How migraine pain signals are generated, and blocked

Date:
February 3, 2022
Source:
New York University
Summary:
An international team of researchers has discovered that Schwann
cells - - which are abundant in the peripheral nervous system and
create a protective sheath around nerve fibers -- play an essential
role in migraine pain. Their study illustrates how pain is signaled
from within Schwann cells and finds several ways to block this
signaling, providing potential targets for new migraine treatments.



FULL STORY ==========================================================================
An international team of researchers has discovered that Schwann cells
-- which are abundant in the peripheral nervous system and create a
protective sheath around nerve fibers -- play an essential role in
migraine pain. Their study, conducted in mice and human Schwann cells
and published in Nature Communications, illustrates how pain is signaled
from within Schwann cells and finds several ways to block this signaling, providing potential targets for new migraine treatments.


========================================================================== Migraines affect more than 15 percent of adults, with women twice
as likely as men to experience these intense headaches. Calcitonin
gene-related peptide (CGRP), a small protein in the nervous system, is
known to play an important role in migraine pain; in fact, a new class
of drugs to prevent migraines use injections of monoclonal antibodies
to target CGRP or its receptor.

"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. Bunnett led the study with
Pierangelo Geppetti, MD, professor of clinical pharmacology at the
University of Florence and director of the Headache Center of Careggi University Hospital.

"The success of CGRP monoclonal antibodies for migraine and the poor
ability of antibodies to penetrate the blood brain barrier suggest that
CGRP causes pain in the periphery rather than within the brain," added
Bunnett, a researcher in the NYU Pain Research Center.

To explore the cellular mechanism of CGRP-evoked pain, Bunnett and his colleagues focused on Schwann cells, which are found outside the brain
in the peripheral nervous system. The researchers studied mice in which
the CGRP receptor, called CLR/RAMP1, was disabled in Schwann cells. They modified the CGRP receptor by deleting RAMP1, one of two important
components of the receptor, from Schwann cells in the facial area of mice.

In normal mice, administering CGRP made the facial region very sensitive,
a proxy for migraine pain. However, in mice lacking the CGRP receptor
in Schwann cells, CGRP did not cause pain. In a second experiment,
the researchers administered capsaicin -- a chemical found in spicy
chili peppers. Capsaicin activates an ion channel called TRPV1, which
releases CGRP and usually causes pain. Again, capsaicin 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.



========================================================================== Using human Schwann cells, the researchers then discovered what occurs
within these cells to signal pain. They found that when CGRP binds to its receptor on a Schwann cell, the receptor moves into a compartment inside
the cell called an endosome. Within endosomes, the CGRP receptor continues
to signal for prolonged periods of time. That signaling generates nitric
oxide -- a mediator of pain - - which is then released from the Schwann
cell and interacts with an ion channel called TRPA1 on an adjacent
neuron. TRPA1 excites the neuron and transmits pain signals.

This new understanding of how pain originates inside Schwann cells
gave the researchers two ideas for treating migraine pain: stopping
the CGRP receptor from entering endosomes in the first place, or using nanoparticles to send drugs targeting the CGRP receptor in endosomes.

To keep CGRP receptors out of endosomes, the researchers inhibited
clathrin and dynamin, two proteins that are important for substances
entering cells.

Inhibiting clathrin and dynamin reduced pain signaling, offering a
promising target for novel migraine treatments.

The researchers also successfully blocked CGRP-evoked pain using
nanoparticles in which they encapsulated a small molecule drug that
binds to and blocks the CGRP receptor. While most drugs only reach the
surface of cells, nanoparticles can be designed to help medicine reach
the endosome inside a cell and to release the drug once it arrives at the intended location. In Schwann cells, the nanoparticles carried the drug
into endosomes and blocked the CGRP receptor, which strongly inhibited
migraine pain.

"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 researchers are working with several partners, including the National Center for Advancing Translational Sciences of the National Institutes
of Health, to continue studying the use and safety of nanoparticle drug delivery before these treatments can be tested in humans.

The study was a collaboration among researchers at the NYU Pain Research
Center at NYU College of Dentistry, the University of Florence and
Careggi University Hospital in Italy, and Monash University and the
University of Queensland in Australia. The research was supported by
grants from the European Research Council (grant agreement No. 835286); National Institutes of Health (NS102722, DE026806, DK118971, DE029951);
and U.S. Department of Defense (W81XWH1810431).

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may be edited for style and length.


========================================================================== Journal Reference:
1. Francesco De Logu, Romina Nassini, Alan Hegron, Lorenzo Landini,
Dane D.

Jensen, Rocco Latorre, Julia Ding, Matilde Marini, Daniel Souza
Monteiro de Araujo, Paulina Rami'rez-Garcia, Michael Whittaker,
Jeffri Retamal, Mustafa Titiz, Alessandro Innocenti, Thomas
P. Davis, Nicholas Veldhuis, Brian L. Schmidt, Nigel W. Bunnett,
Pierangelo Geppetti. Schwann cell endosome CGRP signals elicit
periorbital mechanical allodynia in mice.

Nature Communications, 2022; 13 (1) DOI: 10.1038/s41467-022-28204-z ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220203083601.htm

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