Bimodal effects of cinnamaldehyde and camphor on mouse TRPA1

Abstract

TRPA1 is a nonselective cation channel activated by a wide variety of noxious chemicals. Intriguingly, several TRPA1 modulators induce a bimodal effect, activating the channel at micromolar concentrations and inhibiting it at higher concentrations. Here we report the bimodal action of cinnamaldehyde (CA) and camphor, which are thus far reported as agonist and antagonist of TRPA1, respectively. Whole-cell patch-clamp experiments in TRPA1-expressing CHO cells revealed that, as previously reported, extracellular application of 100 μM CA strongly stimulates TRPA1 currents. However, subsequent application of 3 mM CA induced fast and reversible current inhibition. Application of 3 mM CA in basal conditions induced a rather small current increase, followed by current inhibition and a dramatic rebound of current amplitude upon washout. These observations are reminiscent of the effects of TRPA1 modulators having bimodal effects, e.g., menthol and nicotine. In line with previous reports, extracellular application of 1 mM camphor induced a decrease of basal TRPA1 currents. However, the current amplitude showed a significant overshoot upon washout. On the other hand, application of 100 μM camphor induced a 3-fold increase of the basal current amplitude measured at -75 mV. The bimodal effects of CA and camphor on TRPA1 were also observed in microfluorimetric measurements of intracellular Ca(2+) in intact TRPA1-expressing CHO cells and in primary cultures of mouse dorsal root ganglion neurons. These findings are essential for the understanding of the complex sensory properties of these compounds, as well as their utility when used to study the pathophysiological relevance of TRPA1.

Plant-Derived Tick Repellents Activate the Honey Bee Ectoparasitic Mite TRPA1

“…In fact, this biphasic activation disappeared when the channel was activated by 0.1 mM a-terpineol and carvacrol (Figures 4A and 4B, right panels). Similar biphasic activation by several agonists was also observed with HsTRPA1 (Takaishi et al, 2014) and mouse TRPA1 (Alpizar et al, 2013), suggesting that this could be a common property of TRPA1. Mammalian TRPA1 is activated by carvacrol ( Figure 4F) (Xu et al, 2006), suggesting that DmTRPA1 has lost its sensitivity against this compound.…”

Evidence for the functional involvement of members of the TRP channel family in the uptake of Na+ and NH4 + by the ruminal epithelium

“…Since a thick stratum corneum covers the apical, transporting layer of cells in the rumen, the current profile may reflect a gradual increase in the concentration of the agonist, with an initial stimulation by low concentrations followed by subsequent inhibitory effects [2,28]. If this were the case, only the stimulatory effect should have been seen at lower concentrations of the agonist, which was not the case.…”

“…a Original recordings from five epithelia from four individual animals, showing a biphasic response of I sc after application of thymol. b Four epithelia from two different animals only showed a monophasic response (N/n = 2/4) Cinnamaldehyde is a modulator of TRPA1 [2], with both activation and inhibition reported depending on the concentration applied. Cinnamaldehyde (1 mmol·l −1 ) visibly inhibited NH 4 + -induced currents across bovine ruminal epithelium (ΔI scPeak = −3.14 ± 1.29 μA·cm −2 ) ( Table 5, Exp 6 and Fig.…”

TRPA1 mediates bladder hyperalgesia in a mouse model of cystitis

“…Andersson et al, 2011 [2] showed that intrathecal cinnamaldehyde (used here to confirm increases in the number of TRPA1-responsive neurons) was anti-nociceptive and that metabolites of the analgesic paracetamol are TRPA1 agonists. That TRPA1 agonists like cinnamaldehyde can be both pro- and anti- nociceptive was recently confirmed in studies of CHO cells that showed that a low concentrations cinnamaldehyde increased TRPA1 currents but at higher concentrations produces fast, but reversible current inhibition [1]. …”