Skip to main content
PMC home page
Molecules logoLink to Molecules
. 2018 Dec 3;23(12):3186. doi: 10.3390/molecules23123186

Natural Negative Allosteric Modulators of 5-HT3 Receptors

Lina T Al Kury 1,*, Mohamed Mahgoub 2, Frank Christopher Howarth 3, Murat Oz 4
PMCID: PMC6321066  PMID: 30513973

Abstract

Chemotherapy-induced nausea and vomiting (CINV) remain the most common and devastating side-effects associated with cancer chemotherapy. In recent decades, several lines of research emphasize the importance of 5-hydroxytryptamine3 (5-HT3; serotonin) receptors in the pathogenesis and treatment of CINV. 5-HT3 receptors are members of ligand-gated ion channels that mediate the rapid and transient membrane-depolarizing effect of 5-HT in the central and peripheral nervous system. These receptors play important roles in nausea and vomiting, as well as regulation of peristalsis and pain transmission. The development of antagonists for 5-HT3 receptor dramatically improved the treatment of CINV in cancer patients. In fact, the most common use of 5-HT3 receptor antagonists to date is the treatment of nausea and vomiting. In recent years, there has been an increasing tendency to use natural plant products as important therapeutic entities in the treatment of various diseases. In this article, we examined the results of earlier studies on the actions of natural compounds on the functional properties of 5-HT3 receptors. It is likely that these natural modulators of 5-HT3 receptors can be employed as lead structures for the synthesis of therapeutic agents for treating CINV in future clinical studies.

Keywords: chemotherapy-induced nausea and vomiting, 5-hydroxytryptamine3 receptors, 5-hydroxytryptamine3 receptor antagonists, negative allosteric modulators

1. Introduction

Chemotherapy-induced nausea and vomiting (CINV) remain the most common and devastating side-effects associated with cancer treatment. These side effects can lead to the development of serious clinical complications such as electrolyte imbalance, dehydration, weight loss, weakness, fractures and deterioration in behavioral and mental status of the patient. In addition, these side effects can interfere with compliance with treatment as patients may delay or refuse future treatments because of fear of further nausea and vomiting [1,2]. Recently, a number of approaches have been applied to control CINV including medicinal or complementary therapies and the selection and prescription of appropriate approaches will significantly improve the patients’ quality of life.

Chemotherapy treatments received in cancer patients are classified into high emetic risk (emesis in nearly all patients), moderate emetic risk (30–90% risk of emesis), low emetic risk and minimal emetic risk emetogenic chemotherapies [3,4,5]. Compared to cisplatin, melphalan, cyclophosphamide and dacarbazine, which have high emetogenic potential, other chemotherapy agents such as anthracyclines, methotrexate, oxaliplatin and carboplatin have moderate emetogenic properties [3,4,5]. Depending on the chemotherapeutic agents and frequency of administration, patients can develop both acute and delayed CINV. According to the most recent guidelines from major medical organizations such as National Comprehensive Cancer Network and American Society of Clinical Oncology, the use of 5-hydroxytryptamine3 (5-HT3; serotonin) receptor antagonist, in combination with and neurokinin1 receptor antagonist (aprepitant) and the corticosteroid dexamethasone is recommended in patients receiving moderately emetogenic chemotherapy [4,5]. In the case of highly emetogenic therapy, a four-drug regimen is recommended, including 5-HT3 receptor antagonist, neurokinin1 receptor antagonist, dexamethasone and the antipsychotic drug olanzapine [4,5]. To date, the most commonly used 5-HT3 receptor antagonists are granisetron and ondansetron (first-generation 5-HT3 receptor antagonists) and palonosetron (second-generation 5-HT3 receptor antagonists) [3,5]. While granisetron and ondansetron have significant efficacy in the prevention of acute CINV (0–24 h after chemotherapy) in cancer patients receiving moderately and highly emetogenic chemotherapy, palonosetron has a higher potency and efficacy for the management of delayed CINV (after 24–120 h after chemotherapy) [3,6,7]. When combined with 5-HT3 receptor antagonist and dexamethasone, the neurokinin1 receptor antagonist aprepitant prevents CINV in patients receiving highly emetogenic chemotherapy [8]. This four-drug regimen is recommended for the control of both acute and delayed CINV [3,9].

The concept that 5-HT3 and its receptors are involved in the emetic reflex was revealed in several earlier studies [10,11]. In addition to the classic 5-HT3 receptor antagonists, there are many natural compounds derived from plants which inhibit 5-HT3 receptors such as the alkaloids cocaine and morphine (for review, [12]), the antimalarial drug quinine [13], cannabinoids, nicotine and terpenes [12,14,15]. In fact, there has been an increasing tendency towards using natural plant products as important therapeutic entities in the treatment of different illnesses. As such, these agents have advantages over synthetic drugs because they have fewer side effects (such as headache and constipation) in patients undergoing CINV [16] and are more cost-effective [17].

Allosteric modulators alter the receptor conformation by binding to a site distinct from the endogenous agonist binding site (orthosteric site) [18]. As a result, the binding and/or functional properties of agonist binding to orthosteric site may be affected [19]. Negative allosteric modulators decrease the efficacy of the endogenous receptor agonist without inducing complete receptor inhibition caused by orthosteric inhibitors and therefore, maintain the native pattern of the receptor activation largely intact [18,20,21]. Compared to homomeric receptors, the heteromeric 5-HT3 receptor contains an increased number of potential allosteric sites for drug interaction. As allosteric sites exhibit greater structural diversity than orthosteric sites, they are more likely to allow selective targeting by modulators than orthosteric sites [18,20,21]. In this article, we examine the results of earlier studies on the actions of natural negative allosteric modulators of 5-HT3 receptors. Natural negative allosteric modulators of 5-HT3 receptors could be used as useful therapeutic agents in the treatment of CINV in the future.

2. 5-hydroxytryptamine3 Receptors

5-HT3 receptors represent one of the seven families of serotonin receptors (5-HT1–7). They are members of the Cys-loop ligand-gated ion channel family and therefore, they differ structurally and functionally from the other six classes of G-protein coupled serotonin receptors [22]. The functional 5-HT3 receptor is a pentamere of five subunits that surround a water-filled ion channel [23,24]. Each subunit is made of 3 domains: (1) An extracellular domain that forms the ligand-binding site, (2) A transmembrane domain consisting of four membrane-spanning helices (M1–M4) that facilitate ion movement across the membrane, and (3) An intracellular domain formed by the large M3–M4 intracellular loop, which is responsible for receptor modulation, sorting, and trafficking, and contains openings that impact ion conductance [23,24,25]. The endogenous ligand binding site is located in the extracellular domain at the interface of two adjacent subunits, where binding is coordinated by the convergence of six peptide loops [26]. To date, the five different subunits (A–E) of 5-HT3 receptor have been cloned but only the A and B subunits have been studied extensively. Moreover, all functional 5-HT3 receptors require the presence of at least one A subunit [25].

5-HT3 receptors are located in many brain areas and are believed to play important roles in psychiatric disorders such as depression, motility of gastrointestinal system, emesis, neurodevelopment and nociception, [12,25,27]. Like other channels that are permeable to the cations, Na+, K+, and Ca2+ [28,29,30], the 5-HT3 receptors mediate fast excitatory depolarizing responses in pre- and post-synaptic neurons in the central and peripheral nervous system [31].

3. 5-hydroxytryptamine3 Receptor-Mediated Nausea and Vomiting

The role of 5-HT3 receptors in nausea and vomiting has been well-established [32,33]. The mechanism by which nausea and vomiting are triggered involves 5-HT3 receptors both in the central nervous system and the gastrointestinal tract [34]. Vomiting is triggered when afferent impulses from the cerebral cortex, chemoreceptor trigger zone and vagal afferent fibers of the gastrointestinal tract travel to the vomiting center, located in the medulla. Efferent impulses then travel from the vomiting centre to the abdominal muscles, cranial nerves, salivation centre, and respiratory centre, causing vomiting [35]. Large numbers of 5-HT3 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 [36]. It has been suggested that vomiting occurs because of the stimulation of enterochromaffin cells of the intestinal mucosa which results in the release of 5-HT and subsequent stimulation of peripheral 5-HT3 receptors of ganglionic and synaptic transmission in the myenteric plexus. This action, along with the local release of 5-HT in the area postrema, located on the dorsal surface of the medulla oblongata, is suggested to trigger the vomiting reflex [37].

