Menthol Inhibits 5-HT₃Receptor–Mediated Currents

Abstract

The effects of alcohol monoterpene menthol, a major active ingredient of the peppermint plant, were tested on the function of human 5-hydroxytryptamine type 3 (5-HT 3 ) receptors expressed in Xenopus laevis oocytes. 5-HT (1 mM)-evoked currents recorded by two-electrode voltage-clamp technique were reversibly inhibited by menthol in a concentration-dependent (IC 50 5 163 mM) manner. The effects of menthol developed gradually, reaching a steadystate level within 10-15 minutes and did not involve G-proteins, since GTPgS activity remained unaltered and the effect of menthol was not sensitive to pertussis toxin pretreatment. The actions of menthol were not stereoselective as (2), (1), and racemic menthol inhibited 5-HT 3 receptor-mediated currents to the same extent.Menthol inhibition was not altered by intracellular 1,2-bis(oaminophenoxy)ethane-N,N,N9,N9-tetraacetic acid injections and transmembrane potential changes. The maximum inhibition observed for menthol was not reversed by increasing concentrations of 5-HT. Furthermore, specific binding of the 5-HT 3 antagonist [ 3 H]GR65630 was not altered in the presence of menthol (up to 1 mM), indicating that menthol acts as a noncompetitive antagonist of the 5-HT 3 receptor. Finally, 5-HT 3 receptor-mediated currents in acutely dissociated nodose ganglion neurons were also inhibited by menthol (100 mM). These data demonstrate that menthol, at pharmacologically relevant concentrations, is an allosteric inhibitor of 5-HT 3 receptors.

Allosteric modulation of nicotinic acetylcholine receptors

“…Despite relatively small changes in chemical structure, the compounds examined displayed five distinct pharmacological effects on α7 nAChRs. These included effects typical of type I PAMs, type II PAMs, NAMs, SAMs and allosteric agonists [33] and it has been proposed that all of these pharmacological effects can arise from ligands binding to a broadly similar or overlapping site located within the previously identified intra-subunit transmembrane cavity A transmembrane binding site in nAChRs has also been proposed for monoterpine compounds such as menthol and propofol [116,117] and is consistent with evidence supporting a transmembrane binding site for monoterpines on other pentameric LGICs [143][144][145][146][147]. Affinity labelling studies with a photoreactive analogue of propofol identified three sites at which it bound within the transmembrane domain of muscle-type nAChRs, but concluded that the functionally relevant site for the inhibitory action of propofol was an intra-subunit site [117], similar to that described earlier for α7-selective allosteric modulators such as NS-1738, PNU-120596 and 4BP-TQS [30,139].…”

Activation of Human 5-Hydroxytryptamine Type 3 Receptors via an Allosteric Transmembrane Site

“…Examples of such compounds include verapamil (Hargreaves et al, 1996), cannabinoids (Barann et al, 2002), cannabidiol (Yang et al, 2010), hydrocortisone (Corradi et al, 2011), menthol (Ashoor et al, 2013), and PU02 (6-[(1-naphthylmethyl)thio]-9H-purine) (Trattnig et al, 2012). A variety of positive allosteric modulators of 5-HT 3 Rs have also been identified, including alcohols (Zhou and Lovinger, 1996), 5-hydroxyindole (van Hooft et al, 1997) colchicine (de Oliveira-Pierce et al, 2009), and 5-chloroindole (Newman et al, 2013).…”

Involvement of cholinergic nicotinic receptors in the menthol-induced gastric relaxation

“…However, although the menthol effects were reduced by atropine, the muscarinic receptors are not the target for menthol because carbachol-evoked contraction was unaffected by menthol, whilst a prejunctional regulation of acetylcholine release via involvement of adrenergic pathways is likely to occur (Amato et al, 2013). In the present study, we have investigated whether neural receptors or ionic channels proteins, which are known by the literature to mediate various menthol effects (Boesmans et al, 2011;Hans et al, 2012; Ashoor et al, 2013b), can be target responsible for menthol triggering gastric relaxant.…”

“…Recently, menthol has been hypothesized to exert antiemetic properties by inhibiting the cationic influx through 5-HT 3 receptor (Heimes et al, 2011) and it has been demonstrated to be an allosteric inhibitor of 5-HT 3 receptors using electrophysiological and biochemical methods (Ashoor et al, 2013b;Walstab et al, 2014). 5-HT 3 receptors are expressed by enteric sensory neurons in the mucosal layer and in the nerve cell body of interneurons and motor neurons in the enteric nervous system (Galligan, 2002).…”

“…In these cells TRPA1 agonists cause Ca 2 þ influx and 5-HT release . The 5-hydroxytriptamine 3 (5-HT 3 ) receptor could contribute to the pharmacological actions of menthol, as it has been shown to be inhibited by menthol (Ashoor et al, 2013b). The 5-HT 3 receptors are expressed by enteric sensory neurons in the Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/ejphar mucosa layer and in the cell body of interneurons and motor neurons of the enteric nervous system (Galligan, 2002) and their involvement in nausea, vomiting and irritable bowel syndrome has been well established (Riering et al, 2004;Faerber et al, 2007).…”