A new study published on February 3, in an article in the journal Nature Communications, delves into how Schwann cells that envelop peripheral pain receptors transmit intense pain signals around the eyes (periorbital mechanical allodynia, PMA), a hallmark of migraine. The paper titled “Schwann cell endosome CGRP signals elicit periorbital mechanical allodynia in mice,” provides insights on new molecular targets that could be drugged to block this peripheral signaling mechanism to relieve migraine. Over 15% of all adults suffer from migraines with women twice as likely to suffer these intense headaches.

Earlier studies have shown, the release of a peptide called CGRP (calcitonin gene-related peptide) induces migraines. “While CGRP has been implicated in migraine pain, how it causes pain has been an area of controversy in the scientific community,” said Nigel Bunnett, PhD, professor and chair of the Department of Molecular Pathobiology at NYU College of Dentistry and a senior author of the study.

Monoclonal antibodies to this peptide and its receptor (CLR/RAMP1) and small molecule antagonists of the receptor relieve migraines. However, these monoclonal antibodies and antagonists are not capable of crossing the blood-brain barrier effectively.

This suggested peripheral regions of the body outside the brain, contribute to the mechanism through which CGRP induces migraines. Although the process triggering migraine pain may originate in the brain, the cells and signaling pathway by which CGRP acts in the periphery to cause such pain (proalgesic action) are unknown.

The authors note, “The major findings of the present study are that CGRP causes PMA [periorbital mechanical allodynia] by activating 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.”

The authors selectively delete the RAMP1 gene, one of two important components of the CGRP receptor, in facial Schwann cells in mice to show CGRP released from trigeminal nerve fibers in the skin targets the CGRP receptor in surrounding Schwann cells to evoke PMA. In normal mice, administering CGRP made the facial region very sensitive, a proxy for migraine pain, but in mice lacking the CGRP receptor in Schwann cells, CGRP did not cause pain.

In addition, the researchers show the capsaicin—a chemical found in spicy chili peppers—did not cause migraine-like pain in mice lacking the CGRP receptor in Schwann cells, providing further support for the idea that the CGRP receptor in Schwann cells plays a critical role in migraine pain.

The authors provide further evidence to support that the activation of the CGRP receptor in human and mouse Schwann cells generates long-lasting signals from endosomes—cellular vesicles that sort and transport cargo to and from the cell membrane—that promote the formation of nitric oxide (NO). NO is released from Schwann cells and interacts with an ion channel called TRPA1 on adjacent neurons. TRPA1 excites the neuron and transmits pain signals. This feed-forward loop releases reactive oxygen species (ROS) that sustain migraine pain through the activation of pain receptors.

“While the role of CGRP in migraine pain is well known, our study is the first to directly connect Schwann cells to migraine pain. It offers potential new approaches to treating migraine based on our enhanced understanding of how pain is signaled from within endosomes,” said Bunnett.

The study identifies a mechanistic pathway showing how CGRP promotes migraines [De Logu et. al., Nature Communications, 2022].
To test potential treatment options for migraine, the investigators separately blocked the CGRP receptor from entering endosomes or used nanoparticles to deliver drugs targeting the CGRP receptor in endosomes. The researchers inhibited clathrin and dynamin to block CGRP from entering endosomes and found that this reduced pain signaling. Alternatively, using nanoparticles carrying a small molecule that blocks the CGRP receptor in endosomes, the investigators successfully blocked the CGRP receptor, which strongly inhibited migraine pain.

The team is currently testing the safety and use of nanoparticle drug delivery in collaboration with scientists at the National Institutes of Health.

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