Currently, there is a wide range of 5-HT3 antagonists available for clinical use. In fact, drugs that selectively antagonize 5-HT3 receptors are currently among the most effective antiemetic agents, and therefore are considered the “gold standard” in the treatment of CINV [25,34,37]. However, the wide use of synthetic antiemetic drugs has been accompanied with adverse side effects such as headache, hypotension and extra pyramidal side effects [17]. Furthermore, they are ineffective in up to 30% of CINV cases [16,38], warranting the search for more effective anti-emetics for CINV treatment. In this aspect, plants have drawn significant interest in the field of treatment of CINV as compared to chemical drugs due to having more advantages, fewer side effects in patients undergoing CINV, as well as being more cost-effective [17].

4. Natural Negative Allosteric Modulators of 5-hydroxytryptamine3 Receptors

As 5-HT3 receptor antagonists were found to be effective antiemetic agents against CINV, much interest was drawn towards identifying agents that are capable of affecting/modulating the function of 5-HT3 receptors [11,39]. In the below sections, we review the effects of natural negative allosteric modulators of 5-HT3 receptors.

4.1. Terpenes

Menthol is a monocyclic terpene alcohol (Figure 1) and a natural product of the peppermint plant Mentha × piperita (Lamiaceae). It is commonly used as part of analgesic, antiseptic, topical antipruritic, and cooling formulations. In addition, it is widely used as a natural product in cosmetics, a flavoring agent, and as an intermediate in the production of other compounds. Menthol-containing medications are currently available for a number of conditions, including respiratory diseases, gastrointestinal disorders, common cold, and musculoskeletal pain [40,41,42].

Figure 1.

Figure 1

Open in a new tab

Natural negative allosteric modulators of 5-HT3 receptor.

Several studies have reported the potential modulatory effect of menthol on the 5-HT3 receptor [15,43,44,45] (Table 1). An earlier study conducted by Heimes et al., 2011 used three in vitro models to investigate the effects of peppermint oil and its active constituent, menthol, on 5-HT3 receptors. The models included [14C] guanidinium influx into N1E-115 cells which express 5-HT3 receptors, isotonic contractions of ileum isolated rat and equilibrium competition binding studies using GR65630 (3-(5-methyl-1H-imidazol-4-yl)-1-(1-methyl-1H-indol-3-yl)-1-propanone, a radioactively-labeled 5-HT3 receptor antagonist. Both peppermint oil and menthol, inhibited the serotonin-induced flux of [14C] guanidinium into N1E-115 cells that express 5-HT3 receptors in a concentration-dependent manner. Furthermore, both compounds were able to reduce serotonin-induced contraction of the ileum isolated from rat. Interestingly, peppermint oil and menthol did not compete for the binding site on 5-HT3 receptor, which suggests that they bind to an allosteric binding site that is distinct from the binding site of serotonin [44].

Table 1.

Summary of natural negative allosteric inhibitors of 5HT3 receptor.

Compound Concentration Preparation References
Menthol >100 µM [14C] guanidinium influx into N1E-115 cells.
Isotonic contractions of the ileum isolated rat.
Equilibrium competition binding studies.		 [44]
IC50 = 163 µM Xenopus laevis oocytes [43]
IC50 = 4.75 µM
IC50 = 489 µM		 HEK293 cells
Xenopus laevis oocytes		 [15]
[45]
Boldine IC50 = 5.94 µM HEK293 cells [15]
Citronellol IC50 = 64.3 µM Xenopus laevis oocytes [45]
Geraniol IC50 = 188 µM Xenopus laevis oocytes [45]
Citral IC50 = 120 µM Xenopus laevis oocytes and HEK293 cells [55]
Eucalyptol IC50 = 258 µM Xenopus laevis oocytes and HEK293 cells [55]
Linalool IC50 = 141 µM Xenopus laevis oocytes and HEK293 cells [55]
6-shogaol 100 µM
IC50 = 3.2–10 µM		 [14C] guanidinium influx into N1E-115 cells.
Equilibrium competition binding studies.
Isotonic contractions of the isolated guinea-pig ileum.
Visceral afferent neurons and HEK293 cells.		 [56,57]
8-gingerol 1–3 µM
100 µM		 [14C] guanidinium influx into N1E-115 cells.
Equilibrium competition binding studies.
Isotonic contractions of the isolated guinea-pig ileum.		 [56]
6-gingerol 88 µM
100 µM
IC50 = 9–30 µM		 [14C] guanidinium influx into N1E-115 cells.
Equilibrium competition binding studies.
Isotonic contractions of the isolated guinea-pig ileum.
Visceral afferent neurons and HEK293 cells		 [56,57,58]
10-gingerol IC50 = 9–15 µM [14C] guanidinium influx into N1E-115 cells.
Equilibrium competition binding studies.
Isotonic contractions of the isolated guinea-pig ileum.		 [56]
Zingerone IC50 = 1.19 mM Visceral afferent neurons [58]
Capsaicin IC50 = 98.1 µM Xenopus laevis oocytes [45]
Eugenol IC50 = 1159 µM Xenopus laevis oocytes [45]
Vanillin IC50 = 4744 µM Xenopus laevis oocytes [45]
Thujone - HEK293 cells [59]
Cannabidiol IC50 = 0.6 µM Xenopus laevis oocytes [60]
Quinine IC50 = 1.06 µM Xenopus laevis oocytes [13]
Open in a new tab

The effects of menthol on the functional properties of human 5-HT3A receptors expressed in Xenopus laevis oocytes have been studied by Ashoor et al. [43]. Menthol, at an IC50 value of 163 µM, caused an inhibition of the 5-HT-induced inward current. The menthol effect was concentration-dependent and was G-protein-independent as GTPγS activity was unchanged. Furthermore, pretreatment with Gi and Go inhibitor, pertussis toxin, did not alter the inhibitory effect of menthol. Furthermore, menthol actions were not stereo-selective as (+), (−) and racemic menthol inhibited the currents mediated by 5-HT3 receptor in the same manner [43]. Supporting the data observed by Heimes et al. [44], menthol did not affect the binding of the orthosteric 5-HT3 receptor antagonist, GR65630 the 5-HT binding site. In addition, increasing the concentration of 5-HT did not alter the inhibitory effect of menthol, which indicates that menthol acts as an allosteric modulator of 5-HT3 receptor as a non-competitive antagonist. Interestingly, menthol has also been shown as a negative allosteric inhibitor of α7 [46] and α4β2 [47,48] nicotinic acetylcholine receptors. Apart from its effect on 5-HT3 and nicotinic acetylcholine receptors, menthol was also found to activate TRPM8 receptors [49,50] and receptors for inhibitory neurotransmitters, including GABAA and Glycine [51,52,53,54] (Table 2).

Table 2.

Summary of the effects of natural negative allosteric inhibitors of 5HT3 on other target proteins.

Compound Target protein Effect References
Menthol GABAA Potentiation [52,53,54]
Glycine Potentiation [51]
Nicotinic receptors Reduction
Up-regulation		 [47,61,62]
[63]
TRP channels Potentiation [49,50]
Na+ channels Blocking [64]
Ca2+ channels Inhibition [65,66,67]
K+ channels Activation [68]
TRP channels Activation
Inhibition		 [49,50,69]
[70]
Boldine TRP channels Inhibition [71]
Citral TRP channels Activation [72]
Eucalyptol Na+ channels Inhibition [73]
TRP channels Activation [74,75,76]
Linalool Na+ channels Inhibition [77]
Nicotinic receptors Reduction [78]
TRP channels Activation [74,79]
Gingerol L-type Ca2+ channels Inhibition [80]
6-gingerol Na+ channels Blockage [81]
K+ channels Inhibition [82]
6-shogaol Na+ channels Blockage [81]
Capsaicin K+ channels Inhibition [82]
Eugenol T-type Ca2+ channel Inhibition [83,84]
GABAA receptors Activation [85,86]
K+ channels Inhibition [87,88]
Cannabidiol TRP channels Activation [74,89,90]
α7-nicotinic receptors Inhibition [91]
Glycine receptors Activation [92]
Thujone TRP channels Activation [93]
α7-nicotinic receptors Inhibition [94]
GABAA receptors Inhibition [95]
Open in a new tab

Walstab et al. investigated the actions of the aporphine alkaloid boldine and menthol isomers on human recombinant homomeric 5-HT3A and heteromeric 5-HT3AB receptors expressed in HEK293 cells utilizing luminescence-based Ca2+ assay, membrane potential assay and radioligand binding assay. Both compounds inhibited the 5-HT-induced activation of 5-HT3 receptors at micromolar concentrations. Boldine was a more potent inhibitor to 5-HT3A compared to 5-HT3AB receptors. Interestingly, menthol inhibited both receptors in a non-competitive and stereo-selective manner. (+)-menthol had less potent inhibitory action compared to the (−)-menthol which was 11-fold potent towards the homomeric 5-HT3A receptor [15].

