CBD Oil For Nausea

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Regulation of nausea and vomiting by cannabinoids Considerable evidence demonstrates that manipulation of the endocannabinoid system regulates nausea and vomiting in humans and other animals. The CBD oil, or cannabidiol, is a natural compound found in marijuana and another related plant, hemp. Unlike THC, another compound in the marijuana plant, CBD doesn't cause a "high." However, it may help reduce nausea and other unpleasant…

Regulation of nausea and vomiting by cannabinoids

Considerable evidence demonstrates that manipulation of the endocannabinoid system regulates nausea and vomiting in humans and other animals. The anti-emetic effect of cannabinoids has been shown across a wide variety of animals that are capable of vomiting in response to a toxic challenge. CB1 agonism suppresses vomiting, which is reversed by CB1 antagonism, and CB1 inverse agonism promotes vomiting. Recently, evidence from animal experiments suggests that cannabinoids may be especially useful in treating the more difficult to control symptoms of nausea and anticipatory nausea in chemotherapy patients, which are less well controlled by the currently available conventional pharmaceutical agents. Although rats and mice are incapable of vomiting, they display a distinctive conditioned gaping response when re-exposed to cues (flavours or contexts) paired with a nauseating treatment. Cannabinoid agonists (Δ 9 -THC, HU-210) and the fatty acid amide hydrolase (FAAH) inhibitor, URB-597, suppress conditioned gaping reactions (nausea) in rats as they suppress vomiting in emetic species. Inverse agonists, but not neutral antagonists, of the CB1 receptor promote nausea, and at subthreshold doses potentiate nausea produced by other toxins (LiCl). The primary non-psychoactive compound in cannabis, cannabidiol (CBD), also suppresses nausea and vomiting within a limited dose range. The anti-nausea/anti-emetic effects of CBD may be mediated by indirect activation of somatodendritic 5-HT1A receptors in the dorsal raphe nucleus; activation of these autoreceptors reduces the release of 5-HT in terminal forebrain regions. Preclinical research indicates that cannabinioids, including CBD, may be effective clinically for treating both nausea and vomiting produced by chemotherapy or other therapeutic treatments.

LINKED ARTICLES

This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-7

Keywords: emesis, vomiting, nausea, gaping, conditioned disgust, taste reactivity, cannabinoid, cannabidiol, 5-hydroxytryptamine, serotonin

Introduction

A major advance in the control of acute emesis in chemotherapy treatment was the finding that blockade of one subtype of the 5-hydroxytryptamine (5-HT) receptor, the 5-HT3 receptor, could suppress the acute emetic response (retching and vomiting) induced by cisplatin in the ferret and the shrew (Costall et al., 1986; Miner and Sanger, 1986; Ueno et al., 1987; Matsuki et al., 1988; Torii et al., 1991). In clinical trials with humans, treatment with 5-HT3 antagonists often combined with the corticosteroid dexamethasone during the first chemotherapy treatment reduced the incidence of acute vomiting by approximately 70% (e.g. Bartlett and Koczwara, 2002; Aapro et al., 2003; Ballatori and Roila, 2003; Hickok et al., 2003; Andrews and Horn, 2006). However, the 5-HT3 antagonists are less effective at suppressing acute nausea than they are at suppressing acute vomiting (Morrow and Dobkin, 1988; Bartlett and Koczwara, 2002; Hickok et al., 2003) and they are ineffective at reducing instances of delayed (24 h later) nausea and vomiting (Morrow and Dobkin, 1988; Grelot et al., 1995; Rudd et al., 1996; Rudd and Naylor, 1996; Tsukada et al., 2001; Hesketh et al., 2003) and anticipatory (conditioned) nausea and vomiting (Nesse et al., 1980; Morrow and Dobkin, 1988; Hickok et al., 2003).

More recently, NK1 receptor antagonists (e.g. aprepitant) have been developed that not only decrease acute vomiting, but also decrease delayed vomiting induced by cisplatin-based chemotherapy (Van Belle et al., 2002); however, these compounds alone and in combination with 5-HT3 antagonist/dexamethasone treatment are also much less effective in reducing nausea (e.g. Hickok et al., 2003; Andrews and Horn, 2006; Slatkin, 2007), which is the symptom reported to be the most distressing to patients undergoing treatment with 5-HT3 antagonists (deBoer-Dennert et al., 1997). Considerable evidence suggests that another system that may be an effective target for treatment of chemotherapy-induced nausea, delayed nausea/vomiting and anticipatory nausea (AN)/vomiting is the endocannabinoid system (e.g. for review, Parker and Limebeer, 2008).

Anti-emetic effects of cannabinoids in human clinical trials

The cannabis plant has been used for several centuries for a number of therapeutic applications (Mechoulam, 2005), including the attenuation of nausea and vomiting. Ineffective treatment of chemotherapy-induced nausea and vomiting prompted oncologists to investigate the anti-emetic properties of cannabinoids in the late 1970s and early 1980s, before the discovery of the 5-HT3 antagonists. The first cannabinoid agonist, nabilone (Cesamet), which is a synthetic analogue of Δ 9 -THC was specifically licensed for the suppression of nausea and vomiting produced by chemotherapy. Furthermore, synthetic Δ 9 -THC, dronabinol, entered the clinic as Marinol in 1985 as an anti-emetic and in 1992 as an appetite stimulant (Pertwee, 2009). In these early studies, several clinical trials compared the effectiveness of Δ 9 -THC with placebo or other anti-emetic drugs. Comparisons of oral Δ 9 -THC with existing anti-emetic agents generally indicated that Δ 9 -THC was at least as effective as the dopamine antagonists, such as prochlorperazine (Carey et al., 1983; Ungerleider et al., 1984; Crawford and Buckman, 1986; Cunningham et al., 1988; Tramer et al., 2001; Layeeque et al., 2006).

There is some evidence that cannabis-based medicines may be effective in treating the more difficult to control symptoms of nausea and delayed nausea and vomiting in children. Abrahamov et al. (1995) evaluated the anti-emetic effectiveness of Δ 8 -THC, a close but less psychoactive relative of Δ 9 -THC, in children receiving chemotherapy treatment. Two hours before the start of each cancer treatment and every six hours thereafter for 24 h, the children were given Δ 8 -THC as oil drops on the tongue or in a bite of food. After a total of 480 treatments, the only side effects reported were slight irritability in two of the youngest children (3.5 and 4 years old); both acute and delayed nausea and vomiting were controlled.

Surprisingly, only one reported clinical trial (Meiri et al., 2007) has compared the anti-emetic/anti-nausea effects of cannabinoids with those of the more recently developed 5-HT3 antagonists and none has compared cannabinoids with the NK1 antagonist, aprepitant. Meiri et al. (2007) compared the efficacy and tolerability of dronabinol, ondansetron or the combination for delayed chemotherapy-induced nausea and vomiting in a 5 day, double-blind, placebo-controlled study. Patients that were receiving moderately to highly emetogenic chemotherapy were all given both dexamethasone and ondansetron, with half also receiving placebo and half receiving dronabinol prechemotherapy on Day 1. On Days 2–5, they received placebo, dronabinol, ondansetron or both dronabinol and ondansetron. The results of the study indicated that the efficacy of dronabinol alone was comparable with ondansetron in the treatment of delayed nausea and vomiting, for the total response of no vomiting/retching and nausea less than 5 mm on a visual analogue scale. Rates of absence of nausea were 71% with dronabinol, 64% with ondansetron and 15% with placebo; also the dronabinol group reported the lowest nausea intensity on a visual analogue scale (10.1 mm vs. 24 mm with ondansetron and 48.4 mm with placebo). However, the combined treatment (ondansetron and dronabinol) was no more effective than either agent alone. The dose of dronabinol used in the present study was at least 50% less than in previous studies resulting in a low incidence of CNS-related adverse effects, which did not differ from the incidence in the ondansetron-treated group. Although the study was not explicitly designed to evaluate the effects of combined therapy on acute nausea and vomiting, the combined active treatment group reported less nausea and vomiting on the chemotherapy treatment day than the placebo group.

All reported clinical trials for the effectiveness of cannabinoid compounds on chemotherapy-induced nausea and vomiting have involved oral use of cannabinoids, which may be less effective than sublingual or inhaled cannabinoids, given the need to titrate the dose (Hall et al., 2005). Recently, in 2005, Sativex (GW Pharmaceuticals), a combination of Δ 9 -THC and the non-psychoactive plant cannabinoid, cannabidiol (CBD), was made available as a sublingual spray for the relief of neuropathic pain in patients with multiple sclerosis and in cancer patients with advanced pain (Johnson et al., 2010). However, to the best of our knowledge, the effectiveness of this compound in reducing nausea and vomiting has not been evaluated. Many patients have a strong preference for smoked marijuana over the synthetic cannabinoids delivered orally (Tramer et al., 2001). Several reasons for this have been suggested: (i) advantages of self-titration with the smoked marijuana; (ii) difficulty in swallowing the pills while experiencing emesis; (iii) faster speed of onset for the inhaled or injected Δ 9 -THC than oral delivery; (iv) a combination of the action of other cannabinoids with THC that are found in marijuana. Although many marijuana users have claimed that smoked marijuana is a more effective anti-emetic than oral THC, no controlled studies have yet been published that evaluate this possibility.

Effects of cannabinoids on vomiting in animal models

To evaluate the anti-emetic potential of drug therapies, animal models have been developed. Since rats and mice do not vomit in response to a toxin challenge, it is necessary to use other animal models of vomiting. There is considerable evidence that cannabinoids attenuate vomiting in emetic species (reviewed in Parker et al., 2005; Parker and Limebeer, 2008). Cannabinoid agonists have been shown to reduce vomiting in cats (McCarthy and Borison, 1981), pigeons (Feigenbaum et al., 1989; Ferrari et al., 1999), ferrets (Simoneau et al., 2001; Van Sickle et al., 2001; 2003; 2005;), least shrews, Cryptotis parva (Darmani, 2001a,b,c; 2002; Darmani and Johnson, 2004; Darmani et al., 2005; Ray et al., 2009; Wang et al., 2009) and the house musk shrew, Suncus murinus (Kwiatkowska et al., 2004; Parker et al., 2004). As well as attenuating acute vomiting produced by cisplatin, Δ 9 -THC also attenuates delayed vomiting in the least shrew (Ray et al., 2009).

