Environmental health perspectives · 2023
Xenobiotic Exposure and Migraine-Associated Signaling: A Multimethod Experimental Study Exploring Cellular Assays in Combination with Ex Vivo and In Vivo Mouse Models.
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Rasmussen Rikke H, Christensen Sarah L, Calloe Kirstine, Nielsen Brian Skriver, Rehfeld Anders, Taylor-Clark Thomas E, Haanes Kristian A, Taboureau Olivier, Audouze Karine, Klaerke Dan A, Olesen Jes, Kristensen David M
Аннотация
BACKGROUND: Mechanisms for how environmental chemicals might influence pain has received little attention. Epidemiological studies suggest that environmental factors such as pollutants might play a role in migraine prevalence. Potential targets for pollutants are the transient receptor potential (TRP) channels ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1), which on activation release pain-inducing neuropeptide calcitonin gene-related peptide (CGRP).
OBJECTIVE: In this study, we aimed to examine the hypothesis that environmental pollutants via TRP channel signaling and subsequent CGRP release trigger migraine signaling and pain.
METHODS: A calcium imaging-based screen of environmental chemicals was used to investigate activation of migraine pain-associated TRP channels TRPA1 and TRPV1. Based on this screen, whole-cell patch clamp and in silico docking were performed for the pesticide pentachlorophenol (PCP) as proof of concept. Subsequently, PCP-mediated release of CGRP and vasodilatory responses of cerebral arteries were investigated. Finally, we tested whether PCP could induce a TRPA1-dependent induction of cutaneous hypersensitivity in vivo in mice as a model of migraine-like pain.
RESULTS: A total of 16 out of the 52 screened environmental chemicals activated TRPA1 at 10 or 100μM. None of the investigated compounds activated TRPV1. Using PCP as a model of chemical interaction with TRPA1, in silico molecular modeling suggested that PCP is stabilized in a lipid-binding pocket of TRPA1 in comparison with TRPV1. In vitro, ex vivo, and in vivo experiments showed that PCP induced calcium influx in neurons and resulted in a TRPA1-dependent CGRP release from the brainstem and dilation of cerebral arteries. In a mouse model of migraine-like pain, PCP induced a TRPA1-dependent increased pain response (Ntotal=144).
DISCUSSION: Here we show that multiple environmental pollutants interact with the TRPA1-CGRP migraine pain pathway. The data provide valuable insights into how environmental chemicals can interact with neurobiology and provide a potential mechanism for putative increases in migraine prevalence over the last decades. https://doi.org/10.1289/EHP12413.
OBJECTIVE: In this study, we aimed to examine the hypothesis that environmental pollutants via TRP channel signaling and subsequent CGRP release trigger migraine signaling and pain.
METHODS: A calcium imaging-based screen of environmental chemicals was used to investigate activation of migraine pain-associated TRP channels TRPA1 and TRPV1. Based on this screen, whole-cell patch clamp and in silico docking were performed for the pesticide pentachlorophenol (PCP) as proof of concept. Subsequently, PCP-mediated release of CGRP and vasodilatory responses of cerebral arteries were investigated. Finally, we tested whether PCP could induce a TRPA1-dependent induction of cutaneous hypersensitivity in vivo in mice as a model of migraine-like pain.
RESULTS: A total of 16 out of the 52 screened environmental chemicals activated TRPA1 at 10 or 100μM. None of the investigated compounds activated TRPV1. Using PCP as a model of chemical interaction with TRPA1, in silico molecular modeling suggested that PCP is stabilized in a lipid-binding pocket of TRPA1 in comparison with TRPV1. In vitro, ex vivo, and in vivo experiments showed that PCP induced calcium influx in neurons and resulted in a TRPA1-dependent CGRP release from the brainstem and dilation of cerebral arteries. In a mouse model of migraine-like pain, PCP induced a TRPA1-dependent increased pain response (Ntotal=144).
DISCUSSION: Here we show that multiple environmental pollutants interact with the TRPA1-CGRP migraine pain pathway. The data provide valuable insights into how environmental chemicals can interact with neurobiology and provide a potential mechanism for putative increases in migraine prevalence over the last decades. https://doi.org/10.1289/EHP12413.