In a recent study, the actions of a number of terpenes and pungent substances on human 5-HT3A receptors recombinantly expressed in Xenopus laevis oocyte were tested [45]. The results of this study have shown that 5-HT3A receptors are inhibited by a variety of terpenes and pungent substances with some of them belonging to the vanilloid class. Within the acyclic monoterpenes tested, citronellol and geraniol, which are known as the main constituents of Rosa damascena flower essential oils [96], were the most potent blockers for 5-HT3A receptors. Citronellol decreased the 5-HT3A receptor-mediated currents with an IC50 of 64 µM. Geraniol was less potent compared to citronellol with an IC50 of 188 µM. (−)-Menthol also decreased the 5-HT3A receptor-mediated currents but with lower potency than citronellol (IC50 489 µM) [45]. As citronellol and geraniol have structures similar to menthol, further studies are warranted to test if these compounds utilize the same binding site as menthol on the 5-HT3A receptors.

The effects of terpenoids on 5-HT3 receptors were also recently studied by Jarvis et al. [97]. The terpenoids citral, eucalyptol, and linalool were tested for their effects on the electrophysiological and binding properties of human 5-HT3 receptors expressed in Xenopus oocytes and HEK293 cells, respectively [97]. All of the terpenoids inhibited 5-HT3 receptors with IC50 values in the µM range (citral IC50 = 120 µM; eucalyptol IC50 = 258 µM; linalool IC50 = 141 µM) [97]. The IC50 values were also comparable to those for similar terpenoid compounds, such as menthol (163 µM) [43].

In addition, all the tested compounds non-competitively inhibited the maximal 5-HT in a concentration-dependent manner and did not compete with the fluorescently-labelled antagonist granisetron. Homology modeling and ligand docking predicted the binding to a transmembrane cavity at the interface of adjacent subunits. This can be explained by the lipophilic nature of these compounds. In fact, the results are consistent with the slow wash-in and wash-out that is observed as the compounds diffuse into the membranes before reaching their target [55]. Collectively, the effects of terpenoids on 5-HT3 receptors can be added to the increasing list of structurally related natural plant compounds that modulate voltage- and ligand-gated ion channels [15,45,46,51,98,99,100,101].

4.2. Ginger Constituents

The rhizome of Zingiber officinale Roscoe (Zingiberaceae), commonly known as ginger, has been used for centuries in treating pregnancy-induced nausea and vomiting [102,103]. The anti-emetic effect of ginger and its active constituents have been investigated in earlier studies to establish the mechanism for their antiemetic activity [12,104,105]. The best characterized constituents of ginger are the pungent substances gingerols and shogaols [56,106]. In particular, the compounds 6-, 8-, 10-gingerol and 6-shogaol were shown in different in vivo studies to be, at least, partly responsible for the anti-emetic properties of ginger [107,108]. In this regard, Abdel-aziz et al. [106] used three different in vitro models to investigate the effects of ginger extracts on 5-HT3 receptors: 1) [14C] guanidinium influx into N1E-115 cells which express 5-HT3 receptors, 2) isotonic contractions of the isolated guinea-pig ileum induced by the highly selective HT3 receptor agonist SR57227A ((4-amino)-(6-chloro-2-pyridyl)L-piperidine hydrochloride), and 3) equilibrium competition binding studies using a radioactively labeled 5-HT3 receptor antagonist ([3H]GR65630). All tested ginger extracts caused concentration-dependent inhibition of [14C] guanidinium influx through 5-HT3 receptor channels as well as contractions of the guinea-pig ileum induced by SR57227A. The order of potency for both models was: 6-shogaol ≥ 8-gingerol 10-gingerol ≥ 6-gingerol. These compounds did not displace the 5-HT3 antagonist [3H]GR65630 from the ligand binding site neither on intact N1E-115 cells nor on the purified membranes of HEK-293 cells over-expressing the h5-HT3 receptor indicating that they are non-competitive inhibitors of 5-HT3 receptors [106]. Similarly, in the guinea pig myenteric plexus preparation (bioassay for contractile 5-HT3 receptors), the 5-HT maximal responses were depressed by 10-gingerol and 6-shagoal. 10-gingerol decreased the response to 5-HT from 93% to 65 % at an antagonist concentration of 3 µM and to 48% at an antagonist concentration of 5 µM. 6-Shogaol (3 µM) was less potent compared to 10-gingerol and induced depression to 61% at an antagonist concentration of 3 µM. It is concluded that the efficacy of ginger in reducing nausea and vomiting may be based on the inhibitory effect of gingerols and shogaols at 5-HT3 receptors [56].

In support of the above study, Walstab et al. [109] showed that ginger extracts and its pungent constituents inhibited the activation of human 5-HT3A and 5-HT3AB receptors heterologously expressed in HEK293 cells in a concentration-dependent manner [109]. Furthermore, with increasing concentration of pungent compounds, ginger extracts inhibited both receptors, confirming that they are part of ginger’s active principle. Inhibition potencies of 6-gingerol and 6-shogaol on both receptors were in the low µM range. The non-competitive inhibition of 5-HT3A and 5-HT3AB receptors by ginger extract was confirmed by [3H]GR65630 binding, showing that the ginger extract did not displace the radioligand from 5-HT3A and 5-HT3AB receptors.

In addition to the previously mentioned ginger extracts, Jin et al. reported that zingerone is a non-competitive inhibitor of 5-HT3 on visceral afferent neurons [58]. Using patch-clamp methods, they showed that zingerone inhibited the 5-HT response in a manner similar to the pungent substances 6-shogaol and 6-gingerol. The order of inhibitory potency for these compounds were 6-shogaol >6-gingerol >zingerone. The IC50 of 6-shogaol and 6-gingerol were 128 and 39 times lower than zingerone, respectively, indicating that 6-shogaol and 6-gingerol are more effective than zingerone. Unlike the competitive 5-HT3 receptor antagonist ondansetron, all tested ginger constituents acted as non-competitive antagonists, suggesting that ginger and its pungent constituents exert antiemetic effects by blocking 5-HT-induced emetic signal transmission in vagal afferent neurons [58]. Interestingly, zingerone is the least pungent component of Zingiber officinale and is absent in fresh ginger. However, gingerols is converted to zingerone upon cooking or heating. As a consequence, this process reduces the 5-HT3A blocking activity of ginger [57]. Although all data showed that ginger-derived molecules act allosterically, in silico techniques showed that these compounds can also bind to the orthosteric binding site causing competitive inhibition as well [110]. Ginger extracts were also tested against other ion channels such as L-type Ca2+, Na+ and K+ channels. While gingerol caused a dose-dependent inhibition of L-type Ca2+ channels in longitudinal mycocytes of rats, both 6-gingerol and 6-shagaol inhibited the generation of action potential in the sensory neurons of rats by inhibiting Na+ and K+ channels [80].

4.3. Capsaicin

Capsaicin, from chili pepper, is another pungent substance that has shown effectiveness in reversing emesis in chemotherapy and operation-induced nausea and vomiting [111,112] and in Cannabis hyperemesis syndrome [113,114]. Capsaicin is chemically-related to other vanilloid substances such as gingerols and shogaols. Capsaicin was also found to inhibit 5-HT3 receptor expressed in Xenopus laevis oocytes [45]. When co-applied with 5-HT (5 µM), capsaicin (100 µM) significantly decreased 5-HT-induced currents up to 52% compared to 83% for 8-gingerol, 62% for 6-gingerol, 42% for 6-shogaol, and 65% for polygodial, the hot substance of dorrigo, mountain pepper or black pepper. The concentration-inhibition curves showed that 8-gingerol, 6-gingerol, capsaicin and polygodial blocked 5HT-induced inward currents in a concentration-dependent manner with IC50 values of 40 µM, 46 µM, 98 µM and 71 µM, respectively [45]. Other ion channels were also found to be modulated by capsaicin. In fact, capsaicin was found to modulate both K+ and Ca2+ channels in Xenopus embryo spinal neurons [45].