Anti-emetic effect of cannabinoids: mechanisms of action

The mechanism of action of the suppression of nausea and vomiting produced by cannabinoids has recently been explored with the discovery of the endocannabinoid system and the development of animal models of nausea and vomiting. Recent reviews on the gastrointestinal effects of cannabinoids have concluded that cannabinoid agonists act mainly via peripheral CB1 receptors to decrease intestinal motility (Pertwee, 2001), but may act centrally to attenuate emesis (Van Sickle et al., 2001). The dorsal vagal complex (DVC) is involved in the vomiting reactions induced by either vagal gastrointestinal activation or several humoral cytotoxic agents. The DVC is considered to be the starting point of a final common pathway for the induction of emesis in vomiting species. The DVC consists of the area postrema (AP), nucleus of the solitary tract (NTS) and the dorsal motor nucleus of the vagus (DMNX) in the brainstem of rats, ferrets and the least shrew. CB1 receptors, as well as the catabolic enzyme of anandamide, fatty acid amide hydroxyslase (FAAH), have been found in areas of the brain involved in emesis, including the DMNX (Van Sickle et al., 2001).

CB1 receptors in the NTS are activated by Δ 9 -THC and this activation is blocked by the selective CB1 antagonist/inverse agonists, SR-141716, known as rimonabant (Darmani et al., 2005) and AM251 (Van Sickle et al., 2003). In fact, at higher doses than those required to reverse the anti-emetic effects of Δ 9 -THC, rimonabant produces emesis on its own in the least shrew (Darmani, 2001c) and AM-251 potentiates cisplatin-induced emesis in the ferret (Van Sickle et al., 2001). Molecular markers of activation also implicate the role of central CB1 receptors in the anti-emetic effects of Δ 9 -THC. Cisplatin pretreatment results in c-fos expression in the DMNX, specific subnuclei of the NTS and AP, which is significantly reduced by pretreatment with Δ 9 -THC (Van Sickle et al., 2001; 2003;). Endogenous cannabinoid ligands, such as anandamide and 2-arachidonyol glycerol (2-AG), as well as synthetic cannabinoids, such as WIN 55,212–2, also act on these receptors (Simoneau et al., 2001). However, Darmani and Johnson (2004) provide evidence that both central and peripheral mechanisms contribute to the actions of Δ 9 -THC against emesis produced by 5-hydroxytryptophan (5-HTP), the precursor to 5-HT in the least shrew. At lower doses, Δ 9 -THC acts centrally as an anti-emetic, but at higher doses (10 mg·kg −1 ) it acts peripherally.

Although anandamide has been reported to have anti-emetic properties in the ferret (Van Sickle et al., 2001) and the least shrew (Darmani, 2002), the role of 2-AG in the regulation of nausea and vomiting is less clear. Darmani (2002) found that 2-AG (2.5–10 mg·kg −1 , i.p.) produces emesis in the least shrew, most likely via its downstream metabolites, because its emetic activity can be blocked by both rimonabant and the the COX inhibitor, indomethacin. An evaluation of changes in endocannabinoid levels elicited by cisplatin revealed that cisplatin increased levels of 2-AG in the brainstem, but decreased intestinal levels of both 2-AG and anandamide (Darmani et al., 2005). Darmani et al. (2005) suggested that the central elevation of 2-AG may contribute to the emetic potential of cisplatin (in addition to mobilizing the release of known emetic stimuli such as 5-HT, dopamine and substance P). On the other hand, Van Sickle et al. (2005) reported that 2-AG is anti-emetic in ferrets treated with the emetogenic agent morphine-6-glucuronide (M6G). CB2 receptors in the brainstem may play a role in the regulation of emesis by 2-AG, at least when CB1 receptors are co-stimulated. The anti-emetic effects of 2-AG (0.5–2.0 mg·kg −1 ) in ferrets were reversed by both CB1 (AM251) and CB2 (AM630) antagonists, but the anti-emetic effects of anandamide were only reversed by AM251. Therefore, 2-AG, unlike anandamide, may selectively activate these brainstem CB2 receptors (Van Sickle et al., 2005). Finally, consistent with the anti-emetic effects of 2-AG in the ferret, the monoacylglycerol-lipase (MAGL) inhbitior, JZL-184 (Long et al., 2009a,b;), which elevates endogenous 2-AG, dose-dependently suppresses vomiting in the S. murinus (Sticht et al., 2010). Furthermore, in vitro data revealed that JZL 184 inhibited MAGL expression in shrew tissue.

The FAAH inhibitor, URB597, alone and in combination with exogenously administered anandamide has been shown to interfere with vomiting produced by M6G in the ferret (Van Sickle et al., 2005; Sharkey et al., 2007) and with nicotine and cisplatin in S. murinus (Parker et al., 2009a). Although inhibition of FAAH elevates multiple endocannabinoid-like molecules that show activity at multiple target receptors, the anti-emetic effects of URB 597 were reversed by pretreatment with rimonabant, indicating a CB1 mechanism of action. There may be a species difference in this effect, because URB597 (5 or 10 mg·kg −1 ) administered to the least shrew did not modify toxin-induced vomiting (Darmani et al., 2005); yet in this latter study URB597 was administered only 10 min prior to cisplatin at a time that may not have produced sufficient inhibition of FAAH prior to the onset of the toxin effect (Fegley et al., 2005). In experiments with the S. murinus, a much lower dose (0.9 mg·kg −1 ) administered 2 h prior to the toxin challenge suppressed vomiting.

A relative of the cannabinoid system, vanilloid TRPV1 receptors have recently been shown to regulate emesis in the ferret (Sharkey et al., 2007). The TRPV1 receptor is targeted by capsaicin (the burning component of chili peppers) as well as resiniferatoxin, which can produce pro-emetic and anti-emetic effects at similar doses in S. murinus (Andrews et al., 2000), but produces anti-emetic effects in ferrets (Andrews and Bhandari, 1993; Andrews et al., 2000; Yamakuni et al., 2002). Recent evidence indicates that anandamide and the endovanniloid, N-arachidonoyl-dopamine (NADA), are endogenous agonists for both CB1 and TRPV1 receptors (Di Marzo and Fontana, 1995; van der Stelt and DiMarzo, 2004). Extensive colocalization of CB1 and TRPV1 receptors have been demonstrated (Cristino et al., 2006). Both endogenous (anandamide, NADA) and synthetic (arvanil or O-1861) ‘hybrid’ agonists of CB1 and TRPV1 receptors have been shown to exert more potent pharmacological effects in vivo (Di Marzo et al., 2001) than ‘pure’ agonists of each receptor type, particularly when acting on cells co-expressing the two receptor types (Hermann et al., 2003). Sharkey et al. (2007) found that anandamide, NADA and arvanil were all anti-emetic in the ferret; these effects were attenuated by the CB1 receptor inverse agonist AM251 and the TRPV1 antagonists iodoresiniferatoxin and AMG9810. TRPV1 receptors were localized in the ferret NTS and were co-localized with CB1 in the mouse brainstem.

CB1/5-HT interactions

Recent findings indicate that the cannabinoid system interacts with the 5-hydroxytryptaminergic system in the control of emesis (e.g. Kimura et al., 1998). The DVC not only contains CB1 receptors, but is also densely populated with 5-HT3 receptors (Himmi et al., 1996; 1998;), potentially a site of anti-emetic effects of 5-HT3 antagonists. Cannabinoid receptors are co-expressed with 5-HT3 receptors in some neurones in the CNS (Hermann et al., 2002). The first evidence of an interaction between cannabinoids and 5-HT3 receptors was revealed by the finding that anandamide, WIN55 212 and CP55940 inhibit 5-HT3 receptor-mediated inward currents with IC50 values in the nanomolar concentration range in rat nodose ganglion cells (Fan, 1995). Subsequently, Δ 9 -THC, anandamide and several synthetic cannabinoids were shown to directly inhibit currents through human 5-HT3A receptors (Barann et al., 2002). Since WIN 55,212–2 did not displace a 5-HT3 antagonist ([ 3 H]-GR65630) from the ligand binding site, the results suggest that cannabinoids inhibit 5-HT3A receptors noncompetitively by binding to an allosteric modulatory site of the receptor (Barann et al., 2002). Indeed, anandamide produced analgesia in CB1/CB2 knockout mice that was prevented by pretreatment with the 5-HT3 antagonist, ondansetron (Racz et al., 2008). In the regulation of vomiting, low doses of Δ 9 -THC and ondansetron that were ineffective alone completely suppressed cisplatin-induced vomiting in the S. murinus (Kwiatkowska et al., 2004) and the combination of low doses of tropisetron and Δ 9 -THC were more efficacious in reducing emesis frequency in the least shrew than when given individually (Wang et al., 2009). Additionally, cannabinoids have been shown to reduce the ability of 5-HT3 agonists to produce emesis (Darmani and Johnson, 2004) and this effect was prevented by pretreatment with rimonabant. Cannabinoids may act at CB1 presynaptic receptors to inhibit the release of newly synthesized 5-HT (Schlicker and Kathmann, 2001; Howlett et al., 2002; Darmani and Johnson, 2004). Indeed, Darmani et al. (2003) reported that rimonabant (which produces vomiting in the least shrew) increases brain 5-HT levels and turnover at doses that induce vomiting in the shrew.

