In the last few years, the deeply frustrating medical area of chronic migraine prevention has been revolutionized thanks to the discovery that a protein called calcitonin gene-related peptide, or CGRP, plays a role in the condition.
While several drugs containing antibodies that block or bind the protein have now entered the market and are helping thousands of patients, we still don't entirely understand how CGRP acts on a cellular level, which is necessary to advance the treatments further.
Fortunately, there are clues on where to start looking.
"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," says Nigel Bunnett from the New York University College of Dentistry.
Using genetically altered mice and cultures of human nerve cells, Bunnett and his team mapped CGRP's path from facial nerves to a nearby supporting tissue called a Schwann cell.
These specialized cells coat the neuron's long, spindly axon in a series of fatty sheaths to provide a degree of protection and insulation for the delicate nerve within.
Without this sheath, signals passing through the nerve's body would be prone to interruption, rippling with the painstaking slowness of an all-stops train on an express line.
Schwann cells are also only found outside the brain, potentially explaining why antibody treatments don't need to cross the blood-brain barrier to block CGRP's effects.
Past studies on animal models have shown how CGRP is released under painful responses that trigger neurogenic inflammation. Squirt a few drops of capsaicin on the skin, for instance, and the body will respond by opening blood vessels and dishing out a world of hurt, largely thanks to the release of this particular protein.
For years researchers have known that in some people, CGRP and other blood-vessel-dilating proteins can be released in certain facial nerves when cranial blood vessels open up, exacerbating dilation and causing intense pain.
Building on this knowledge, Bunnett and his team focused on a receptor in Schwann cells that could be activated by CGRP.
By knocking the receptor out of cells in mice and testing their pain responses, the researchers demonstrated there was a clear stepping stone from the protein's release in facial nerves and its activity in Schwann cells.
Further tests using inhibitory molecules that target the production of tiny transport bubbles called endosomes helped flesh out the rest of the pathway.
Endosomes carry the receptor into a position where it can signal the release of nitric oxide, which then triggers pain receptors which switch on when stressed by reactive oxygen.
Not only does this detailed pathway provide a better understanding of how current therapies targeting CGRP might work, it highlights new potential targets for short-circuiting the entire biochemical pathway.
"While the role of CGRP in migraine pain is well known, our study is the first to directly connect Schwann cells to migraine pain," says Bunnett.
"It offers potential new approaches to treating migraine based on our enhanced understanding of how pain is signaled from within endosomes."
Future medications could, for example, prevent the CGRP receptor from the endosome, cutting the entire signaling pathway short. Or they might simply target the endosome directly.
For the roughly one in ten people who deal with not just the pain of migraine attacks, but the debilitating effects that include loss of sleep, poor mental health, and impact on social and personal domains, every improvement to current treatments would be life-changing.
This research was published in Nature Communications.