4.4. Eugenol and Vanilin

In addition to the previously mentioned compounds, other agents such as eugenol and vanillin were also found to modulate the activity of 5-HT3 receptors. Both agents showed a non-competitive antagonistic activity on 5-HT3 receptors expressed in Xenopus laevis oocytes, however, very high concentrations of both compounds were needed to inhibit 5-HT response (IC50 1159 µM for eugenol and IC50 4744 µM for vanillin) making them less effective compared to the other antagonists [45]. Eugenol could also inhibit the actions of different isoforms of T-type Ca2+ channels [83] and activate the inhibitory receptor GABA [85,86].

4.5. Thujone

The monoterpene thujone is chemically related to menthol and found in plants such as wormwood, thyme and sage [19]. Similar to menthol, thujone has been shown to non-competitively suppress the function of 5-HT3 receptors. Using patch clamp technique, Alpha-thujone was found to cause a significant inhibition of both homomeric and heteromeric 5-HT3 receptors expressed in HEK293 cells. However, the effective concentration was typically in the high µM range [115]. Furthermore, other ligand-gated ion channels were reported to be sensitive to thujone, including GABAA receptors and α7-nicotinic receptors. Thujone caused a non-competitive inhibition of both receptors expressed in HEK 293 cells and Xenopus oocytes, respectively [94].

4.6. Cannabidiol

Previous studies showed that both 5-HT3 receptor antagonists and cannabinoids produce antiemetic effects [32,59]. In fact, dronabinol and nabilone which are synthetically produced from Δ9-tetrahydrocannabinol, the main psychoactive constituent of Cannabis sativa, were approved by the United States FDA for use in CINV refractory to conventional antiemetic therapy [32,59,116]. The limitation of the therapeutic use of THC and its other chemical analogs is the potential development of psychoactive effects through cannabinoid receptors (CB1) present in the central nervous system.

The compound cannabidiol is one of the most abundant cannabinoids of Cannabis plant with reported antioxidant, anti-inflammatory, and antiemetic effects. Furthermore, this compound lacks any psychoactive properties due to the low affinity for the cannabinoid receptors, CB1 and CB2 [117,118,119]. Thus, pharmaceutical interest in this compound has increased significantly in recent years [19,117,119,120]. The effect of cannabidiol on the function of 5-HT3A receptors expressed in Xenopus laevis oocytes was investigated using two-electrode voltage-clamp techniques. Cannabidiol was capable of reversing 5-HT-evoked currents in a concentration-dependent manner, with an IC50 = 0.6 µM [121]. Although the potency of the 5-HT was not altered, its efficacy was significantly decreased by cannabidiol, indicating that cannabidiol did not compete with the 5-HT binding site on the receptor. In agreement with these findings, radioligand binding studies indicated that displacement of [3H]GR65630 by 5-HT was not significantly altered by cannabidiol, further suggesting that the compound does not bind with 5-HT binding site. These findings indicate that cannabidiol acts as an allosteric modulator of 5-HT3 receptor. Allosteric modulation by cannabidiol has also been reported for several structurally different ion channels [117]. Cannabidiol caused a noncompetitive inhibition of the α7-nicotinic receptors [91] in a manner similar to its action on the 5-HT3A receptors, while it activated glycine receptors and TRPA1 channels [85,86].

4.7. Other Compounds

There are other natural compounds derived from plants which also target 5-HT3 receptors such as the alkaloids cocaine and morphine (for review [60], both of which are potent competitive inhibitors of 5-HT3 receptors (for review, [12]). Interestingly, quinine, the antimalarial drug, is a competitive inhibitor of 5-HT3A receptors whereas it non-competitively inhibits 5-HT3AB receptors with a tenfold less potency [13]. Local anesthetics such as lidocaine and bupivacaine, are also competitive and allosteric antagonists at the 5-HT3A receptor [122].

In the current article, we have reviewed the effects of natural negative allosteric compounds on 5-HT3 receptors according to different preparations and a wide variety of techniques, ranging from two-electrode voltage clamp to binding assays. Unlike 5-HT3 receptor selective antiemetic drugs which bind at the 5-HT binding site, all the compounds reviewed in this article inhibit the 5-HT3 receptor by binding to a modulatory binding site distinct from the 5-HT recognition site. These compounds did not compete with or displace the 5-HT3 antagonist, as evident in electrophysiological and ligand binding studies. The therapeutic potential of allosteric ligands stems from their ability to modulate receptor function while maintaining the native pattern of the receptor activation largely intact [20,21]. By decreasing the efficacy of endogenous 5-HT3 receptor agonist, negative allosteric modulators of 5-HT3 receptors can act as fine-tuning tools that may not affect physiological conditions, but may be very active in pathophysiological states such as CINV, without causing complete receptor inhibition [12]. This would lead to better safety profile compared to competitive antagonists. Since allosteric sites exhibit greater structural diversity than orthosteric sites [18], they are more likely to allow selective targeting by natural modulators.

In conclusion, the identification of allosteric binding sites for natural plant extracts and compounds is expected to possess a promising outcome in developing novel anti-emetics lacking the typical side effects caused by setrons [106]. Considering the reported effects of allosteric modulatory compounds, the development of novel antiemetic drugs based on naturally produced compounds may be possible.