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CBD: a special case

Another major cannabinoid found in marijuana is CBD. Unlike Δ 9 -THC, CBD does not produce intoxicating effects and has a low affinity for the CB1 and CB2 receptors (Mechoulam et al., 2002). At a low dose, CBD (5 mg·kg −1 , i.p.) inhibits cisplatin-induced (Kwiatkowska et al., 2004) and LiCl-induced (Parker et al., 2004) vomiting and anticipatory retching (Parker et al., 2006) in S. murinus. As has been reported by others (e.g. Pertwee, 2004), the effects of CBD are biphasic with high doses (20–40 mg·kg −1 , i.p.) potentiating toxin-induced vomiting in the S. murinus (Parker et al., 2004; Kwiatkowska et al., 2004), but a dose as high as 20 mg·kg −1 of CBD had no effect on 2-AG-induced emesis in the least shrew (Darmani, 2002). A wide range of doses was not effective in reducing motion-induced emesis in the S. murinus (Cluny et al., 2008), which may reflect a different mechanism of action of motion and toxin-induced vomiting (Cluny et al., 2008).

The anti-emetic effect of CBD does not appear to be mediated by its action at CB1 receptors, because it is not reversed by the CB1 antagonist, rimonabant (Kwiatkowska et al., 2004; Parker et al., 2004). Recent evidence indicates that CBD may act as an indirect agonist on the 5-HT1A autoreceptors, to reduce the availability of 5-HT (Russo et al., 2005; E.M. Rock et al., unpubl. obs.). Known 5-HT1A autoreceptor agonists such as 8-OH-DPAT, buspirone, and > LY228729, have been found to suppress vomiting in emetic species such as pigeons (Wolff and Leander, 1994; 1995; 1997;), shrews (Okada et al., 1994; Andrews et al., 1996; Javid and Naylor, 2006), cats (Lucot and Crampton, 1989; Lucot, 1990) and dogs (Gupta and Sharma, 2002). Indeed, Russo et al. (2005) reported that CBD displaces the agonist [ 3 H]-8-OH-DPAT from a cloned human 5HT1A receptor in a concentration-dependent manner. Furthermore, CBD was shown to act as an agonist at the 5HT1A receptor, because, like 5HT, it increased GTP binding to the receptor coupled G protein, Gi, characteristic of a receptor agonist. Finally, the agonist CBD was shown to reduce cAMP production, characteristic of Gi activation.

Recently, our laboratory has investigated the mechanism of action for the anti-emetic effects of CBD. Consistent with previous results, CBD (5 mg·kg −1 , s.c.) was shown to be effective in suppressing vomiting in the S. murinus induced by either nicotine, LiCl or cisplatin (20 mg·kg −1 , but not 40 mg·kg −1 ). Interestingly, this CBD-induced suppression of vomiting was reversed by systemic pretreatment with the 5-HT1A antagonist WAY100135 (E.M. Rock et al., unpubl. obs.), suggesting that the anti-emetic effect of CBD may be mediated by activation of somatodendritic autoreceptors. This activation of the 5-HT1A receptors results in a reduction of the rate of firing of 5-HT neurones, ultimately reducing the release of forebrain 5-HT (Blier and de Montigny, 1987). It is this reduction in 5-HT release that is probably mediating CBD’s anti-emetic effects. In addition, a recent finding suggests that CBD may also act as an allosteric modulator of the 5-HT3 receptor (Yang et al., 2010); CBD reversibly inhibited 5-HT-evoked currents in 5-HT3A receptors expressed in Xenopus laevis oocytes in a concentration-dependent manner (1 µM), but did not alter the specific binding of a 5-HT3A antagonist. These findings suggest that allosteric inhibition of 5-HT3 receptors by CBD may also contribute to its role in the modulation of emesis.

Effects of cannabinoids on nausea in animal models

Nausea is more resistant to effective treatment with new anti-emetic agents than is vomiting (e.g. Andrews and Horn, 2006) and therefore remains a significant problem in chemotherapy treatment and as a side effect from other pharmacological therapies, such as anti-depressants. Even when the cisplatin-induced emetic response is blocked in the ferret by administration of a 5-HT3 receptor antagonist, c-fos activation still occurs in the AP, suggesting that an action here may be responsible for some of the other effects of cytotoxic drugs, such as nausea or reduced food intake (Reynolds et al., 1991). In rats, the gastric afferents respond in the same manner to physical and chemical (intragastric copper sulphate and cisplatin) stimulation that precedes vomiting in ferrets, presumably resulting in nausea that precedes vomiting (Hillsley and Grundy, 1998; Billig et al., 2001). Furthermore, 5-HT3 antagonists that block vomiting in ferrets also disrupt this preceding neural afferent reaction in rats. That is, in the rat the detection mechanism of nausea is present, but the vomiting response is absent. Nauseogenic doses of cholecystokinin and LiCl induce specific patterns of brainstem and forebrain c-fos expression in ferrets that are similar to c-fos expression patterns in rats (Reynolds et al., 1991; Billig et al., 2001). In a classic review paper, Borrison and Wang (1953) suggest that the rats’ inability to vomit can be explained as a species-adaptive neurological deficit and that, in response to emetic stimuli, the rat displays autonomic and behavioural signs corresponding to the presence of nausea, called the prodromata (salivation, papillary dilation, tachypnoea and tachycardia).

Conditioned taste avoidance: a nonselective measure of nausea in rats

The typical measure used in the literature to evaluate the nauseating potential of a drug is conditioned taste avoidance. However, taste avoidance is not only produced by nauseating doses of drugs, it is also produced by drugs that animals choose to self-administer or that establish a preference for a distinctive location (e.g. Berger, 1972; Wise et al., 1976; Reicher and Holman, 1977). In fact, when a taste is presented prior to a drug self-administration session, the strength of subsequent avoidance of the taste is a direct function of intake of the drug during the self-administration session (Wise et al., 1976; Grigson and Twining, 2002). This paradoxical phenomenon was initially interpreted as another instance of taste aversion learning. Because Garcia et al. (1974) had developed a model to account for taste aversion produced by emetic agents, it was reasonable for early investigators to assume that rewarding doses of drugs also produce taste avoidance because they produce a side effect of nausea that becomes selectively associated with a flavour (Reicher and Holman, 1977). However, in an animal capable of vomiting, the S. murinus, rewarding drugs do not produce a conditioned taste avoidance, in fact they produce a conditioned taste preference and a conditioned place preference (Parker et al., 2002a). Since rats are incapable of vomiting, it is likely that conditioned taste avoidance produced by rewarding drugs in this species is based upon a learned fear of anything that changes their hedonic state (e.g. Gamzu, 1977) when that change is paired with food previously eaten.

Another approach to understanding the role that nausea plays in the establishment of taste avoidance in rats is to evaluate the potential of anti-nausea treatments to interfere with avoidance of a flavour paired with an emetic treatment. Early work suggested that anti-nausea agents interfered with the expression of previously established taste avoidance produced by LiCl (Coil et al., 1978); however, more recent findings suggest that similar anti-nausea treatments (Goudie et al., 1982; Rabin and Hunt, 1983; Parker and McLeod, 1991) and different anti-nausea treatments (Gadusek and Kalat, 1975; Limebeer and Parker, 2000; 2003; Parker et al., 2002b; 2003;) failed to interfere with the expression of LiCl-induced taste avoidance. Furthermore, there is considerable evidence that anti-nausea treatments either do not interfere with the establishment of conditioned taste avoidance learning (Rabin and Hunt, 1983; Rudd et al., 1998; Limebeer and Parker, 2000; Parker et al., 2002b) or at least only interfere with the establishment of very weak LiCl-induced taste avoidance (Wegener et al., 1997; Gorzalka et al., 2003). Two prominent anti-nausea treatments include drugs that reduce 5-HT availability and drugs that elevate the activity of the endocannabinoid system in rats (see Parker et al., 2005; 2009b; Parker and Limebeer, 2008). These treatments interfere with the establishment and/or the expression of conditioned disgust reactions, but not conditioned taste avoidance (for review, see Parker, 2003; Parker et al., 2009b).

Conditioned gaping: a selective measure of nausea in rats

Over the past number of years, our laboratory has provided considerable evidence that conditioned nausea in rats may be displayed as conditioned disgust reactions (Parker, 1982; 1995; 1998; 2003; Limebeer and Parker, 2000; 2003; Limebeer et al., 2004; Parker et al., 2008; 2009b;) using the taste reactivity (TR) test (Grill and Norgren, 1978). Rats display a distinctive pattern of disgust reactions (including gaping, chin rubbing and paw treading) when they are intraorally infused with a bitter tasting quinine solution. Rats also display this disgust pattern when infused with a sweet tasting solution (that normally elicits hedonic reactions of tongue protrusions) that has previously been paired with a drug that produces vomiting (such as LiCl or cyclophosphamide) in species capable of vomiting. Only drugs with emetic properties produce this conditioned disgust reaction when paired with a taste.

The most reliable conditioned disgust reaction in the rat is that of gaping (Breslin et al., 1992; Parker, 2003). If conditioned gaping reflects nausea in rats, then anti-nausea drugs should interfere with this reaction. Limebeer and Parker (2000) demonstrated that when administered prior to a saccharin-LiCl pairing, the 5-HT3 antagonist, ondansetron, prevented the establishment of conditioned gaping in rats, presumably by interfering with LiCl-induced nausea. Since ondansetron did not modify unconditioned gaping elicited by bitter quinine solution, the effect was specific to nausea-induced gaping. Subsequently, Limebeer and Parker (2003) demonstrated a very similar pattern following pretreatment with the 5-HT1A autoreceptor antagonist, 8-OH-DPAT, that also reduces 5-HT availability and serves as an anti-emetic agent in animal models. Most recently, Limebeer et al. (2004) reported that lesions of the dorsal raphe nucleus (DRN) and median raphe nucleus (MRN) that reduced forebrain 5-HT availability interfered with the establishment of LiCl-induced conditioned gaping consistent with reports that reduced 5-HT availability interferes with nausea. Since rats are incapable of vomiting, we have argued that the gape represents an ‘incipient vomiting response’. The orofacial characteristics of the rat gape are very similar to those of the shrew retch just before it vomits (Parker, 2003). Indeed, Travers and Norgren (1986) suggest that the muscular movements involved in the gaping response mimic those seen in species capable of vomiting.

