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 6N-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.
Highlights
1.1 transient receptor potential ankyrin 1 (TRPA1) agonists activate the trigeminovascular systemHeadache is an almost universal experience
Cell bodies of trigeminal nerve fibers are located in the trigeminal ganglia (TG) [8], which projects centrally to the trigeminal nucleus caudalis (TNC) in the brainstem, where sensory signals are projected onto thalamo-cortical pathways [11]
This level of analysis constitutes ~6000 data points; the detailed list of levels and the statistical analyses of analytes detected in each of the 3 tissues assayed from acute acrolein rats, chronic acrolein rats, and the room air controls are available in the Supplemental Data section
Summary
1.1 TRPA1 agonists activate the trigeminovascular systemHeadache is an almost universal experience. One of the most common triggers for migraine episodes is exposure to airborne toxins in air pollution [4]; the mechanism is largely unknown [7]. Activation of the trigeminovascular system (TVS), the trigeminal innervation of cranial vasculature [8], is hypothesized to underlie headache pain [7]. With repeated TVS activations, sensitization can occur, which may underlie the phenomenon of heightened headache pain after repeated chemical exposure [7]. The TRPA1 agonist acrolein (Supplementary Figure 1) is an irritant and a major component of air pollution [15, 16]. Molecular mechanisms of inflammatory pain and hypersensitization of the TVS caused by irritants like acrolein depend, in part, on TRPA1 activity [10, 13]
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