Hydroxy-epoxide and keto-epoxide derivatives of linoleic acid activate trigeminal neurons

Endogenous lipid mediators are proposed to contribute to headache and facial pain by activating trigeminal neurons (TN). We recently identified 11-hydroxy-epoxide- and 11-keto-epoxide derivatives of linoleic acid (LA) that are present in human skin and plasma and potentially contribute to nociception. Here we expand upon initial findings by examining the effects of 11-hydroxy- and 11-keto-epoxide-LA derivatives on TN activation in comparison to LA, the LA derivative [9-hydroxy-octadecadienoic acid (9-HODE)] and prostaglandin E₂ (PGE₂). 11-hydroxy- and 11-keto-epoxide-LA derivatives elicited Ca²⁺ transients in TN subpopulations. The proportion of neurons responding to test compounds (5 μM, 5 min) ranged from 16.2 ± 3.8 cells (11 K-9,10E-LA) to 34.1 ± 2.4 cells (11H-12,13E-LA). LA and 9-HODE (5 μM, 5 min) elicited responses in 11.6 ± 3.1% and 9.7 ± 3.4% of neurons, respectively. 11H-12,13E-LA, 11K-12,13E-LA, and 11H-9,10E-LA produced Ca²⁺ responses in significantly higher proportions of neurons compared to either LA or 9-HODE (F (6, 36) = 5.12, P = 0.0007). 11H-12,13E-LA and 11H-9,10E-LA increased proportions of responsive neurons in a concentration-dependent fashion, similar to PGE₂. Most sensitive neurons responded to additional algesic agents (32.9% to capsaicin, 40.1% to PGE₂, 58.0% to AITC), however 20.6% did not respond to any other agent. In summary, 11-hydroxy-epoxide derivatives of LA increase trigeminal neuron excitability, suggesting a potential role in headache or facial pain.

Keywords: 11-HEL, 11-hydroxy-epoxide-linoleic acid; 11H-12,13E-LA, 11-hydroxy-12,13-trans-epoxy-(9Z)-octadecenoate; 11H-9,10E-LA, 11-hydroxy-9,10-trans-epoxy-(12Z)-octadecenoate; 9-HODE, 9-hydroxy-octadecadienoic acid; CGRP, calcitonin gene related peptide; DiHOMEs, dihydroxy-octadecenoic acids; EpOMEs, epoxy-octadecenoic; HODEs, octadecadienoic acids; HpODEs, hydroperoxy-octadecadienoic acids; Hyperalgesia; LA, linoleic acid; Linoleic acid; Oxylipin; PGE2, prostaglandin E2; Pain; Peroxidation; TN, trigeminal neuron; aCSF, artificial cerebrospinal fluid.