Effects of cannabinoids on nausea in rats

Using the conditioned gaping response as a measure of nausea in rats, we have demonstrated that a low dose (0.5 mg·kg −1 , i.p.) of Δ 9 -THC interferes with the establishment and the expression of cyclophosphamide-induced conditioned gaping (Limebeer and Parker, 1999). The potent agonist, HU-210 (0.001–0.01 mg·kg −1 ), also suppressed LiCl-induced conditioned gaping (Parker and Mechoulam, 2003; Parker et al., 2003) and this suppression was reversed by the CB1 antagonist/inverse agonist, rimonabant, suggesting that the effect of HU-210 was mediated by its action at CB1 receptors. When administered 30 min prior to the conditioning trial, rimonabant did not produce conditioned gaping on its own, but it did potentiate the ability of LiCl to produce conditioned gaping. This same pattern has been reported in the emesis literature (Van Sickle et al., 2001; Chambers et al., 2007). Van Sickle et al. (2001) reported that although the CB1 antagonist/inverse agonist AM251 did not produce vomiting on its own, it potentiated the ability of an emetic stimulus to produce vomiting in the ferret.

More compelling evidence that the endocannabinoid system may serve as a regulator of nausea is the recent finding that prolonging the duration of action of anandamide by pretreatment with URB597, a drug that inhibits the enzyme FAAH, also disrupts the establishment of LiCl-induced conditioned gaping reactions in rats (Cross-Mellor et al., 2007). Rats pretreated with URB597 (0.3 mg·kg −1 , i.p.) 2 h prior to a saccharin-LiCl pairing displayed suppressed conditioned gaping reactions in a subsequent drug free test. Rats given the combination of URB597 (0.3 mg·kg −1 , i.p.) and anandamide (5 mg·kg −1 , i.p.) displayed even greater suppression of conditioned gaping reactions. Although inhibition of FAAH produces an elevation of a variety of fatty acids that act at different receptors, the effect of URB597 on conditioned nausea was reversed by AM251, indicating that it was mediated by CB1 receptors.

At doses (greater than 4 mg·kg −1 ) that effectively suppress feeding in rats, the CB1 antagonist/inverse agonist AM251 produces conditioned gaping reactions when explicitly paired with saccharin solution (McLaughlin et al., 2005) reflective of nausea. This finding suggests that the appetite suppressant effect of the newly marketed CB1 antagonist/inverse agonist, rimonabant, may be partially mediated by the side effect of nausea, which is the most commonly reported side effect in human randomized control trials (Pi-Sunyer et al., 2006). On the other hand, the silent CB1 antagonists, AM4113 and AM6527, which do not have inverse agonist properties, do not produce conditioned gaping (Sink et al., 2007; Limebeer et al., 2010). In addition, the peripherally restricted silent CB1 antagonist, AM6545, which also suppresses feeding at equivalent doses of AM251 (Cluny et al., 2010; Randall et al., 2010; Tam et al., 2010), does not produce the side effect of nausea (Cluny et al., 2010). Finally, neither the silent antagonist, AM6527 (which crosses the blood–brain barrier) nor AM6545 (with limited CNS penetration), potentiate LiCl-induced nausea, an effect evident with low doses (2.5 mg·kg −1 ) of systemic administration of AM-251 (Limebeer et al., 2010). AM251-induced conditioned nausea is thus mediated by inverse agonism of the CB1 receptor. This effect may be mediated peripherally, because intracranial administration of AM251 at doses up to 1/10 the peripheral dose into the lateral ventricle or the 4th ventricle did not potentiate LiCl-induced nausea that is evident with systemic administration of this inverse agonist of the CB1 receptor.

CBD reduces nausea by a non-cannabinoid mechanism of action

In addition, the non-intoxicating compound found in marihuana smoke, CBD (5 mg·kg −1 , i.p.) as well as its synthetic dimethylheptyl homologue (5 mg·kg −1 , i.p.), suppresses the establishment and the expression of LiCl-induced conditioned gaping (Parker et al., 2002b; Parker and Mechoulam, 2003). Recent research (Rock et al., 2010) demonstrates that the anti-nausea effects of CBD (5 mg·kg −1 , s.c.) are suppressed by systemic pretreatment with the 5-HT1A receptor antagonist WAY100135 (10 mg·kg −1 , i.p.). In addition, the more selective 5-HT1A receptor antagonist, WAY100635, administered systemically (0.1 mg·kg −1 , i.p.) or intracranially (21 ng in 0.5 µL) into the DRN, a site of somatodendritic 5-HT1A autoreceptors, interferes with the CBD-induced suppression of LiCl-induced conditioned gaping in rats. This effect was selective to receptors located in the DRN, as those rats with misplaced cannulae that received CBD outside of the DRN did not show a similar effect. In addition, when administered directly into the DRN, CBD (10 µg·µL −1 ) suppressed LiCl-induced gaping. These results suggest that CBD produces its anti-emetic/anti-nausea effects by activation of somatodentritic autoreceptors located in the DRN, reducing the release of forebrain 5-HT. Since depletion of forebrain 5-HT by 5,7-DHT lesions of the DRN and MRN also prevented the establishment of LiCl-induced conditioned gaping (Limebeer et al., 2004), nausea appears to be mediated by 5-HT action in forebrain regions. Research aimed at determining the forebrain regions (e.g. insular cortex) responsible for the sensation of nausea are currently being conducted in our laboratory (Tuerke et al., 2010).

Cannabinoids and AN in rats and shrews

AN often develops over the course of repeated chemotherapy sessions (Nesse et al., 1980; Morrow and Dobkin, 1988; Reynolds et al., 1991; Stockhorst et al., 1993; Aapro et al., 1994; Ballatori and Roila, 2003; Hickok et al., 2003). For instance, Nesse et al. (1980) described the case of a patient who had severe nausea and vomiting during repeated chemotherapy treatments. After his third treatment, the patient became nauseated as soon as he walked into the clinic building and noticed a ‘chemical smell’, that of isopropyl alcohol. He experienced the same nausea when returning for routine follow-up visits, even though he knew he would not receive treatment. The nausea gradually disappeared over repeated follow-up visits. Nesse et al. (1980) reported that about 44% of the patients being treated for lymphoma demonstrated such AN. AN is best understood as a classically conditioned response (CR) (Pavlov, 1927).

Control over AN could be exerted at the time of conditioning or at the time of re-exposure to the conditioned stimulus (CS). If an anti-emetic drug is presented at the time of conditioning, then a reduction in AN would be the result of an attenuated unconditioned response (UCR); that is, reduced nausea produced by the toxin at the time of conditioning thereby attenuating the establishment of the CR. Indeed, when administered during the chemotherapy session, the 5-HT3 antagonist, granisetron, has been reported to reduce the incidence of AN in repeat cycle chemotherapy treatment (Aapro et al., 1994). On the other hand, if a drug is delivered prior to re-exposure to cues previously paired with the toxin-induced nausea, then suppressed AN would be the result of attenuation of the expression of the CR (conditioned nausea); the 5-HT3 antagonists are ineffective at this stage (Nesse et al., 1980; Morrow and Dobkin, 1988; Reynolds et al., 1991; Stockhorst et al., 1993; Aapro et al., 1994; Ballatori and Roila, 2003; Hickok et al., 2003).

Anecdotal evidence suggests that Δ 9 -THC alleviates AN in chemotherapy patients (Grinspoon and Bakalar, 1993; Iversen, 2000). Although there has been considerable experimental investigation of unconditioned retching and vomiting in response to toxins, there have been relatively few reports of conditioned retching; that is, emetic reactions elicited by re-exposure to a toxin paired cue. Conditioned retching has been observed to occur in coyotes, wolves and hawks upon re-exposure to cues previously paired with lithium-induced toxicosis (Garcia et al., 1977) and ferrets have been reported to display conditional emetic reactions during exposure to a chamber previously paired with lithium-induced toxicosis (Davey and Biederman, 1998).

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The S. murinus displays conditioned retching when returned to a chamber previously paired with a dose of lithium that produced vomiting (Parker and Kemp, 2001). Furthermore, this conditioned retching reaction is suppressed by pretreatment with Δ 9 -THC. This effect was replicated more recently and extended to demonstrate that CBD also interferes with the expression of conditioned retching in the shrew, but the 5-HT3 antagonist ondansetron was completely ineffective (Parker et al., 2006). The doses employed were selected on the basis of their potential to interfere with toxin-induced vomiting in the S. murinus (Kwiatkowska et al., 2004, Parker et al., 2004).

Rats also display conditioned gaping reactions when re-exposed to a context previously paired with LiCl-induced nausea (Limebeer et al., 2006; 2008; Rock et al., 2008). Following four pairings of a distinctive, vanilla odour-laced chamber with LiCl-induced illness, rats were returned to the context for 30 min and received a 1 min intraoral infusion of novel saccharin solution every 5 min. During the infusions, the rats displayed gaping reactions. Surprisingly, the rats also gaped during intervals when they were not being infused with saccharin while in the LiCl-paired context. It was further demonstrated that Δ 9 -THC, but not ondansetron, interfered with the conditioned gaping response during both infusion and inter-infusion intervals.

