Heat generates oxidized linoleic acid metabolites that activate TRPV1 and produce pain in rodents

Abstract

The transient receptor potential vanilloid 1 (TRPV1) channel is the principal detector of noxious heat in the peripheral nervous system. TRPV1 is expressed in many nociceptors and is involved in heat-induced hyperalgesia and thermoregulation. The precise mechanism or mechanisms mediating the thermal sensitivity of TRPV1 are unknown. Here, we have shown that the oxidized linoleic acid metabolites 9-and 13-hydroxyoctadecadienoic acid (9-and 13-HODE) are formed in mouse and rat skin biopsies by exposure to noxious heat. 9-and 13-HODE and their metabolites, 9-and 13-oxoODE, activated TRPV1 and therefore constitute a family of endogenous TRPV1 agonists. Moreover, blocking these substances substantially decreased the heat sensitivity of TRPV1 in rats and mice and reduced nociception. Collectively, our results indicate that HODEs contribute to the heat sensitivity of TRPV1 in rodents. Because oxidized linoleic acid metabolites are released during cell injury, these findings suggest a mechanism for integrating the hyperalgesic and proinflammatory roles of TRPV1 and linoleic acid metabolites and may provide the foundation for investigating new classes of analgesic drugs. IntroductionThe TRP family of ligand-gated ion channels consists of several subgroups, including the vanilloid subfamily (transient receptor potential vanilloid [TRPV]). The first member of the subfamily to be discovered, TRPV1, is an extensively studied channel (1-5) that is expressed in a substantial proportion of pain-sensing sensory neurons, termed nociceptors. TRPV1 can be activated by a variety of endogenous lipids (including lipoxygenase and phospholipase D metabolites of arachidonic acid) and by exogenous substances such as capsaicin (the pungent compound in hot chili peppers) (6). We recently discovered that linoleic acid metabolites are synthesized in the spinal dorsal horn following the afferent barrage due to stimuli such as peripheral inflammation and constitute what we believe to be a novel, physiologically active family of endogenous TRPV1 ligands that mediates central sensitization to mechanical stimuli (7).In the periphery, TRPV1 also serves as a detector for noxious heat (> 43°C) (6), and pharmacological and gene deletion studies have shown that TRPV1 is important in inflammatory heat hyperalgesia and thermoregulation (8-9). However, the precise mechanism of heat activation of TRPV1 remains unknown. We found that endogenous TRPV1 agonists are formed on exposure of cell membranes to noxious heat. The released compounds activate TRPV1 and contribute to the thermal responsiveness of this channel.

Fat location defines sensation

“…Now linoleic acid, an essential -6 fatty acid precursor of arachidonic acid and a major membrane constituent of mammalian cells, has been found to have a related role. Hargreaves and colleagues (1) have shown that oxidized linoleic acid products produced from heated skin are potent activators of TRPV1, the capsaicin receptor, which plays a major role in thermal hyperalgesia. They make a strong case that these mediators contribute substantially to heat-activated TRPV1 currents in sensory neurons.…”

TRPV1 Gates Tissue Access and Sustains Pathogenicity in Autoimmune Encephalitis

“…Extravasation into peripheral tissues can be induced by activating transient receptor potential vanilloid-1 (TRPV1), a prominent member of the TRP ion channel superfamily (10). TRPV1 is expressed on the major subset of sensory afferent neurons that integrate noxious stimuli including heat and acidity (11)(12)(13). The outcome of peripheral TRPV1 activation and consequent cation influx in TRPV1 + sensory neuron is two-fold; (i) electric afferent signal transduction to the CNS, generating pain perception and (ii), local efferent release of neuropeptides such as substance P (sP) and calcitonin generelated peptide (CGRP) …”

TRPV1 Antagonists as Analgesic Agents

“…anandamide, arachidonic acid metabolites such as N-arachidonoyl-dopamine [NADA], 12-hydroperoxyeicosatetraenoic acid, oxidized linoleic acid metabolites, essential oils, octadecadienoids), and a variety of pungent plant products as exemplified by capsaicin (responsible for the piquancy of hot chilli peppers), resiniferatoxin, piperine (the pungent ingredient in black pepper), gingerol and zingerone (from ginger), camphor, as well as eugenol (a powerful essential oil found in cloves). Interestingly (and somewhat unexpectedly), TRPV1 is also activated by ethanol and venoms from jellyfish and spiders [9,[40][41][42][43][44][45][46][47][48][49].…”