Pain Pathways: Linking Environmental Pollutants with Migraine-Associated Pain Signaling

A woman sits on a bed holding her head in her hands. She is silhouetted by light filtered through window blinds that reveal a cityscape in the background.

The California bay laurel tree (Umbellularia californica) offers a textbook example of scientists learning from nature.The scent of this tree gives some people a headache, hence its nickname "headache tree," and triggers a migraine attack in those who are susceptible. 1Through a series of in vitro and rodent experiments, researchers reported in 2012 1 that umbellulone, the chemical behind the scent, activates pain-signaling pathways that were first implicated in migraine more than 30 years ago. 2,3Drugs that block these pathways now benefit 50%-60% of migraine patients. 4n a study that builds on findings related to umbellulone, researchers recently reported in Environmental Health Perspectives that several environmental pollutants activate the same migraineassociated pain pathways in rodents and human cells. 5Their findings provide intriguing, though preliminary, evidence that pesticides, phthalates, hormone-like compounds, and other chemicals may directly affect the neurobiology of pain.
"The 2012 study showed that umbellulone activates a pain receptor called TRPA1 [transient receptor potential ankyrin 1], which causes the release of a neuropeptide targeted by recently developed migraine drugs," says senior author David Kristensen, a professor of molecular physiology at Roskilde University and senior scientist at Copenhagen University Hospital, Denmark."That was our motivation for testing if other chemicals also activate TRPA1-like pain receptors." TRPA1 is a calcium channel, meaning its activation causes an influx of calcium into cells. 6These calcium currents help cells communicate with each other.In the case of migraine, the flow of calcium into specialized cells of the peripheral nervous systemthe trigeminal neurons-helps communicate the sensation of pain to the brain. 7hese neurons also contain the transient receptor potential vanilloid 1 (TRPV1) channel, which is structurally similar to TRPA1. 7pon activation, both channels cause the release of a compound called calcitonin gene-related peptide (CGRP) into the brain stem and the dilation of blood vessels overlying the brain. 8Whether the sensation of pain is caused by the vessel dilation or the activation of pain-signaling pathways by CGRP alone is still debated. 8Regardless, taking this neuropeptide out of circulation with CGRP-binding drugs can prevent a headache-a game changer, says Kristensen, that has improved the quality of life for many migraine patients. 9n their initial calcium imaging screen, the researchers exposed human cells containing only TRPA1, only TRPV1, or neither

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channel (control) to 52 pollutants, one at a time. 5They used fluorescent tags to measure calcium concentrations inside the cells, indicating whether a tested chemical activated one, both, or neither channel.
The team observed that 16 of the 52 chemicals activated TRPA1, and none of them activated TRPV1.So they selected one of those 16 TRPA1-activating chemicals, pentachlorophenol (PCP), for a proof-of-concept study that illustrates a general strategy for verifying the screen results.
PCP was used for decades as a wood preservative to protect home construction materials from fungal decay and wood-boring insects. 10Despite its ban in many countries, it persists in the environment and the human body. 11irst, in vitro experiments using electrophysiological techniques verified that PCP caused calcium to enter human cells through TRPA1. 5Next, the researchers performed an ex vivo analysis of trigeminal neurons from live mouse tissue, confirming the first finding.Finally, they fed different doses of PCP-containing water to two groups of mice: those with the Trpa1 gene (wild-type) and those without it (Trpa1 -=-knockout mice).A third groupincluding both wild-type and knockout mice-did not receive PCP (control).
The researchers measured CGRP in the brain stem and the diameter of brain arteries in the three groups of mice.They also tested the sensitivity of the animals' hind paws to pressure-a standard model for migraine-associated pain signaling. 12n the wild-type mice, increasing doses of PCP resulted in greater CGRP release from brain stem neurons, greater blood vessel dilation, and greater pressure sensitivity.That sensitivity was observed both acutely (2-4 hours postexposure) and chronically (up to 10 days later).In contrast, the knockout mice did not exhibit any of these changes after exposure to the chemical.This link between PCP and migraine-associated pain signaling in living mice confirmed the PCP results from the calcium imaging screen.
One strength of the study is the use of multiple techniques to identify relevant mechanisms, ruling out TRPV1 and confirming TRPA1, says Alan M. Rapoport, a clinical professor of neurology at the University of California, Los Angeles, who was not involved in the project.From a clinical perspective, "knowing that environmental pollutants may affect human migraine by releasing CGRP could become important in educating patients and doctors alike and could lead to changes in therapy," he adds.
Diana Krause, an adjunct professor of pharmaceutical sciences at the University of California, Irvine, who was not involved in the study, considers the screen and follow-up strategy an excellent model for others to follow."Knowing that the activation of TRPA1 increases acute and chronic pain sensitivity via the release of CGRP is relevant not only for migraine-associated pain signaling but also other types of chronic pain," she says."These are important findings, especially since the effects of environmental chemicals on pain pathways have received little attention in the past." Silke Schmidt, PhD, writes about science, health, and the environment from Madison, Wisconsin.
With a combination of human cell line and mouse studies, researchers assessed how certain chemicals present in the environment affected pain pathways.Image: © Thananit/AdobeStock.
A Section 508-conformant HTML version of this article is available at https://doi.org/10.1289/EHP14416.