The finding that rats express conditioned gaping responses when re-exposed to an odour-laced context previously paired with LiCl during inter-infusion intervals (Limebeer et al., 2006) suggests that LiCl-paired cues in the absence of the flavour can elicit conditioned nausea. Meachum and Bernstein (1992) had previously shown the re-exposure to a lithium-paired odour cue elicited gaping reactions in rats. Recently, Limebeer et al. (2008) found that even in the absence of a flavoured solution or a distinctive odour, rats display conditioned gaping reactions during exposure to a distinctive context previously paired with a high dose of lithium, as well as a low dose of lithium and provocative motion. Most recently, Rock et al. (2008) reported that CBD (within a limited dose range 1–5 mg·kg −1 , but not 10 mg·kg −1 ) and the FAAH inhibitor, URB597, prevented the expression of conditioned gaping elicited by the lithium-paired context. The effect of URB597 was reversed by rimonabant, indicating a CB1 mechanism of action. Indeed, inhibition of FAAH by URB597 also prevented the establishment of LiCl-induced conditioned gaping elicited by the contextual cues when administered 2 h prior to each conditioning trial. These results suggest that cannabinoid compounds may be effective agents in the treatment of AN in chemotherapy patients.

Conclusions

Since the discovery of the mechanism of action of cannabinoids, our understanding of the role of the endocannabinoid system in the control of nausea and vomiting has greatly increased. In the ferret and shrew models, the site of action has been identified in the emetic area of the brainstem, the DVC. The shrew model, in particular, is cost effective for the evaluation of the anti-emetic properties of agents. The conditioned gaping response in the rat has provided a glimpse into the anti-nausea mechanisms of action of cannabinoids, in the absence of a vomiting response. Since nausea is a more difficult symptom to control than vomiting, the gaping model may serve as a useful tool for the development of new anti-nausea treatments, as well as for the evaluation of the potential side effects of nausea in newly developed pharmacological treatments. Recent work has also supported anecdotal reports that cannabis may attenuate AN. Using the S. murinus and the rat models of AN, both Δ 9 -THC and CBD effectively prevented conditioned retching and conditioned gaping (respectively) elicited by re-exposure to a lithium-paired chamber.

Although chemotherapy-induced vomiting is well controlled in most patients by conventionally available drugs, nausea (acute, delayed and anticipatory) continues to be a challenge. Nausea is often reported as more distressing than vomiting, because it is a continuous sensation (e.g. deBoer-Dennert et al., 1997; Andrews and Horn, 2006). Indeed, this distressing symptom of chemotherapy treatment (even when vomiting is pharmacologically controlled) can become so severe that as many as 20% of patients discontinue the treatment (Jordan et al., 2005). Both preclinical and human clinical (e.g. Abrahamov et al. 1995; Meiri et al., 2007) research suggests that cannabinoid compounds may have promise in treating nausea in chemotherapy patients.

Animal models of vomiting have been valuable in elucidating the neural mechanisms of the emetic reflex (e.g. Hornby, 2001); however, the neural mechanisms of nausea are still not well understood (Andrews and Horn, 2006). One limitation in the preclinical screening of the nauseating side effect of compounds and the potential of compounds to treat nausea has been the lack of a reliable preclinical rodent model of nausea. For years researchers have been using conditioned taste avoidance in rats as a model of nausea, but it has been well documented that non-nauseating treatments also produce taste avoidance – it is not a selective measure of nausea (e.g. Parker et al., 2008). However, the considerable amount of evidence reviewed above indicates that conditioned disgust in rats elicited by an illness-paired flavour (e.g. Parker et al., 2008) or an illness-paired context (e.g. Rock et al., 2008) represents a selective and sensitive rodent model of nausea. This model may be a useful tool for elucidating the neurobiology of nausea and the role that the endocannabinoid system plays in the regulation of this distressing condition.

Acknowledgments

This research was supported by a research grant to L.P. (92057) from the Natural Sciences and Engineering Research Council of Canada.

Glossary

Abbreviations
2-AG 2-arachidonolylglycerol
5-HT 5-hydroxytryptamine
5-HT3 5-hydroxytryptamine receptor 3
5-HT1A 5-hydroxytryptamine receptor 1A
5-HTP 5-hydroxytryptophan
5 7-DHT, 5,7-dihydroxytryptamine
8-OH-DPAT 8-hydroxy-N,N-dipropyl-2-aminotetralin
Δ 9 -THC Δ 9 -tetrahydrocannabinol
AN anticipatory nausea
AP area postrema
CB1 cannabinoid receptor 1
CB2 cannabinoid receptor 2
CBD cannabidiol
DMNX doral motor nucleus of the vagus
DRN dorsal raphe nucleus
DVC dorsal vagal complex
FAAH fatty acid amide hydrolase
Gi inhibitory G protein subunit
LiCl lithium chloride
MAGL monoacylglycerol-lipase
M6G morphine-6-glucuronide
MRN medial raphe nucleus
NADA n-arachidonoyl-dopamine
NTS nucleus of the solitary tract
S murinus, Suncus murinus
TRPV1 transient receptor potential vanilloid 1