Author Contributions

L.T.A.; writing—original draft preparation, L.T.A. and M.M.; writing—review and editing, F.C.; writing—review and editing, M.O.; writing—review and editing.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  • 1.Janelsins M.C., Tejani M.A., Kamen C., Peoples A.R., Mustian K.M., Morrow G.R. Current pharmacotherapy for chemotherapy-induced nausea and vomiting in cancer patients. Expert. Opin. Pharmacother. 2013;14:757–766. doi: 10.1517/14656566.2013.776541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Haniadka R., Popouri S., Palatty P.L., Arora R., Baliga M.S. Medicinal plants as antiemetics in the treatment of cancer: A review. Integr. Cancer Ther. 2012;11:18–28. doi: 10.1177/1534735411413266. [DOI] [PubMed] [Google Scholar]
  • 3.Navari R.M. Management of chemotherapy-induced nausea and vomiting: focus on newer agents and new uses for older agents. Drugs. 2013;73:249–262. doi: 10.1007/s40265-013-0019-1. [DOI] [PubMed] [Google Scholar]
  • 4.Hesketh P.J., Kris M.G., Basch E., Bohlke K., Barbour S.Y., Clark-Snow R.A., Danso M.A., Dennis K., Dupuis L.L., Dusetzina S.B., et al. Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J. Clin. Oncol. 2017;35:3240–3261. doi: 10.1200/JCO.2017.74.4789. [DOI] [PubMed] [Google Scholar]
  • 5.Gilmore J., D’Amato S., Griffith N., Schwartzberg L. Recent advances in antiemetics: new formulations of 5HT3-receptor antagonists. Cancer Manag. Res. 2018;10:1827–1857. doi: 10.2147/CMAR.S166912. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Rojas C., Li Y., Zhang J., Stathis M., Alt J., Thomas A.G. The antiemetic 5-HT3 receptor antagonist Palonosetron inhibits substance P-mediated responses in vitro and in vivo. J. Pharmacol. Exp. Ther. 2010;335:362–368. doi: 10.1124/jpet.110.166181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Saito M., Aogi K., Sekine I., Yoshizawa H., Yanagita Y., Sakai H. Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy, randomised, comparative phase III trial. Lancet. Oncol. 2009;10:115–124. doi: 10.1016/S1470-2045(08)70313-9. [DOI] [PubMed] [Google Scholar]
  • 8.Curran M.P., Robinson D.M. Aprepitant: a review of its use in the prevention of nausea and vomiting. Drugs. 2009;69:1853–1878. doi: 10.2165/11203680-000000000-00000. [DOI] [PubMed] [Google Scholar]
  • 9.Basch E., Prestrud A.A., Hesketh P.J., Kris M.G., Feyer P.C., Somerfield M.R., Chesney M., Clark-Snow R.A., Flaherty A.M., Freundlich B., et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J. Clin. Oncol. 2011;29:4189–4198. doi: 10.1200/JCO.2010.34.4614. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Smith H.S., Cox L.R., Smith E.J. 5-HT3 receptor antagonists for the treatment of nausea/vomiting. Ann. Palliat. Med. 2012;1:115–120. doi: 10.3978/j.issn.2224-5820.2012.07.07. [DOI] [PubMed] [Google Scholar]
  • 11.Johnston K.D., Lu Z., Rudd J.A. Looking beyond 5-HT(3) receptors: a review of the wider role of serotonin in the pharmacology of nausea and vomiting. Eur. J. Pharmacol. 2014;722:13–25. doi: 10.1016/j.ejphar.2013.10.014. [DOI] [PubMed] [Google Scholar]
  • 12.Walstab J., Rappold G., Niesler B. 5-HT(3) receptors: role in disease and target of drugs. Pharmacol. Ther. 2010;128:146–169. doi: 10.1016/j.pharmthera.2010.07.001. [DOI] [PubMed] [Google Scholar]
  • 13.Thompson A.J., Lummis S.C. Antimalarial drugs inhibit human 5-HT(3) and GABA(A) but not GABA(C) receptors. Br. J. Pharmacol. 2008;153:1686–1696. doi: 10.1038/bjp.2008.34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Schreiner B.S., Lehmann R., Thiel U., Ziemba P.M., Beltran L.R., Sherkheli M.A. Direct action and modulating effect of (+)- and (−)-nicotine on ion channels expressed in trigeminal sensory neurons. Eur. J. Pharmacol. 2014;728:48–58. doi: 10.1016/j.ejphar.2014.01.060. [DOI] [PubMed] [Google Scholar]
  • 15.Walstab J., Wohlfarth C., Hovius R., Schmitteckert S., Roth R., Lasitschka F. Natural compounds boldine and menthol are antagonists of human 5-HT3 receptors: implications for treating gastrointestinal disorders. Neurogastroenterol. Motil. 2014;26:810–820. doi: 10.1111/nmo.12334. [DOI] [PubMed] [Google Scholar]
  • 16.De Leon A. Palonosetron (Aloxi): A second-generation 5-HT(3) receptor antagonist for chemotherapy-induced nausea and vomiting. Proc. (Bayl. Univ. Med. Cent.) 2006;19:413–416. doi: 10.1080/08998280.2006.11928210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Sheikhi M.A., Ebadi A., Talaeizadeh A., Rahmani H. Alternative Methods to Treat Nausea and Vomiting from Cancer Chemotherapy. Chemother. Res. Pract. 2015;2015 doi: 10.1155/2015/818759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Uteshev V.V. The therapeutic promise of positive allosteric modulation of nicotinic receptors. Eur. J. Pharmacol. 2014;727:181–185. doi: 10.1016/j.ejphar.2014.01.072. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Davies P.A. Allosteric modulation of the 5-HT(3) receptor. Curr. Opin. Pharmacol. 2011;11:75–80. doi: 10.1016/j.coph.2011.01.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Newman A.S., Batis N., Grafton G., Caputo F., Brady C.A., Lambert J.J. 5-Chloroindole: a potent allosteric modulator of the 5-HT(3) receptor. Br. J. Pharmacol. 2013;169:1228–1238. doi: 10.1111/bph.12213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Williams D.K., Wang J., Papke R.L. Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics: Advantages and limitations. Biochem. Pharmacol. 2011;82:915–930. doi: 10.1016/j.bcp.2011.05.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Barnes N.M., Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology. 1999;38:1083–1152. doi: 10.1016/S0028-3908(99)00010-6. [DOI] [PubMed] [Google Scholar]
  • 23.Boess F.G., Lummis S.C., Martin I.L. Molecular properties of 5-hydroxytryptamine3 receptor-type binding sites purified from NG108-15 cells. J. Neurochem. 1992;59:1692–1701. doi: 10.1111/j.1471-4159.1992.tb11000.x. [DOI] [PubMed] [Google Scholar]
  • 24.Green T., Stauffer K.A., Lummis S.C. Expression of recombinant homo-oligomeric 5-hydroxytryptamine3 receptors provides new insights into their maturation and structure. J. Biol. Chem. 1995;270:6056–6061. doi: 10.1074/jbc.270.11.6056. [DOI] [PubMed] [Google Scholar]
  • 25.Lummis SC.R. 5-HT(3) Receptors. J. Biolog. Chem. 2012;287:40239–40245. doi: 10.1074/jbc.R112.406496. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Hassaine G., Deluz C., Grasso L., Wyss R., Tol M.B., Hovius R. X-ray structure of the mouse serotonin 5-HT3 receptor. Nature. 2014;512:276–281. doi: 10.1038/nature13552. [DOI] [PubMed] [Google Scholar]
  • 27.Engel M., Smidt M.P., van Hooft J.A. The serotonin 5-HT3 receptor: a novel neurodevelopmental target. Front Cell Neurosci. 2013;7 doi: 10.3389/fncel.2013.00076. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Yang J. Ion permeation through 5-hydroxytryptamine-gated channels in neuroblastoma N18 cells. J. Gen. Physiol. 1990;96:1177–1198. doi: 10.1085/jgp.96.6.1177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Maricq A.V., Peterson A.S., Brake A.J., Myers R.M., Julius D. Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel. Science. 1991;254:432–437. doi: 10.1126/science.1718042. [DOI] [PubMed] [Google Scholar]
  • 30.Derkach V., Surprenant A., North R.A. 5-HT3 receptors are membrane ion channels. Nature. 1989;339:706–709. doi: 10.1038/339706a0. [DOI] [PubMed] [Google Scholar]
  • 31.Yakel J.L., Jackson M.B. 5-HT3 receptors mediate rapid responses in cultured hippocampus and a clonal cell line. Neuron. 1988;1:615–621. doi: 10.1016/0896-6273(88)90111-0. [DOI] [PubMed] [Google Scholar]
  • 32.Riering K., Rewerts C., Zieglgansberger W. Analgesic effects of 5-HT3 receptor antagonists. Scand. J. Rheumatol. Suppl. 2004;119:19–23. doi: 10.1080/03009740410006970. [DOI] [PubMed] [Google Scholar]
