Apomorphine Is a Bimodal Modulator of TRPA1 Channels

Abstract

Apomorphine is a non-narcotic derivative of morphine, which acts as a dopamine agonist and is clinically used to treat "offstates" in patients suffering from Parkinson's disease. Adverse effects of apomorphine treatment include severe emesis and nausea, and ulceration and pain at the injection site. We wanted to test whether sensory transient receptor potential (TRP) channels are a molecular target for apomorphine. Here, we show that rTRPV1, rTRPV2, rTRPV3, and mTRPV4, as well as hTRPM8, and rTRPM3, which are expressed in dorsal root ganglion neurons, are insensitive toward apomorphine treatment. This also applied to the cellular redox sensor hTRPM2. On the contrary, human TRPA1 could be concentrationdependently modulated by apomorphine. Whereas the addition of apomorphine in the low micromolar range produced an irreversible activation of the channel, application of higher concentrations caused a reversible voltage-dependent inhibition of heterologously expressed TRPA1 channels, resulting from a reduction of single-channel open times. In addition, we provide evidence that apomorphine also acts on endogenous TRPA1 in cultured dorsal root ganglion neurons from rats and in the enterochromaffin model cell line QGP-1, from which serotonin is released upon activation of TRPA1. Our study shows that human TRPA1 is a target for apomorphine, suggesting that an activation of TRPA1 might contribute to adverse side effects such as nausea and painful injections, which can occur during treatment with apomorphine.

Inflammatory pain control by blocking oxidized phospholipid-mediated TRP channel activation

“…5) HEK-293 TRPA1 and HEK-293 TRPV1 cells as well as the parental control cell line were stimulated with OxPAPC (1, 10 and/or 30 µM). Measurements on HEK-293 TRPA1 were performed in calcium-free extracellular bath solution to prevent calcium-induced desensitization of TRPA1 34 . In addition, 50% of sodium ions were replaced by N-methyl-D-glucamine to limit OxPAPC-evoked inward currents of TRPA1 35 .…”

“…For HEK-293 cells stably expressing rTRPV1-YFP, medium was supplemented with geneticin (0.5 mg/ml). HEK-293 cells expressing TRPV2, TRPV3, and TRPV4 were described earlier 34 .…”

“…Preparation of DRG from adult wildtype mice and adult rats were carried out as described 34 . DRG neurons were grown at a density of 7 × 10 3 cells per glass cover slip coated with poly-L-lysine (20 µg/ml) and cultured at 37 °C, 5% CO 2 atmosphere for one day.…”

Interaction between intra‐oral cinnamaldehyde and nicotine assessed by psychophysical and physiological responses

“…In vitro studies have shown that both nicotine and cinnamaldehyde induce a bimodal action on TRPA1, involving TRPA1 activation at low concentrations and inhibition at high concentrations . Several lines of evidence indicate that TRPA1 activation in general is characterized by a bimodal response because nicotine , menthol , apomorphine , umbellulone , camphor, and cinnamaldehyde show this pattern. Previously, it was assumed that the irritant effects of nicotine were mainly caused by nAChRs , yet nAChRs quickly desensitize following nicotine application, but the irritation persists.…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…These "cold turkey" patients may be helped to overcome their cold sensitivity by TRPM8 antagonists. Of note, the painful adverse effect of apomorphine (a nonnarcotic morphine TRP Channels as Drug Targets derivative used in the pharmacotherapy of patients with Parkinson disease) involves TRPA1 activation (Schulze et al, 2013).…”