References

  • Aapro MS, Kirchner V, Terrey JP. The incidence of anticipatory nausea and vomiting after repeat cycle chemotherapy: the effect of granisetron. Br J Cancer. 1994; 69 :957–960. [PMC free article] [PubMed] [Google Scholar]
  • Aapro MS, Thuerlimann B, Sessa C, De Pree C, Bernhard J, Maibach R, Swiss Group for Clinical Cancer Research A randomized double-blind trial to compare the clinical efficacy of granisetron with metoclopramide, both combined with dexamethasone in the prophylaxis of chemotherapy-induced delayed emesis. Ann Oncol. 2003; 14 :291–297. [PubMed] [Google Scholar]
  • Abrahamov A, Abrahamov A, Mechoulam R. An efficient new cannabinoid antiemetic in pediatric oncology. Life Sci. 1995; 56 :2097–2102. [PubMed] [Google Scholar]
  • Andrews PL, Bhandari P. Resiniferatoxin, an ultrapotent capsaicin analogue, has anti-emetic properties in the ferret. Neuropharmacology. 1993; 32 :799–806. [PubMed] [Google Scholar]
  • Andrews PL, Horn CC. Signals for nausea and emesis: implications for models diseases. Auton Neurosci. 2006; 125 :100–115. [PMC free article] [PubMed] [Google Scholar]
  • Andrews PL, Torii Y, Saito H, Matsuki N. The pharmacology of the emetic response to upper gastrointestinal tract stimulation in Suncus murinus. Eur J Pharmacol. 1996; 307 :305–313. [PubMed] [Google Scholar]
  • Andrews PL, Okada F, Woods AJ, Hagiwara H, Kakaimoto S, Toyoda M, et al. The emetic and anti-emetic effects of the capsaicin analogue resiniferatoxin in Suncus murinus, the house musk shrew. Br J Pharmacol. 2000; 130 :1247–1254. [PMC free article] [PubMed] [Google Scholar]
  • Ballatori E, Roila F. Impact of nausea and vomiting on quality of life in cancer patients during chemotherapy. Health Qual Life Outcomes. 2003; 1 :46. [PMC free article] [PubMed] [Google Scholar]
  • Barann M, Molderings G, Bruss M, Bonisch H, Urban BW, Gothert M. Direct inhibition by cannabinoids of human 5-HT3A receptors: probable involvement of an allosteric modulatory site. Br J Pharmacol. 2002; 137 :589–596. [PMC free article] [PubMed] [Google Scholar]
  • Bartlett N, Koczwara B. Control of nausea and vomiting after chemotherapy: what is the evidence? Int Med J. 2002; 32 :401–407. [PubMed] [Google Scholar]
  • Berger B. Conditioning of food aversions by injections of psychoactive drugs. J Comp Phys Psychol. 1972; 81 :21–26. [PubMed] [Google Scholar]
  • Billig I, Yates BJ, Rinaman L. Plasma hormone levels and central c-Fos expression in ferrets after systemic administration of cholecystokinin. Am J Physiol Regul Integr Comp Physiol. 2001; 281 :R1243–R1255. [PubMed] [Google Scholar]
  • Blier P, de Montigny C. Modification of 5-HT neuron properties by sustained administration of the 5-HT1A agonist gepirone: electrophysiological studies in the rat brain. Synapse. 1987; 1 :470–480. [PubMed] [Google Scholar]
  • Borrison HL, Wang SC. Physiology and pharmacology of vomiting. Pharmacol Rev. 1953; 5 :193–230. [PubMed] [Google Scholar]
  • Breslin PA, Spector AC, Grill HJ. A quantitative comparison of taste reactivity behaviors to sucrose before and after lithium chloride pairings: a unidimensional account of palatability. Behav Neurosci. 1992; 106 :820–836. [PubMed] [Google Scholar]
  • Carey MP, Burish TG, Brenner DE. Delta-9-tetrahydrocannabinol in cancer chemotherapy: research problems and issues. Ann Intern Med. 1983; 99 :106–114. [PubMed] [Google Scholar]
  • Chambers AP, Vemuri VK, Peng Y, Wood JT, Olszewska T, Pittman QJ, et al. A neutral CB1 receptor antagonist reduces weight gain in rat. Am J Physciol Regul Integr Comp Physiol. 2007; 293 :R2185–R2193. [PubMed] [Google Scholar]
  • Cluny NL, Naylor RJ, Whittle BA, Javid FA. The effects of cannabidiol and tetrahydrocannabinol on motion-induced emesis in Suncus murinus. Basic Clin Pharmacol Toxicol. 2008; 103 :150–156. [PubMed] [Google Scholar]
  • Cluny NL, Chambers AP, Limebeer CL, Keenan CM, Bedard H, Vemuri VK, et al. A novel, peripherally resitricted cannabinoid 1 (CB1) receptor antagonist AM6545 recuces food intake and body weight, but does not cause malaise in rodents. Br J Pharmacol. 2010; 161 :629–642. [PMC free article] [PubMed] [Google Scholar]
  • Coil JD, Hankins WG, Jenden DJ, Garcia J. The attenuation of a specific cue-to-consequence association by antiemetic agents. Psychopharmacology. 1978; 56 :21–25. [PubMed] [Google Scholar]
  • Costall B, Domeney AM, Naylor RJ, Tattersall FD. 5-Hydroxytryptamine receptor antagonism to prevent cisplatin-induced emesis. Neuropharmacology. 1986; 25 :959–961. [PubMed] [Google Scholar]
  • Crawford SM, Buckman R. Nabilone and metoclopramide in the treatment of nausea and vomiting due to cisplatin: a double blind study. Med Oncol Tumor Pharmacother. 1986; 3 :39–42. [PubMed] [Google Scholar]
  • Cristino L, De Petrocellis L, Pryce G, Baker D, Guglielmotti V, DiMarzo V. immunohistochemical localization of cannabinoid type 1 and vanilloid transient receptor potential vanilloid type 1 receptors in the mouse brain. Neuroscience. 2006; 139 :1405–1415. [PubMed] [Google Scholar]
  • Cross-Mellor SK, Ossenkopp KP, Piomelli D, Parker LA. Effects of the FAAH inhibitor, URB597, and anandamide on lithium-induced taste reactivity responses: a measure of nausea in the rat. Psychopharmacology. 2007; 190 :135–143. [PubMed] [Google Scholar]
  • Cunningham D, Bradley CJ, Forrest GJ, Hutcheon AW, Adams L, Sneddon M, et al. A randomized trial of oral nabilone and prochlorperazine compared to intravenous metoclopramide and dexamethasone in the treatment of nausea and vomiting induced by chemotherapy regimens containing cisplatin or cisplatin analogues. Eur J Cancer Clin Oncol. 1988; 24 :685–689. [PubMed] [Google Scholar]
  • Darmani NA. Delta-9-tetrahydrocannabinol and synthetic cannabinoids prevent emesis produced by the cannabinoid CB1 receptor antagonist/inverse agonist SR 141716A. Neuropsychopharmacology. 2001a; 24 :198–203. [PubMed] [Google Scholar]
  • Darmani NA. Delta-9-tetrahydrocannabinol differentially suppresses cisplatin-induced emesis and indices of motor function via cannabinoid CB1 receptor in the least shrew. Pharmacol Biochem Behav. 2001b; 69 :239–249. [PubMed] [Google Scholar]
  • Darmani NA. The cannabinoid CB1 receptor antagonist SR 141716A reverses the antiemetic and motor depressant actions of WIN 55, 212-2. Eur J Pharmacol. 2001c; 430 :49–58. [PubMed] [Google Scholar]
  • Darmani NA. The potent emetogenic effects of the endocannabinoid, 2-AG (2-arachidonoylglycerol) are blocked by Delta (9)-tetrahydrocannabinol and other cannabinoids. J Pharmacol Exp Ther. 2002; 300 :34–42. [PubMed] [Google Scholar]
  • Darmani NA, Johnson CJ. Central and peripheral mechanisms contribute to the antiemetic actions of delta-9-tetrahydrocannabinol against 5-hydroxytryptophan-induced emesis. Eur J Pharmacol. 2004; 488 :201–212. [PubMed] [Google Scholar]
  • Darmani NA, Janoyan JJ, Kumar N, Crim JL. Behaviorally active doses of the CB1 receptor antagonist SR 141716A increase brain serotonin and dopamine levels and turnover. Pharmacol Biochem Behav. 2003; 75 :777–787. [PubMed] [Google Scholar]
  • Darmani NA, McClanahan BA, Trinh C, Petrosino S, Valenti M, DiMarzo V. Cisplatin increases brain 2-arachidonoylglycerol (2-AG) and concomitantly reduces intestinal 2-AG and anandamide levels in the least shrew. Neuropharmacology. 2005; 49 :502–513. [PubMed] [Google Scholar]
  • Davey VA, Biederman GB. Conditioned antisickness: indirect evidence from rats and direct evidence from ferrets that conditioning alleviates drug-induced nausea and emesis. J Exp Psychol Anim Behav Process. 1998; 24 :483–491. [PubMed] [Google Scholar]
  • deBoer-Dennert M, deWit R, Schmitz I, Djontono J, Beurden V, Stoter G, et al. Patient perceptions of the side-effects of chemothareapy: the influence of 5HT3 antagonists. Br J Cancer. 1997; 76 :1055–1061. [PMC free article] [PubMed] [Google Scholar]
  • Di Marzo V, Fontana A. Anandamide, an endogenous cannabinomimetic eicosanoid: ‘killing two birds with one stone’ Prostaglandins Leukot Essent Fatty Acids. 1995; 53 :1–11. [PubMed] [Google Scholar]
  • Di Marzo V, Lastres-Becker I, Bisogno T, DePetrocellis L, Milone A, Davis JB, et al. Unsaturated long-chain N-acyl-vanillyl-amides (N-AVAMs): vanilloid receptor ligands that inhibit anandamide-facilitated transport and bind to CB1 cannabinoid receptors. Biochem Biophys Res Commun. 2001; 262 :275–284. [PubMed] [Google Scholar]
  • Fan P. Cannabinoid agonists inhibit the activation of 5-HT3 receptors in rat nodose ganglion neurons. J Neurophysiol. 1995; 73 :907–910. [PubMed] [Google Scholar]
  • Fegley D, Gaetani S, Duranti A, Tontini A, Mor M, Tarzia G, et al. Characterization of the fatty acid amide hydrolase inhibitor cyclohexyl ceramic acid 3′-carbamoyl-biphenyl-3-yl ester (URB597): effects on anandamide and oleoylethanolamide deactivation. J Pharmacol Exp Ther. 2005; 313 :352–358. [PubMed] [Google Scholar]
  • Feigenbaum JJ, Richmond SA, Weissman Y, Mechoulam R. Inhibition of cisplatin-induced emesis in the pigeon by a non-psychotropic synthetic cannabinoid. Eur J Pharmacol. 1989; 4 :159–165. [PubMed] [Google Scholar]
  • Ferrari F, Ottanik A, Giuliani D. Cannabimimetic activity in rats and pigeons of HU-210, a potent antiemetic drug. Pharmacol Biochem Behav. 1999; 62 :75–80. [PubMed] [Google Scholar]
  • Gadusek FJ, Kalat JW. Effects of scopolamine on retention of taste-aversion learning in rats. Physiol Psychol. 1975; 3 :130–132. [Google Scholar]
  • Gamzu E. The multifaceted nature of taste aversion inducing agents: is there a single common factor? In: Barker L, Domjan M, Best M, editors. Learning Mechanisms of Food Selection. Waco, TX: Baylor Univ. Press; 1977. pp. 447–511. [Google Scholar]
