Abstract text (incl. figure legends and references)

The prevalence of the disabling pain disorder migraine is rising. Here, we test the hypothesis that ubiquitous environmental pollutants evoke the release of migraine-inducing neuropeptide calcitonin gene-related peptide (CGRP), via the activation of transient receptor potential (TRP) channels, thereby increasing pain.

To understand if environmental pollutants target migraine-associated TRP channels ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1), we used a calcium imaging-based screen of pollutants known to be abundant in industrialized regions. Based on this screen, patch clamping and in silico docking, we selected a pesticide (pentachlorophenol; PCP) to perform proof-of-concept experiments. We tested ex vivo release of CGRP and ex vivo vasodilatory responses of isolated cerebral arteries to PCP. Finally, we tested in vivo induction of cutaneous hypersensitivity in wild type and Trpa1 deficient mice.

16 of 53 screened environmental pollutants activated TRPA1, while none of the investigated compounds activated TRPV1. Focusing on PCP, in silico molecular modelling suggested that PCP is stabilized in a known lipid binding pocket of TRPA1. In vitro, ex vivo and in vivo experiments showed that PCP induced calcium influx in neurons, TRPA1-dependent CGRP release from the brainstem, dilation of cerebral arteries, and TRPA1-dependent increased pain response in mice.

These findings establish that abundant pollutants from the environment interact with the TRPA1-CGRP migraine pain pathway. Therefore, exposure to ubiquitous pollutants might be a contributing factor to the increased migraine prevalence.