  • 33.Faerber L., Drechsler S., Ladenburger S., Gschaidmeier H., Fischer W. The neuronal 5-HT3 receptor network after 20 years of research--evolving concepts in management of pain and inflammation. Eur. J. Pharmacol. 2007;560:1–8. doi: 10.1016/j.ejphar.2007.01.028. [DOI] [PubMed] [Google Scholar]
  • 34.Machu T.K. Therapeutics of 5-HT3 receptor antagonists: current uses and future directions. Pharmacol. Ther. 2011;130:338–347. doi: 10.1016/j.pharmthera.2011.02.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Navari R.M. 5-HT3 receptors as important mediators of nausea and vomiting due to chemotherapy. Biochim. Biophys. Acta. 2015;1848:2738–2746. doi: 10.1016/j.bbamem.2015.03.020. [DOI] [PubMed] [Google Scholar]
  • 36.Galligan J.J. Ligand-gated ion channels in the enteric nervous system. Neurogastroenterol. Motil. 2002;14:611–623. doi: 10.1046/j.1365-2982.2002.00363.x. [DOI] [PubMed] [Google Scholar]
  • 37.Thompson A.J., Lummis S.C. The 5-HT3 receptor as a therapeutic target. Expert Opin. Ther. Targets. 2007;11:527–540. doi: 10.1517/14728222.11.4.527. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Rapoport B.L. Delayed Chemotherapy-Induced Nausea and Vomiting: Pathogenesis, Incidence, and Current Management. Front. Pharmacol. 2017;8 doi: 10.3389/fphar.2017.00019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Andrews P.L., Sanger G.J. Nausea and the quest for the perfect anti-emetic. Eur. J. Pharmacol. 2014;722:108–121. doi: 10.1016/j.ejphar.2013.09.072. [DOI] [PubMed] [Google Scholar]
  • 40.Eccles R. Menthol and related cooling compounds. J. Pharm. Pharmacol. 1994;46:618–630. doi: 10.1111/j.2042-7158.1994.tb03871.x. [DOI] [PubMed] [Google Scholar]
  • 41.Patel T., Ishiuji Y., Yosipovitch G. Menthol: A refreshing look at this ancient compound. J. Am. Acad. Dermatol. 2007;57:873–878. doi: 10.1016/j.jaad.2007.04.008. [DOI] [PubMed] [Google Scholar]
  • 42.Oz M., El Nebrisi E.G., Yang K.S., Howarth F.C., Al Kury L.T. Cellular and Molecular Targets of Menthol Actions. Front. Pharmacol. 2017;8 doi: 10.3389/fphar.2017.00472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Ashoor A., Nordman J.C., Veltri D., Yang K.H., Shuba Y., Al Kury L.T. Menthol inhibits 5-HT3 receptor-mediated currents. J. Pharmacol. Exp. Ther. 2013;347:398–409. doi: 10.1124/jpet.113.203976. [DOI] [PubMed] [Google Scholar]
  • 44.Heimes K., Hauk F., Verspohl E.J. Mode of action of peppermint oil and (−)-menthol with respect to 5-HT3 receptor subtypes: binding studies, cation uptake by receptor channels and contraction of isolated rat ileum. Phytother. Res. 2011;25:702–708. doi: 10.1002/ptr.3316. [DOI] [PubMed] [Google Scholar]
  • 45.Ziemba P.M., Schreiner B.S., Flegel C., Herbrechter R., Stark T.D., Hofmann T. Activation and modulation of recombinantly expressed serotonin receptor type 3A by terpenes and pungent substances. Biochem. Biophys. Res. Commun. 2015;467:1090–1096. doi: 10.1016/j.bbrc.2015.09.074. [DOI] [PubMed] [Google Scholar]
  • 46.Ashoor A., Nordman J.C., Veltri D., Yang K.H., Al Kury L., Shuba Y. Menthol binding and inhibition of alpha7-nicotinic acetylcholine receptors. PLoS ONE. 2013;8 doi: 10.1371/journal.pone.0067674. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Hans M., Wilhelm M., Swandulla D. Menthol Suppresses Nicotinic Acetylcholine Receptor Functioning in Sensory Neurons via Allosteric Modulation. Chem. Senses. 2012;37:463–469. doi: 10.1093/chemse/bjr128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Ton H.T., Smart A.E., Aguilar B.L., Olson T.T., Kellar K.J., Ahern G.P. Menthol Enhances the Desensitization of Human alpha3beta4 Nicotinic Acetylcholine Receptors. Mol. Pharmacol. 2015;88:256–264. doi: 10.1124/mol.115.098285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.McKemy D.D., Neuhausser W.M., Julius D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature. 2002;416:52–58. doi: 10.1038/nature719. [DOI] [PubMed] [Google Scholar]
  • 50.Peier A.M., Moqrich A., Hergarden A.C., Reeve A.J., Andersson D.A., Story G.M. A TRP channel that senses cold stimuli and menthol. Cell. 2002;108:705–715. doi: 10.1016/S0092-8674(02)00652-9. [DOI] [PubMed] [Google Scholar]
  • 51.Hall A.C., Turcotte C.M., Betts B.A., Yeung W.Y., Agyeman A.S., Burk L.A. Modulation of human GABAA and glycine receptor currents by menthol and related monoterpenoids. Eur. J. Pharmacol. 2004;506:9–16. doi: 10.1016/j.ejphar.2004.10.026. [DOI] [PubMed] [Google Scholar]
  • 52.Lau B.K., Karim S., Goodchild A.K., Vaughan C.W., Drew G.M. Menthol enhances phasic and tonic GABAA receptor-mediated currents in midbrain periaqueductal grey neurons. Br. J. Pharmacol. 2014;171:2803–2813. doi: 10.1111/bph.12602. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Tani M., Onimaru H., Ikeda K., Kawakami K., Homma I. Menthol inhibits the respiratory rhythm in brainstem preparations of the newborn rats. Neuroreport. 2010;21:1095–1099. doi: 10.1097/WNR.0b013e3283405bad. [DOI] [PubMed] [Google Scholar]
  • 54.Zhang X.B., Jiang P., Gong N., Hu X.L., Fei D., Xiong Z.Q. A-type GABA receptor as a central target of TRPM8 agonist menthol. PLoS ONE. 2008;3 doi: 10.1371/journal.pone.0003386. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Turina A.V., Nolan M.V., Zygadlo J.A., Perillo M.A. Natural terpenes: self-assembly and membrane partitioning. Biophys. Chem. 2006;122:101–113. doi: 10.1016/j.bpc.2006.02.007. [DOI] [PubMed] [Google Scholar]
  • 56.Pertz H.H., Lehmann J., Roth-Ehrang R., Elz S. Effects of ginger constituents on the gastrointestinal tract: role of cholinergic M3 and serotonergic 5-HT3 and 5-HT4 receptors. Planta Med. 2011;77:973–978. doi: 10.1055/s-0030-1270747. [DOI] [PubMed] [Google Scholar]
  • 57.Ahmad B., Rehman M.U., Amin I., Arif A., Rasool S., Bhat S.A. A Review on Pharmacological Properties of Zingerone (4-(4-Hydroxy-3-methoxyphenyl)-2-butanone) Sci. World J. 2015;2015 doi: 10.1155/2015/816364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Jin Z., Lee G., Kim S., Park C.S., Park Y.S., Jin Y.H. Ginger and its pungent constituents non-competitively inhibit serotonin currents on visceral afferent neurons. Korean J. Physiol. Pharmacol. 2014;18:149–153. doi: 10.4196/kjpp.2014.18.2.149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Tramer M.R., Carroll D., Campbell F.A., Reynolds D.J., Moore R.A., McQuay H.J. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ. 2001;323:16–21. doi: 10.1136/bmj.323.7303.16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Oz M., Lozon Y., Sultan A., Yang K.H., Galadari S. Effects of monoterpenes on ion channels of excitable cells. Pharmacol. Ther. 2015;152:83–97. doi: 10.1016/j.pharmthera.2015.05.006. [DOI] [PubMed] [Google Scholar]
  • 61.Amato A., Serio R., Mule F. Involvement of cholinergic nicotinic receptors in the menthol-induced gastric relaxation. Eur. J. Pharmacol. 2014;745:129–134. doi: 10.1016/j.ejphar.2014.10.012. [DOI] [PubMed] [Google Scholar]
  • 62.Ruskin D.N., Anand R., LaHoste G.J. Chronic menthol attenuates the effect of nicotine on body temperature in adolescent rats. Nicotine Tob. Res. 2008;10:1753–1759. doi: 10.1080/14622200802443734. [DOI] [PubMed] [Google Scholar]
  • 63.Brody A.L., Mukhin A.G., La Charite J., Ta K., Farahi J., Sugar C.A. Up-regulation of nicotinic acetylcholine receptors in menthol cigarette smokers. Int. J. Neuropsychopharmacol. 2013;16:957–966. doi: 10.1017/S1461145712001022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Gaudioso C., Hao J., Martin-Eauclaire M.F., Gabriac M., Delmas P. Menthol pain relief through cumulative inactivation of voltage-gated sodium channels. Pain. 2012;153:473–484. doi: 10.1016/j.pain.2011.11.014. [DOI] [PubMed] [Google Scholar]