  • Garcia J, Hankins WG, Rusiniak KW. Behavioral regulation of the milieu interne in man and rat. Science. 1974; 185 :824–831. [PubMed] [Google Scholar]
  • Garcia J, Rusiniak KW, Brett LP. Conditioning food-illness aversions in wild animals: caveant canonici. In: Davis H, Hurowitz HMB, editors. Operant Pavlovian Interactions. Hillsdale: NJ: Lawrence Erlbaum; 1977. pp. 273–316. [Google Scholar]
  • Gorzalka B, Hanson L, Harrington J, Killam S, Campbell-Meiklejohn D. Conditioned taste aversion: modulation by 5-HT receptor activity and corticosterone. Eur J Pharamcol. 2003; 47 :129–134. [PubMed] [Google Scholar]
  • Goudie AJ, Stolerman IP, Demellweek C, D’Mello GD. Does conditioned nausea mediate drug-induced conditioned taste aversion? Psychopharmacology. 1982; 78 :277–282. [PubMed] [Google Scholar]
  • Grelot L, Milano S, LeStunff H. Does 5-HT play a role in the delayed phase of cisplatin-induced emesis? In: Reynolds J, Andrews PLR, Davis CJ, editors. Serotonin and the Scientific Basis of Anti-Emetic Therapy. Oxford: Oxford Clinical Communications; 1995. pp. 181–191. [Google Scholar]
  • Grigson PS, Twining R. Cocaine-induced suppression of saccharin intake: a model of drug-induced devaluation of natural rewards. Behav Neurosci. 2002; 116 :321–333. [PubMed] [Google Scholar]
  • Grill HC, Norgren R. The taste reactivity test. I. Mimetic responses to gustatory stimuli in neurologically normal rats. Brain Res. 1978; 143 :263–279. [PubMed] [Google Scholar]
  • Grinspoon L, Bakalar JB. Marijuana: The Forbidden Medicine. New Haven: Yale University Press; 1993. [Google Scholar]
  • Gupta YK, Sharma SS. Involvement of 5-HT1A and 5-HT2 receptor in cisplatin induced emesis in dogs. Indian J Physiol Pharmacol. 2002; 46 :463–467. [PubMed] [Google Scholar]
  • Hall W, Christie M, Currow D. Cannabinoids and cancer: causation, remediation, and palliation. Lancet Oncol. 2005; 6 :35–42. [PubMed] [Google Scholar]
  • Hermann H, Marsicano G, Lutz B. Coexpression of the cannabinoid receptor type 1 with dopamine and serotonin receptors in distinct neuronal subpopulations of the adult mouse forebrain. Neuroscience. 2002; 109 :541–460. [PubMed] [Google Scholar]
  • Hermann H, DePetrocellis L, Bisogno T, Schiano-Morello A, Lutz B, DiMarzo V. Dual effect of cannabinoid CB1 recptor stimulation on a vanniloid VR receptor-mediated response. Cell Mol Life Sci. 2003; 60 :607–616. [PubMed] [Google Scholar]
  • Hesketh PJ, Van Belle S, Aapro M, Tattersall FD, Naylor RJ, Hargreaves R, et al. Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur J Cancer. 2003; 39 :1074–1080. [PubMed] [Google Scholar]
  • Hickok JT, Roscoe JA, Morrow GR, King DK, Atkins JN, Fitch TR. Nausea and emesis remain significant problems of chemotherapy despite prophylaxis with 5-hydroxytryptamine-3 antiemetics. Cancer. 2003; 97 :2880–2886. [PubMed] [Google Scholar]
  • Hillsley K, Grundy D. Serotonin and cholecystokinin activate different populations of rat mesenteric vagal afferents. Neurosci Lett. 1998; 255 :63–66. [PubMed] [Google Scholar]
  • Himmi T, Dallaporta M, Perrin J, Orsini JC. Neuronal responses to delta9-tetrahyrocannabinol in the solitary tract nucleus. Eur J Pharmacol. 1996; 312 :273–279. [PubMed] [Google Scholar]
  • Himmi T, Perrin J, El Ouazzani T, Orsini JC. Neuronal responses to cannabinoid receptor ligands in the solitary tract nucleus. Eur J Pharmacol. 1998; 359 :49–54. [PubMed] [Google Scholar]
  • Hornby PJ. Central neurocircuitry associated with emesis. Am J Med. 2001; 1111 :106S–1112. [PubMed] [Google Scholar]
  • Howlett AC, Barth F, Bonner TI, Cabral P, Casellaa G, Devane WA, et al. International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors. Pharmacol Rev. 2002; 54 :161–202. [PubMed] [Google Scholar]
  • Iversen LL. The Science of Marijuana. New York: Oxford University Press; 2000. [Google Scholar]
  • Javid FA, Naylor RJ. The effect of the 5-HT1A receptor agonist, 8-OH-DPAT, on motion-induced emesis in Suncus murinus. Pharmacol Biochem Behav. 2006; 5 :820–826. [PubMed] [Google Scholar]
  • Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED, Potts R, Fallon MT. Multicenter, double-blind, randomized, placebo controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD Extract and THC extract in patients with intractable cancer-related pain. J Pain Symptom Manage. 2010; 39 :167–179. [PubMed] [Google Scholar]
  • Jordan K, Kasper C, Schmoll HJ. Chemotherapy-induced nausea and vomiting: current and new standards in the antiemetic prophylaxis and treatment. Eur J Cancer. 2005; 41 :199–205. [PubMed] [Google Scholar]
  • Kimura T, Ohta T, Watanabe K, Yoshimura H, Yamamoto I. Anandamide, an endogenous cannabinoid receptor ligand, also interacts with 5-hydroxytryptamine (5HT) receptor. Biol Pharm Bull. 1998; 21 :224–226. [PubMed] [Google Scholar]
  • Kwiatkowska M, Parker LA, Burton P, Mechoulam R. A comparative analysis of the potential of cannabinoids and ondansetron to suppress cisplatin-induced emesis in the Suncus murinus (house musk shrew) Psychopharmacology. 2004; 174 :254–259. [PubMed] [Google Scholar]
  • Layeeque R, Siegel E, Kass R, Henry-Tillman RS, Colvert M, Mancino A, et al. Prevention of nausea and vomiting following breast surgery. Am J Surg. 2006; 191 :767–772. [PubMed] [Google Scholar]
  • Limebeer CL, Parker LA. Delta-9-tetrahydrocannabinol interferes with the establishment and the expression of conditioned disgust reactions produced by cyclophosphamide: a rat model of nausea. Neuroreport. 1999; 26 :371–384. [PubMed] [Google Scholar]
  • Limebeer CL, Parker LA. Ondansetron interferes with the establishment and the expression of conditioned disgust reactions: a rat model of nausea. J Exp Psychol Anim Behav Process. 2000; 26 :371–384. [PubMed] [Google Scholar]
  • Limebeer CL, Parker LA. The 5-HT1A agonist 8-OH-DPAT dose-dependently interferes with the establishment and the expression of lithium-induced conditioned rejection reactions in rats. Psychopharmacology. 2003; 166 :120–126. [PubMed] [Google Scholar]
  • Limebeer CL, Parker LA, Fletcher P. 5,7-dihydroxytryptamine lesions of the dorsal and median raphe nuclei interfere with lithium-induced conditioned gaping, but not conditioned taste avoidance, in rats. Behav Neurosci. 2004; 118 :1391–1399. [PubMed] [Google Scholar]
  • Limebeer CL, Hall G, Parker LA. Exposure to a lithium-paired context elicits gaping in rats: a model of anticipatory nausea. Physiol Behav. 2006; 88 :398–403. [PubMed] [Google Scholar]
  • Limebeer CL, Krohn JP, Rock EM, Cross-Mellor SK, Parker LA, Ossenkopp KP. Exposure to a context previously associated with toxin(LiCl)- or motion-induced sickness elicits conditioned gaping in rats: evidence in support of a model of anticipatory nausea. Behav Brain Res. 2008; 187 :33–40. [PubMed] [Google Scholar]
  • Limebeer CL, Vemuri VK, Bedard H, Lang ST, Ossenkopp KP, Makriyannis A, et al. Inverse agonism of CB1 recpotrs potentiates LiCl-induced nausea: evidence from the conditioned gaping model in rats. Br J Pharmacol. 2010; 161 :336–349. [PMC free article] [PubMed] [Google Scholar]
  • Long JZ, Li W, Booker L, Burston JJ, Kinsey SG, Schlosburg JE, et al. Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioural effects. Nat Chem Biol. 2009a; 5 :37–44. [PMC free article] [PubMed] [Google Scholar]
  • Long JZ, Nomura DK, Cravatt BF. Characterization of Monoacylglycerol lipase inhibition reveals differences in central and peripheral endocannabinoid metabolism. Chem Biol. 2009b; 16 :744–753. [PMC free article] [PubMed] [Google Scholar]
  • Lucot JB. Effects of serotonin antagonists on motion sickness and its suppression by 8-OH-DPAT in cats. Pharmacol Biochem Behav. 1990; 37 :283–287. [PubMed] [Google Scholar]
  • Lucot JB, Crampton GH. 8-OH DPAT suppresses vomiting in the cat elicited by motion, cisplatin, or xylazine. Pharmacol Biochem Behav. 1989; 33 :627–631. [PubMed] [Google Scholar]
  • McCarthy LE, Borison HL. Anti-emetic activity of N-methyllevonantrobil and naboline in cisplatin treated cats. J Clin Pharmacol. 1981; 21 :30S–37S. [PubMed] [Google Scholar]
  • McLaughlin PJ, Winston KM, Limebeer CL, Parker LA, Makriyannis A, Salamone JD. The cannabinoid antagonist AM 251 produces food avoidance and behaviors associated with nausea but does not impair feeding efficiency in rats. Psychopharmacology. 2005; 180 :286–293. [PubMed] [Google Scholar]
  • Matsuki N, Ueno S, Kaji T, Ishihara A, Wang CH, Saito H. Emesis induced by cancer chemotherapeutic agents in the Suncus murinus: a new experimental model. Jpn J Pharmacol. 1988; 48 :303–306. [PubMed] [Google Scholar]
  • Meachum CL, Bernstein IL. Behavioral conditioned responses to contextual and odor stimuli paired with LiCl administration. Physiol Behav. 1992; 52 :895–899. [PubMed] [Google Scholar]
  • Mechoulam R. Plant cannabinoids: a neglected pharmacological treasure trove. Br J Pharmacol. 2005; 146 :913–915. [PMC free article] [PubMed] [Google Scholar]
  • Mechoulam R, Parker LA, Gallily R. Cannabidiol: an overview of some pharmacological aspects. J Clin Pharmacol. 2002; 42 :11S–19S. [PubMed] [Google Scholar]
  • Meiri E, Jhangiani H, Vredenburgh JJ, Barbato LM, Carter FJ, Yang HM, et al. Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting. Curr Med Res Opin. 2007; 23 :533–543. [PubMed] [Google Scholar]
  • Miner WJ, Sanger GJ. Inhibition of cisplatin-induced vomiting by selective 5-hydroxytryptamine M-receptor antagonism. Br J Pharmacol. 1986; 88 :497–499. [PMC free article] [PubMed] [Google Scholar]
  • Morrow GR, Dobkin PL. Anticipatory nausea and vomiting in cancer patients undergoing chemotherapy treatment: prevalence, etiology and behavioral interventions. Clin Psychol Rev. 1988; 8 :517–556. [Google Scholar]
