Environmental Chemicals Can Trigger Migraine Signaling

By Fred Schwaller | February 16, 2024 | Posted in

A proof-of-concept study in mice shows that pesticides and pollutants activate migraine signaling pathways via the ion channel TRPA1. It’s unclear if the findings relate to migraine in people.

There are long-standing concerns about the contribution of environmental chemicals like pesticides, industrial chemicals, and pollutants to human disease. Could those chemicals play a role in the development of migraine, too? And how might they do so?

Now, a new study in mice addresses the second question, showing that a number of environmental chemicals were capable of activating TRPA1, an ion channel known to contribute to migraine signaling.

Focusing on one particular environmental chemical – a pesticide called pentachlorophenol (PCP) – researchers led by David Kristensen, Copenhagen University Hospital, Denmark, further showed that PCP spurs the release of calcitonin gene-related peptide (CGRP) in brainstem tissue taken from mice. The pesticide also caused pain hypersensitivity in vivo.

“This paper shows that environmental agents or pollutants can act on TRPA1. I think this shows early evidence that headache produced by certain chemicals in the workplace can be ascribed to TRPA1,” said Pierangelo Geppetti, a migraine and pain researcher at the University of Florence, Italy, who studies TRPA1 but was not involved in the research.

Still, the current animal study notwithstanding, there are no human data available yet proving an association of environmental chemicals with migraine in people, arguing for caution in interpreting the new findings.

The study appeared in the November 2023 issue of Environmental Health Perspectives.

“The headache tree”
Kristensen told Migraine Science Collaborative that the idea for the study came, in part, from learning about Umbellularia californica, more familiarly known as the California bay laurel tree, which is known to trigger headache.

“It’s known that if you are suffering from migraine, going near the tree can trigger a migraine attack. It was proof of the idea that substances are emitted in our environment, in this case from a tree, that can induce a migraine attack from inhalation,” Kristensen said. The tree can also trigger headache in people with cluster headache.

This all made Kristensen think about what other environmental chemicals foreign to the human body (known as xenobiotics) might contribute to migraine.

“There have been studies showing a general increase in prevalence of migraine, for example, in Denmark. Of course, there are many reasons for this, but we thought exposure to chemical compounds like pesticides could play a role,” Kristensen said.

Activating a well-known ion channel
In the study, the authors aimed to investigate links between various xenobiotics and migraine signaling. They first asked which molecular sensors present on sensory neurons linked to headache might detect xenobiotics.

Kristensen’s team focused on a family of ion channels called TRP channels, and on two specific family members called TRPA1 and TRPV1. Ion channels are proteins that form pores across the cell membrane, allowing ions to flow into or out of cells.

TRPA1 is widely known as a sensor of chemical irritants, including umbellulone, which is emitted from the bay laurel tree. Meanwhile, TRPV1 is widely known as the capsaicin receptor (capsaicin is the active component of chili peppers that makes them “hot”) and for its role in heat sensation.

The TRPA1 and TRPV1 ion channels, which are present on trigeminal sensory neurons, were of particular interest since their activation leads to the release of CGRP, implicating them in migraine signaling.

In the first experiments, the authors screened 52 different xenobiotics for their ability to activate TRPA1 and TRPV1 in vitro. They used genetic technology to insert the human version of the channels into a human cell line cultured in a dish. Then, they used a microscopy technique called calcium imaging to measure calcium signaling after exposing the cells to the chemicals. Calcium signaling is an indirect measure of cell activation.

Ten of the chemicals caused strong activation of cells containing TRPA1. But none of the chemicals activated cells containing TRPV1, which surprised Kristensen and Rikke Rasmussen, the first author of the study.

“This shows that a substantial number of compounds activate TRPA1. We originally thought that both TRPV1 and TRPA1 would be activated by the chemicals because they are both known to be activated by painful chemicals, but it turned out that only TRPA1 reacted to the chemicals,” said Kristensen.

Geppetti said the data support previous studies linking environmental agents to TRPA1.

“TRPA1 is a very sensitive environmental sensor. There is data showing that molecules in cigarette smoke, like aldehyde and acetaldehyde, can powerfully activate TRPA1. In fact, acetaldehyde, also produced by metabolism of ethanol, could be a cause of pro-migraine activity after drinking wine,” Geppetti told MSC.

Effects on migraine signaling and on pain 
The authors then focused on one particular chemical that activated the channel, PCP. PCP is a pesticide that is banned in most countries, but is still found in the environment today. For instance, a 2018 study in France found that 100% of women giving birth had measurable levels of PCP in hair samples, long after the European Union banned it in 1994.