  • 65.Hawthorn M., Ferrante J., Luchowski E., Rutledge A., Wei X.Y., Triggle D.J. The actions of peppermint oil and menthol on calcium channel dependent processes in intestinal, neuronal and cardiac preparations. Aliment. Pharmacol. Ther. 1988;2:101–118. doi: 10.1111/j.1365-2036.1988.tb00677.x. [DOI] [PubMed] [Google Scholar]
  • 66.Sidell N., Verity M.A., Nord E.P. Menthol blocks dihydropyridine-insensitive Ca2+ channels and induces neurite outgrowth in human neuroblastoma cells. J. Cell Physiol. 1990;142:410–419. doi: 10.1002/jcp.1041420226. [DOI] [PubMed] [Google Scholar]
  • 67.Cheang W.S., Lam M.Y., Wong W.T., Tian X.Y., Lau C.W., Zhu Z. Menthol relaxes rat aortae, mesenteric and coronary arteries by inhibiting calcium influx. Eur. J. Pharmacol. 2013;702:79–84. doi: 10.1016/j.ejphar.2013.01.028. [DOI] [PubMed] [Google Scholar]
  • 68.Wondergem R., Bartley J.W. Menthol increases human glioblastoma intracellular Ca2+, BK channel activity and cell migration. J. Biomed. Sci. 2009;16 doi: 10.1186/1423-0127-16-90. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Macpherson L.J., Hwang S.W., Miyamoto T., Dubin A.E., Patapoutian A., Story G.M. More than cool: promiscuous relationships of menthol and other sensory compounds. Mol. Cell Neurosci. 2006;32:335–343. doi: 10.1016/j.mcn.2006.05.005. [DOI] [PubMed] [Google Scholar]
  • 70.Parnas M., Peters M., Dadon D., Lev S., Vertkin I., Slutsky I. Carvacrol is a novel inhibitor of Drosophila TRPL and mammalian TRPM7 channels. Cell Calcium. 2009;45:300–309. doi: 10.1016/j.ceca.2008.11.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Iturriaga-Vasquez P., Perez E.G., Slater E.Y., Bermudez I., Cassels B.K. Aporphine metho salts as neuronal nicotinic acetylcholine receptor blockers. Bioorg. Med. Chem. 2007;15:3368–3372. doi: 10.1016/j.bmc.2007.03.023. [DOI] [PubMed] [Google Scholar]
  • 72.Stotz S.C., Vriens J., Martyn D., Clardy J., Clapham D.E. Citral sensing by Transient [corrected] receptor potential channels in dorsal root ganglion neurons. PLoS ONE. 2008;3 doi: 10.1371/annotation/6ba8e9d9-0035-405e-a7c7-45ee22b2e381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Ferreira-da-Silva F.W., da Silva-Alves K.S., Alves-Fernandes T.A., Coelho-de-Souza A.N., Leal-Cardoso J.H. Effects of 1,8-cineole on Na(+) currents of dissociated superior cervical ganglia neurons. Neurosci. Lett. 2015;595:45–49. doi: 10.1016/j.neulet.2015.04.005. [DOI] [PubMed] [Google Scholar]
  • 74.Behrendt H.J., Germann T., Gillen C., Hatt H., Jostock R. Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay. Br. J. Pharmacol. 2004;141:737–745. doi: 10.1038/sj.bjp.0705652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Sherkheli M.A., Benecke H., Doerner J.F., Kletke O., Vogt-Eisele A.K., Gisselmann G. Monoterpenoids induce agonist-specific desensitization of transient receptor potential vanilloid-3 (TRPV3) ion channels. J. Pharm. Pharm. Sci. 2009;12:116–128. doi: 10.18433/J37C7K. [DOI] [PubMed] [Google Scholar]
  • 76.Takaishi M., Fujita F., Uchida K., Yamamoto S., Sawada Shimizu M., Hatai Uotsu C. 1,8-cineole, a TRPM8 agonist, is a novel natural antagonist of human TRPA1. Mol. Pain. 2012;8 doi: 10.1186/1744-8069-8-86. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Leal-Cardoso J.H., da Silva-Alves K.S., Ferreira-da-Silva F.W., dos Santos-Nascimento T., Joca H.C., de Macedo F.H. Linalool blocks excitability in peripheral nerves and voltage-dependent Na+ current in dissociated dorsal root ganglia neurons. Eur. J. Pharmacol. 2010;645:86–93. doi: 10.1016/j.ejphar.2010.07.014. [DOI] [PubMed] [Google Scholar]
  • 78.Re L., Barocci S., Sonnino S., Mencarelli A., Vivani C., Paolucci G. Linalool modifies the nicotinic receptor-ion channel kinetics at the mouse neuromuscular junction. Pharmacol. Res. 2000;42:177–182. doi: 10.1006/phrs.2000.0671. [DOI] [PubMed] [Google Scholar]
  • 79.Riera C.E., Menozzi-Smarrito C., Affolter M., Michlig S., Munari C., Robert F. Compounds from Sichuan and Melegueta peppers activate, covalently and non-covalently, TRPA1 and TRPV1 channels. Br. J. Pharmacol. 2009;157:1398–1409. doi: 10.1111/j.1476-5381.2009.00307.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Cai Z.X., Tang X.D., Wang F.Y., Duan Z.J., Li Y.C., Qiu J.J. Effect of gingerol on colonic motility via inhibition of calcium channel currents in rats. World J. Gastroenterol. 2015;21:13466–13472. doi: 10.3748/wjg.v21.i48.13466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Hitomi S., Ono K., Terawaki K., Matsumoto C., Mizuno K., Yamaguchi K. [6]-gingerol and [6]-shogaol, active ingredients of the traditional Japanese medicine hangeshashinto, relief oral ulcerative mucositis-induced pain via action on Na+ channels. Pharmacol. Res. 2017;117:288–302. doi: 10.1016/j.phrs.2016.12.026. [DOI] [PubMed] [Google Scholar]
  • 82.Beltran L.R., Dawid C., Beltran M., Gisselmann G., Degenhardt K., Mathie K. The pungent substances piperine, capsaicin, 6-gingerol and polygodial inhibit the human two-pore domain potassium channels TASK-1, TASK-3 and TRESK. Front. Pharmacol. 2013;4 doi: 10.3389/fphar.2013.00141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Seo H., Li H.Y., Perez-Reyes E., Lee J.H. Effects of eugenol on T-type Ca2+ channel isoforms. J. Pharmacol. Exp. Ther. 2013;347:310–317. doi: 10.1124/jpet.113.207936. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Damiani C.E., Moreira C.M., Zhang H.T., Creazzo T.L., Vassallo D.V. Effects of eugenol, an essential oil, on the mechanical and electrical activities of cardiac muscle. J. Cardiovasc. Pharmacol. 2004;44:688–695. doi: 10.1097/00005344-200412000-00011. [DOI] [PubMed] [Google Scholar]
  • 85.Ding J., Huang C., Peng Z., Xie Y., Deng S., Nie Y.Z. Electrophysiological characterization of methyleugenol: A novel agonist of GABA(A) receptors. ACS Chem. Neurosci. 2014;5:803–811. doi: 10.1021/cn500022e. [DOI] [PubMed] [Google Scholar]
  • 86.Lee S.H., Moon J.Y., Jung S.J., Kang J.G., Choi S.P., Jang J.H. Eugenol inhibits the GABAA current in trigeminal ganglion neurons. PLoS ONE. 2015;10 doi: 10.1371/journal.pone.0117316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Huang C.W., Chow J.C., Tsai J.J., Wu S.N. Characterizing the effects of Eugenol on neuronal ionic currents and hyperexcitability. Psychopharmacology (Berl) 2012;221:575–587. doi: 10.1007/s00213-011-2603-y. [DOI] [PubMed] [Google Scholar]
  • 88.Li H.Y., Park C.K., Jung S.J., Choi S.Y., Lee S.J., Park K. Eugenol inhibits K+ currents in trigeminal ganglion neurons. J. Dent. Res. 2007;86:898–902. doi: 10.1177/154405910708600918. [DOI] [PubMed] [Google Scholar]
  • 89.Bandell M., Story G.M., Hwang S.W., Viswanath V., Eid S.R., Petrus M.J. Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron. 2004;41:849–857. doi: 10.1016/S0896-6273(04)00150-3. [DOI] [PubMed] [Google Scholar]
  • 90.Yang B.H., Piao Z.G., Kim Y.B., Lee C.H., Lee J.K., Park K. Activation of vanilloid receptor 1 (VR1) by eugenol. J. Dent. Res. 2003;82:781–785. doi: 10.1177/154405910308201004. [DOI] [PubMed] [Google Scholar]
  • 91.Mahgoub M., Keun-Hang S.Y., Sydorenko V., Ashoor A., Kabbani N., Al Kury L. Effects of cannabidiol on the function of alpha7-nicotinic acetylcholine receptors. Eur. J. Pharmacol. 2013;720:310–319. doi: 10.1016/j.ejphar.2013.10.011. [DOI] [PubMed] [Google Scholar]
  • 92.Ahrens J., Demir R., Leuwer M., de la Roche J., Krampfl K., Foadi N. The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alpha-1-Beta glycine receptor function. Pharmacology. 2009;83:217–222. doi: 10.1159/000201556. [DOI] [PubMed] [Google Scholar]
  • 93.Devinsky O., Cilio M.R., Cross H., Fernandez-Ruiz J., French J., Hill C. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014;55:791–802. doi: 10.1111/epi.12631. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94.Sultan A., Yang K.S., Isaev D., Nebrisi E.E., Syed N., Khan N. Thujone inhibits the function of alpha7-nicotinic acetylcholine receptors and impairs nicotine-induced memory enhancement in one-trial passive avoidance paradigm. Toxicology. 2017;384:23–32. doi: 10.1016/j.tox.2017.04.005. [DOI] [PubMed] [Google Scholar]
