Environmental toxin acrolein alters levels of endogenous lipids, including TRP agonists: A potential mechanism for headache driven by TRPA1 activation

Abstract

Exposure to airborne toxins can trigger headaches, but the mechanisms are not well understood. Some environmental toxins, such as acrolein, activate transient receptor potential ankyrin 1 (TRPA1), a receptor involved in pain sensation that is highly expressed in the trigeminovascular system. It has been shown in rat models that repeated exposure to acrolein induces trigeminovascular sensitization to both TRPA1 and TRP vanilloid 1 (TRPV1) agonists, a phenomenon linked to headache. In this study, we test the hypothesis that the sensitization of trigeminovascular responses in rats after acrolein exposure via inhalation is associated with changes in levels of endogenous lipids, including TRPV1 agonists, in the trigeminal ganglia, trigeminal nucleus, and cerebellum. Lipidomics analysis of 80 lipids was performed on each tissue after acute acrolein, chronic acrolein, or room air control. Both acute and chronic acrolein exposure drove widespread alterations in lipid levels. After chronic acrolein exposure, levels of all 6 N-acyl ethanolamines in the screening library, including the endogenous cannabinoid and TRPV1 agonist, N-arachidonoyl ethanolamine, were elevated in trigeminal tissue and in the cerebellum. This increase in TRPV1 ligands by acrolein exposure may indicate further downstream signaling, in that we also show here that a combination of these TRPV1 endogenous agonists increases the potency of the individual ligands in TRPV1-HEK cells. In addition to these TRPV1 agonists, 3 TRPV3 antagonists, 4 TRPV4 agonists, and 25 orphan lipids were up and down regulated after acrolein exposure. These data support the hypothesis that lipid signaling may represent a mechanism by which repeated exposure to the TRPA1 agonist and environmental toxin, acrolein, drives trigeminovascular sensitization.

Broad and Region-Specific Impacts of the Synthetic Cannabinoid CP 55,940 in Adolescent and Adult Female Mouse Brains

“…Tissue extracts were performed as previously described ( Bradshaw et al, 2006 ; Stuart et al, 2013 ; Raboune et al, 2014 ; Leishman et al, 2016a , b , 2017 , 2018 ). First, samples were shock frozen in liquid nitrogen, weighed, and transferred to a centrifuge tube.…”

“…Lipids were partially purified on C18 solid phase extraction columns (Agilent, Palo Alto, CA, United States). A series of four elutions with 1.5 mL of 60%, 75%, 85%, and 100% methanol were collected ( Stuart et al, 2013 ; Leishman et al, 2016a , b , 2018 ).…”

Current Evidence on the Role of Epigenetic Mechanisms in Migraine: The Way Forward to Precision Medicine

“…TRPA1 agonists acrolein and formaldehyde are environmental irritants found in indoor and outdoor pollution. Although few studies [119,120] have examined whether environmental irritant exposures induce migraine behavioral phenotypes, the results from these studies suggest that inhalation exposure to environmental irritants induces trigeminovascular and central nervous system sensitization, reproducing some features of chronic migraine models [119,120]. These studies highlight that TRPA1 receptors have important roles in migraine and that they could be targeted for therapeutic purposes [119,121].…”

“…These studies highlight that TRPA1 receptors have important roles in migraine and that they could be targeted for therapeutic purposes [119,121]. Lipid signaling may be another potential mechanism by which repeated exposure to acrolein may drive trigeminovascular sensitization [120].…”

Role of intraganglionic transmission in the trigeminovascular pathway

“…54 In addition to inducing trigeminal sensitization and chronic migraine phenotypes in our animal model, 19,20 acrolein exposure induced changes in several endocannabinoids, including anandamide, in trigeminal tissue. 55 Indeed, interactions between endocannabinoids and TRP channels are strongly implicated in pain 53 and particularly migraine. 56 While additional studies are necessary to understand the regulation of TRPA1 expression and putative roles of endogenous lipids, both should be considered as viable targets for pain relief in migraine.…”