Considering that, the authors further tested PCP’s effects on TRPA1. They also sought to understand what happened after activation of the ion channel by the pesticide.

First, they found that PCP not only strongly activated the cell lines containing TRPA1 but also trigeminal neurons from mice.

Then, the team saw that PCP caused a significant release of CGRP in the trigeminal nucleus caudalis, as shown by postmortem measurements of the peptide in mice. This increase in CGRP was absent in genetically engineered mice lacking the TRPA1 channel, providing further evidence for the channel’s role.

“These experiments don’t necessarily mean that [xenobiotics] influence migraine, but they show a key link between them and migraine signaling. It was important to show that these chemicals do trigger activation of TRPA1 and release of CGRP. It’s a strong argument to make it relevant to migraine,” said Rasmussen.

The authors went further into migraine mechanisms and investigated whether PCP could dilate cerebral blood vessels. They found that PCP dilated the basilar artery in mice, and the higher the concentration of PCP they used, the more dilation they observed.

“It’s heavily debated in the field whether vasodilation is part of the pain or a proxy for headache. Either way, I think it’s an important measurement that shows further evidence that xenobiotics play a role in migraine signaling,” said Kristensen.

PCP causes pain hypersensitivity in mice
In the final experiments, the team investigated whether PCP could cause pain in animals. Here, they tested whether an oral dose of PCP produced tactile hypersensitivity of the hind paw in mice.

They measured that outcome by poking the animals in the hind paw with thin filaments called von Frey hairs (a common experimental technique in pain research) and then measuring the threshold at which the animals withdrew their hind paws in response to the filaments.

The team found that PCP significantly reduced the withdrawal threshold of mice within two hours of the animals receiving the chemical, meaning that it took less pressure from the von Frey hairs to cause a painful withdrawal response compared to control animals. This effect was blocked in mice lacking TRPA1, showing a clear role for the ion channel in pain elicited by PCP.

Environmental irritants and migraine signaling.

Schematic illustration of the proposed signaling pathway involved in PCP-induced hypersensitivity. Interpretation of data [from the study]. PCP was shown to activate TRPA1 with subsequent release of CGRP, resulting in dilation of blood vessels. PCP administration also induced hypersensitivity in mice via TRPA1. Created with Biorender.com. Note: CGRP, calcitonin gene-related peptide; CGRP-R, CGRP receptor; PCP, pentachlorophenol; TNC, trigeminal nucleus caudalis. Credit: Image and caption from Rasmussen et al.

A cautious interpretation
The authors emphasized that their new work is a proof-of-concept study showing effects only on migraine signaling pathways – the molecular and cellular communication taking place within and between cells.

“It shows that these [environmental] signals could influence migraine signaling, but not that there is necessarily a direct correlation between xenobiotic exposure and migraine,” said Rasmussen.

The reason for Rasmussen’s cautious interpretation of the findings is that there are still no studies correlating migraine with exposure to xenobiotics. According to Geppetti, those types of multifactorial studies are hard to do.

Another issue, Geppetti said, is that the actual levels of xenobiotics people are exposed to is unclear, making it difficult to know if the doses of PCP used in the study are relevant to migraine in humans. The authors also acknowledge this.

“These exposures are indeed probably higher than you see in people working with PCP. But our aim was to show a link between the chemicals and migraine signaling. In the future we will try to recapitulate this study with doses of chemicals you or I have in our bodies today,” said Kristensen.

Kristensen said there could be a “cocktail effect,” where multiple chemicals in the body might act synergistically to exacerbate toxic effects in humans. While future studies can help fill in the knowledge gaps, the new research is a good starting point.

“I see this kind of study as part of a bigger discussion about pollutants in our society, of which migraine is [only] one aspect,” Kristensen said.

Fred Schwaller, PhD, is a freelance science writer based in Germany. Follow him on Twitter @SchwallerFred

Reference
Xenobiotic exposure and migraine-associated signaling: A multimethod experimental study exploring cellular assays in combination with ex vivo and in vivo mouse models.
Rasmussen et al.
Environ Health Perspect. 2023 Nov;131(11):117003.

Featured image (at top of news article): 3D representation of PCP in the lipid pocket of hTRPA1. Two [monomers] of hTRPA1 are represented in green and magenta. The PCP is colored in cyan. Credit: Image and caption from Rasmussen et al.

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Fred Schwaller is a science writer and communicator based in Berlin, Germany. Fred spent a decade in pain research during his doctoral degree at University College London, UK, and his postdoc at the Max Delbrück Centre in Berlin, Germany. After transferring to science communication in 2020, he has been writing and podcasting about life sciences and medicine, specializing in somatosensation and pain. Follow him on Twitter @SchwallerFred.

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