  • 95.Czyzewska M.M., Mozrzymas J.W. Monoterpene alpha-thujone exerts a differential inhibitory action on GABA(A) receptors implicated in phasic and tonic GABAergic inhibition. Eur. J. Pharmacol. 2013;702:38–43. doi: 10.1016/j.ejphar.2013.01.032. [DOI] [PubMed] [Google Scholar]
  • 96.Sadraei H., Asghari G., Jalali F. Assessment of hydroalcoholic and hexane extracts of Rosa persica Mich. flower on rat ileum spasm. Res. Pharm. Sci. 2016;11:160–167. [PMC free article] [PubMed] [Google Scholar]
  • 97.Jarvis G.E., Barbosa R., Thompson A.J. Noncompetitive Inhibition of 5-HT3 Receptors by Citral, Linalool, and Eucalyptol Revealed by Nonlinear Mixed-Effects Modeling. J. Pharmacol. Exp. Ther. 2016;356:549–562. doi: 10.1124/jpet.115.230011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Hales T.G., Lambert J.J. The actions of propofol on inhibitory amino acid receptors of bovine adrenomedullary chromaffin cells and rodent central neurones. Br. J. Pharmacol. 1991;104:619–628. doi: 10.1111/j.1476-5381.1991.tb12479.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 99.Barann M., Dilger J.P., Bonisch H., Gothert M., Dybek A., Urban B.W. Inhibition of 5-HT3 receptors by propofol: equilibrium and kinetic measurements. Neuropharmacology. 2000;39:1064–1074. doi: 10.1016/S0028-3908(99)00205-1. [DOI] [PubMed] [Google Scholar]
  • 100.Garcia D.A., Bujons J., Vale C., Sunol C. Allosteric positive interaction of thymol with the GABAA receptor in primary cultures of mouse cortical neurons. Neuropharmacology. 2006;50:25–35. doi: 10.1016/j.neuropharm.2005.07.009. [DOI] [PubMed] [Google Scholar]
  • 101.Lansdell S.J., Sathyaprakash C., Doward A., Millar N.S. Activation of human 5-hydroxytryptamine type 3 receptors via an allosteric transmembrane site. Mol. Pharmacol. 2015;87:87–95. doi: 10.1124/mol.114.094540. [DOI] [PubMed] [Google Scholar]
  • 102.Ding M., Leach M., Bradley H. The effectiveness and safety of ginger for pregnancy-induced nausea and vomiting: a systematic review. Women Birth. 2013;26:e26–e30. doi: 10.1016/j.wombi.2012.08.001. [DOI] [PubMed] [Google Scholar]
  • 103.Haniadka R., Saldanha E., Sunita V., Palatty P.L., Fayad R., Baliga M.S. A review of the gastroprotective effects of ginger (Zingiber officinale Roscoe) Food Funct. 2013;4:845–855. doi: 10.1039/c3fo30337c. [DOI] [PubMed] [Google Scholar]
  • 104.Ernst E., Pittler M.H. Efficacy of ginger for nausea and vomiting: a systematic review of randomized clinical trials. Br. J. Anaesth. 2000;84:367–371. doi: 10.1093/oxfordjournals.bja.a013442. [DOI] [PubMed] [Google Scholar]
  • 105.Marx W.M., Teleni L., McCarthy A.L., Vitetta L., McKavanagh D., Thomson D. Ginger (Zingiber officinale) and chemotherapy-induced nausea and vomiting: a systematic literature review. Nutr. Rev. 2013;71:245–254. doi: 10.1111/nure.12016. [DOI] [PubMed] [Google Scholar]
  • 106.Abdel-Aziz H., Windeck T., Ploch M., Verspohl E.J. Mode of action of gingerols and shogaols on 5-HT3 receptors: binding studies, cation uptake by the receptor channel and contraction of isolated guinea-pig ileum. Eur. J. Pharmacol. 2006;530:136–143. doi: 10.1016/j.ejphar.2005.10.049. [DOI] [PubMed] [Google Scholar]
  • 107.Kawai T., Kinoshita K., Koyama K., Takahashi K. Anti-emetic principles of Magnolia obovata bark and Zingiber officinale rhizome. Planta Med. 1994;60:17–20. doi: 10.1055/s-2006-959399. [DOI] [PubMed] [Google Scholar]
  • 108.Yang Y., Kinoshita K., Koyama K., Takahashi K., Kondo S., Watanabe K. Structure-antiemetic-activity of some diarylheptanoids and their analogues. Phytomedicine. 2002;9:146–152. doi: 10.1078/0944-7113-00091. [DOI] [PubMed] [Google Scholar]
  • 109.Walstab J., Kruger D., Stark T., Hofmann T., Demir I.E., Ceyhan G.O. Ginger and its pungent constituents non-competitively inhibit activation of human recombinant and native 5-HT3 receptors of enteric neurons. Neurogastroenterol. Motil. 2013;25:439–447. doi: 10.1111/nmo.12107. [DOI] [PubMed] [Google Scholar]
  • 110.Lohning A.E., Marx W., Isenring L. In silico investigation into the interactions between murine 5-HT3 receptor and the principle active compounds of ginger (Zingiber officinale) J. Mol. Graph. Model. 2016;70:315–327. doi: 10.1016/j.jmgm.2016.10.008. [DOI] [PubMed] [Google Scholar]
  • 111.Darmani N.A., Chebolu S., Zhong W., Trinh C., McClanahan B., Brar R.S. Additive antiemetic efficacy of low-doses of the cannabinoid CB(1/2) receptor agonist Delta(9)-THC with ultralow-doses of the vanilloid TRPV1 receptor agonist resiniferatoxin in the least shrew (Cryptotis parva) Eur. J. Pharmacol. 2014;722:147–155. doi: 10.1016/j.ejphar.2013.08.051. [DOI] [PubMed] [Google Scholar]
  • 112.Koo M.S., Kim K.S., Lee H.J., Jeong J.S., Lee J.W. Antiemetic efficacy of capsicum plaster on acupuncture points in patients undergoing thyroid operation. Korean J. Anesthesiol. 2013;65:539–543. doi: 10.4097/kjae.2013.65.6.539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 113.Dezieck L., Hafez Z., Conicella A., Blohm E., O’Connor M.J., Schwarz E.S. Resolution of cannabis hyperemesis syndrome with topical capsaicin in the emergency department: A case series. Clin. Toxicol. (Phila) 2017;55:908–913. doi: 10.1080/15563650.2017.1324166. [DOI] [PubMed] [Google Scholar]
  • 114.Pelissier F., Claudet I., Gandia-Mailly P., Benyamina A., Franchitto N. Use of Capsaicin Cream in Cannabis Hyperemesis Syndrome. J. Emerg. Med. 2017;52:760–761. doi: 10.1016/j.jemermed.2017.01.046. [DOI] [PubMed] [Google Scholar]
  • 115.Deiml T., Haseneder R., Zieglgansberger W., Rammes G., Eisensamer B., Rupprecht R. Alpha-thujone reduces 5-HT3 receptor activity by an effect on the agonist-reduced desensitization. Neuropharmacology. 2004;46:192–201. doi: 10.1016/j.neuropharm.2003.09.022. [DOI] [PubMed] [Google Scholar]
  • 116.Slatkin N.E. Cannabinoids in the treatment of chemotherapy-induced nausea and vomiting: Beyond prevention of acute emesis. J. Support Oncol. 2007;5:1–9. [PubMed] [Google Scholar]
  • 117.Izzo A.A., Borrelli F., Capasso R., Di Marzo V., Mechoulam R. Non-psychotropic plant cannabinoids: New therapeutic opportunities from an ancient herb. Trends Pharmacol. Sci. 2009;30:515–527. doi: 10.1016/j.tips.2009.07.006. [DOI] [PubMed] [Google Scholar]
  • 118.Mechoulam R., Peters M., Murillo-Rodriguez E., Hanus L.O. Cannabidiol--recent advances. Chem. Biodivers. 2007;4:1678–1692. doi: 10.1002/cbdv.200790147. [DOI] [PubMed] [Google Scholar]
  • 119.Pertwee R.G. Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br. J. Pharmacol. 2009;156:397–411. doi: 10.1111/j.1476-5381.2008.00048.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 120.Scuderi C., Filippis D.D., Iuvone T., Blasio A., Steardo A., Esposito G. Cannabidiol in medicine: a review of its therapeutic potential in CNS disorders. Phytother. Res. 2009;23:597–602. doi: 10.1002/ptr.2625. [DOI] [PubMed] [Google Scholar]
  • 121.Yang K.H., Galadari S., Isaev D., Petroianu G., Shippenberg T.S., Oz M. The nonpsychoactive cannabinoid cannabidiol inhibits 5-hydroxytryptamine3A receptor-mediated currents in Xenopus laevis oocytes. J. Pharmacol. Exp. Ther. 2010;333:547–554. doi: 10.1124/jpet.109.162594. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 122.Ueta K., Suzuki T., Sugimoto M., Uchida I., Mashimo T. Local anesthetics have different mechanisms and sites of action at recombinant 5-HT3 receptors. Reg. Anesth. Pain Med. 2007;32:462–470. doi: 10.1097/00115550-200711000-00002. [DOI] [PubMed] [Google Scholar]

Articles from Molecules are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

RESOURCES