et al, 2014), hind limb ischemia and reperfusion (De Logu et al, 2020), partial sciatic nerve ligation (pSNL) (De Logu et al, 2017), alcoholic polyneuropathy , melanoma cells inoculation (De Logu et al, 2021) and CGRP injection into the periorbital skin (De Logu et al, 2022). In addition to the contribution of neuronal TRPA1, which signals agonistinduced acute nociception, a critical role of Schwann cell TRPA1 has been identified in macrophage-dependent (De Logu et al, 2021, 2017) and macrophage-independent sustained mechanical allodynia.…”