Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1

Abstract

Wasabi, horseradish and mustard owe their pungency to isothiocyanate compounds. Topical application of mustard oil (allyl isothiocyanate) to the skin activates underlying sensory nerve endings, thereby producing pain, inflammation and robust hypersensitivity to thermal and mechanical stimuli. Despite their widespread use in both the kitchen and the laboratory, the molecular mechanism through which isothiocyanates mediate their effects remains unknown. Here we show that mustard oil depolarizes a subpopulation of primary sensory neurons that are also activated by capsaicin, the pungent ingredient in chilli peppers, and by Delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana. Both allyl isothiocyanate and THC mediate their excitatory effects by activating ANKTM1, a member of the TRP ion channel family recently implicated in the detection of noxious cold. These findings identify a cellular and molecular target for the pungent action of mustard oils and support an emerging role for TRP channels as ionotropic cannabinoid receptors.

TRPA1 channel activation induces cholecystokinin release via extracellular calcium

“…CCK secretion from STC-1 cells and from native intestinal endocrine I-cells is tightly coupled to increased intracellular calcium levels since food derived secretagogues and luminal CCK releasing peptides stimulate CCK secretion via influx of calcium. AITC stimulated CCK release was dependent on extracellular calcium since the response was completely blocked with EGTA and ruthenium red [3]. Similarly, also AITC induced contraction of rat urinary bladder is dependent on extracellular calcium since the response was totally abolished in the absence of calcium and presence of EGTA [10].…”

Temperature sensing across species

“…Expression in gustatory bristles in the labial palpus, leg tarsus, and the anterior wing margin was observed and, in many cases, overlapped with neurons expressing markers via the gustatory neuron reporter Gr66a, which have been implicated in aversive responses to tastants [38,39]. The only TRPA channel in mammals is a receptor for many pungent compounds, including allyl isothiocyanate (AITC), the pungent ingredient in wasabi (see below) [40,41]. In a two-choice preference test, wild type flies exhibit a strong aversion to AITC, whereas painless mutants do not [38].…”

“…Therefore, these genetic and behavioral data demonstrate that the Drosophila painless is likely the functional orthologue of the mammalian wasabi receptor TRPA1. However, this hypothesis needs to be solidified by a demonstration that isothiocyanates can directly activate Painless in heterologous expression systems, as is the case for the mammalian channel [40]. Similarly, genetic and behavioral evidence clearly shows that painless mediates thermosensory and mechanosensory signaling in vivo.…”

Nalfurafine, the kappa opioid agonist, inhibits icilin-induced wet-dog shakes in rats and antagonizes glutamate release in the dorsal striatum

“…Icilin is a cold-inducing agent that activates two transient receptor potential channels, TRPM8 and TRPA1, in the dorsal root ganglia and trigeminal neurons of the periphery (McKemy et al, 2002;Peier et al, 2002;Reid et al, 2002;Story et al, 2003;Bandell et al, 2004;Jordt et al, 2004;Liu et al, 2006). Upon application to the skin or on the tongue, icilin produces "mild, pleasant sensations of coolness, similar to menthol but discrete and non-irritating" and is 400-600 times more potent than menthol (Wei and Seid, 1983;Behrendt et al,2004;Wei, 2005).Icilin may potentially be used in the treatment of pruritus, hemorrhoids, canker sores, arthritis and pain (Wei and Seid, 1983;Wei, 2005).…”

“…TRPM8 is activated by cool temperatures (<25°C), menthol and icilin (McKemy et al, 2002;Peier et al, 2002); whereas TRPA1 is activated by noxious cold (<17°C), icilin, pungent natural compounds (mustard oil, wintergreen oil, clove oil, cinnamon oil, ginger oil) (Bandell et al, 2004), and raw garlic (Bandell et al, 2004;Bautista et al, 2005;Macpherson et al, 2005), but not by menthol (Story et al, 2003;Jordt et al, 2004). Activation of these channels by their respective agonists results in calcium ion influx and desensitization (McKemy et al, 2002;Peier et al, 2002;Story et al, 2003;Jordt et al, 2004;Liu et al, 2006). Investigation of the downstream effect of channel activation remains unclear, supporting the need to investigate the pharmacology of cold-inducing compounds in vivo.…”