  • Nesse RM, Carli T, Curtis GC, Kleinman PD. Pretreatment nausea in cancer chemotherapy: a conditioned response? Psychosom Med. 1980; 42 :33–36. [PubMed] [Google Scholar]
  • Okada F, Torii Y, Saito H, Matsuki N. Antiemetic effects of serotonergic 5-HT1A-receptor agonists in Suncus murinus. Jpn J Pharmacol. 1994; 64 :109–114. [PubMed] [Google Scholar]
  • Parker LA. Nonconsummatory and consummatory behavioral CRs elicited by lithium-paired and amphetamine-paired flavors. Learn Motiv. 1982; 13 :281–303. [Google Scholar]
  • Parker LA. Rewarding drugs produce taste avoidance, but not taste aversion. Neurosci Biobehav Rev. 1995; 19 :143–151. [PubMed] [Google Scholar]
  • Parker LA. Emetic drugs produce conditioned rejection reactions in the taste reactivity test. J Psychophysiol. 1998; 12 :3–13. [Google Scholar]
  • Parker LA. Taste avoidance and taste aversion: evidence for two different processes. Learn Behav. 2003; 31 :165–172. [PubMed] [Google Scholar]
  • Parker LA, Kemp S. Tetrahydrocannabinol (THC) interferes with conditioned retching in Suncus murinus: an animal model of anticipatory nausea and vomiting (ANV) Neuroreport. 2001; 12 :749–751. [PubMed] [Google Scholar]
  • Parker LA, Limebeer CL. Cannabinoids in the management of nausea and vomiting. In: Kofalvi A, editor. Cannabinoids and the Brain. New York: Springer-Verlag Press; 2008. [Google Scholar]
  • Parker LA, McLeod KB. Chin rub CRs may reflect conditioned sickness elicited by a lithium-paired sucrose solution. Pharmacol Biochem Behav. 1991; 40 :983–986. [PubMed] [Google Scholar]
  • Parker LA, Mechoulam R. Cannabinoid agonists and an antagonist modulate conditioned gaping in rats. Integr Physiol Behav Sci. 2003; 38 :134–146. [Google Scholar]
  • Parker LA, Corrick ML, Limebeer CL, Kwiatkowska M. Amphetamine and morphine produce a conditioned taste and place preference in the house musk shrew (Suncus murinus) J Exp Psychol Anim Behav Process. 2002a; 28 :75–82. [PubMed] [Google Scholar]
  • Parker LA, Mechoulam R, Schlievert C. Cannabidiol, a non-psychoactive component of cannabis, and its dimethylheptyl homolg suppress nausea in an experimental model with rats. Neuroreport. 2002b; 13 :567–570. [PubMed] [Google Scholar]
  • Parker LA, Mechoulam R, Shlievert C, Abbott L, Fudge ML, Burton P. Effects of cannabinoids on lithium-induced conditioned rejection reactions in a rat model of nausea. Psychopharmacology. 2003; 166 :156–162. [PubMed] [Google Scholar]
  • Parker LA, Kwiatkowska M, Burton P, Mechoulam R. Effect of cannabinoids on lithium-induced vomiting in the Suncus murinus. Psychopharmacology. 2004; 171 :156–161. [PubMed] [Google Scholar]
  • Parker LA, Limebeer CL, Kwiatkowska M. Cannabinoids: effects on vomiting and nausea in animal model. In: Mechoulam R, editor. Cannabinoids As Therapeutics. Switzerland: Birkhauser Verlag, Basel; 2005. pp. 183–200. [Google Scholar]
  • Parker LA, Kwiatkowska M, Mechoulam R. Delta-9-tetrahydrocannabinol and cannabidiol, but not ondansetron, interfere with conditioned retching reactions elicited by a lithium-paired context in Suncus murinus: an animal model of anticipatory nausea and vomiting. Physiol Behav. 2006; 87 :61–71. [PubMed] [Google Scholar]
  • Parker LA, Rana SA, Limebeer CL. Conditioned disgust, but not conditioned taste avoidance: a measure of conditioned nausea in rats. Can J Exp Psychol. 2008; 6 :198–209. [PubMed] [Google Scholar]
  • Parker LA, Limebeer CL, Rock EM, Litt DL, Kwiatkowska M, and Piomelli D. The FAAH inhibitor URB-597 interferes with cisplatin- and nicotine- induced vomiting in the Suncus murinus (house musk shrew) Physiol Behav. 2009a; 97 :121–124. [PMC free article] [PubMed] [Google Scholar]
  • Parker LA, Limebeer CL, Rana SA. Conditioned disgust, but not conditioned taste avoidance, may reflect conditioned nausea in rats. In: Reilly S, Schachtman TR, editors. Conditioned Taste Aversions: Behavioral and Neural Processes. NY: Oxford University Press; 2009b. [Google Scholar]
  • Pavlov IP. Conditioned Reflexes. London, England: Oxford University Press; 1927. G.V. anrep, trans. [Google Scholar]
  • Pertwee RG. Cannabinoids and the gastrointestinal tract. Gut. 2001; 48 :859–867. [PMC free article] [PubMed] [Google Scholar]
  • Pertwee RG. In: The Pharmacology and Therapeutic Potential of Cannabidiol. DiMarzo V, editor. Cannabinoids: Kluver Academic/Plenum Publishers; 2004. [Google Scholar]
  • Pertwee RG. Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br J Pharmacol. 2009; 156 :397–411. [PMC free article] [PubMed] [Google Scholar]
  • Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J, RIO-North American Study Group Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients. JAMA. 2006; 295 :761–775. [PubMed] [Google Scholar]
  • Rabin BM, Hunt WA. Effects of anti-emetics on the acquisition and recall of radiation and lithium chloride induced conditioned taste aversions. Pharmacol Biochem Behav. 1983; 18 :629–636. [PubMed] [Google Scholar]
  • Racz I, Bilkei-Gorzo A, Markert A, Stamer F, Göthert M, Zimmer Z. Anandamide effects on 5-HT3 receptors in vivo. Eur J Pharmacol. 2008; 596 :98–101. [PubMed] [Google Scholar]
  • Randall PA, Vemuri VK, Segovia KN, Torres EF, Hosmer S, Nunes EJ, et al. The novel cannabinoid CB1 antagonists AM6545 suppresses food intake and food-reinforced behavior. Pharmacol Biochem Behav. 2010; 97 :179–184. [PMC free article] [PubMed] [Google Scholar]
  • Ray AP, Griggs L, Darmani NA. Δ 9 -tetrahydrocannabinol suppresses vomiting behavior and Fos expression in both acute and delayed phases of cisplatin-induced emesis in the least shrew. Behav Brain Res. 2009; 196 :30–36. [PMC free article] [PubMed] [Google Scholar]
  • Reicher MA, Holman EW. Location preference and flavor aversion reinforced by amphetamine in rats. Anim Learn Behav. 1977; 5 :343–346. [Google Scholar]
  • Reynolds DJM, Barber NA, Grahame-Smith DG, Leslie RA. Cisplatin-evoked induction of c-fos protein in the brainstem of the ferret: the effect of cervical vagotomy and the antiemetic 5HT-3 receptor antagonist granisetron. Brain Res. 1991; 565 :321–336. [PubMed] [Google Scholar]
  • Rock EM, Limebeer CL, Mechoulam R, Piomelli D, Parker LA. The effect of cannabidiol and URB597 on conditioned gaping (a model of nausea) elicited by a lithium-paired context in the rat. Psychopharmacol. 2008; 196 :389–395. [PubMed] [Google Scholar]
  • Rock EM, Limebeer CL, Fletcher PJ, Mechoulam R, Parker LA. Cannabidiol (the non-psychoactive component of cannabis) may act as a 5-HT1A auto-receptor agonist to reduce toxin-induced nausea and vomiting. CA: Poster presented at the Society for Neuroscience meeting, San Diego; 2010. [Google Scholar]
  • Rudd JA, Naylor RJ. An interaction of ondansetron and dexamethasone antagonizing cisplatin-induced acute and delayed emesis in the ferret. Br J Pharmacol. 1996; 118 :209–214. [PMC free article] [PubMed] [Google Scholar]
  • Rudd JA, Jordan CC, Naylor RJ. The action of the NK1 tachykinin receptor antagonist, CP 99,994, in antagonizing the acute and delayed emesis induced by cisplatin in the ferret. Br J Pharmacol. 1996; 119 :931–936. [PMC free article] [PubMed] [Google Scholar]
  • Rudd JA, Ngan MP, Wai MK. 5-HT3 receptors are not involved in conditioned taste aversions induced by 5-hydroxytryptamine, ipecacuanha or cisplatin. Eur J Pharmacol. 1998; 352 :143–149. [PubMed] [Google Scholar]
  • Russo EB, Burnett A, Hall B, Parker KK. Agonist properties of cannabidiol at 5-HT1a receptors. Neurochem Res. 2005; 30 :1037–1043. [PubMed] [Google Scholar]
  • Schlicker E, Kathmann M. Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci. 2001; 22 :571–572. [PubMed] [Google Scholar]
  • Sharkey KA, Cristino L, Oland LD, Van Sickle MD, Starowicz K, Pittman QJ, et al. Arvanil, anandamide and N-arachidonolyl-dopamine (NADA) inhibit emesis through cannabinoid CB1 and vanilloid TRPV1 receptors in the ferret. Eur J Neurosci. 2007; 25 :2773–2782. [PubMed] [Google Scholar]
  • Simoneau II, Hamza MS, Mata HP, Siegel EM, Vanderah TW, Porreca F, et al. The cannabinoid agonist WIN 55,212-2 suppresses opioid-induced emesis in ferrets. Anesthesiology. 2001; 94 :882–886. [PubMed] [Google Scholar]
  • Sink KS, McLaughlin PJ, Brown C, Xu W, Fan P, Vemuri VK, et al. The novel cannabinoid CB1 receptor neutral antagonist AM4113 suppresses food intake and food-reinforced behavior but does not induce signs of nausea in rats. Neuropsychopharmacology. 2007; 33 :1–10. [PMC free article] [PubMed] [Google Scholar]
  • Slatkin NE. Cannabinoids in the treatment of chemotherapy-induced nausea and vomiting: beyond prevention of acute emesis. J Support Oncol. 2007; 5S :1–9. [PubMed] [Google Scholar]
  • Sticht MA, Long JZ, Rock EM, Limebeer CL, Mechoulam R, Cravatt BJ, et al. Effect of MAGL inhibitor, JZL184, on LiCl-induced emesis in the Suncus murinus and 2-AG on LiCl-induced conditioned gaping (a model of nausea) in rats. CA: Poster presented at the Society for Neuroscience, San Diego; 2010. [Google Scholar]
  • Stockhorst U, Klosterhalfen S, Klosterhalfen W, Winkelmann M, Steingrueber HJ. Anticipatory nausea in cancer patients receiving chemotherapy: classical conditioning etiology and therapeutical implications. Integr Physiol Behav Sci. 1993; 28 :177–181. [PubMed] [Google Scholar]
  • Tam J, Vemuri VK, Liu J, Batkai S, Mukhopadhyay B, Godlewski G, et al. Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J Clin Invest. 2010; 120 :2953–2966. [PMC free article] [PubMed] [Google Scholar]
  • Torii Y, Saito H, Matsuki N. Selective blockade of cytotoxic drug-induced emesis by 5-HT3 receptor antagonists in Suncus Murinus. Jpn J Pharmacol. 1991; 55 :107–113. [PubMed] [Google Scholar]
  • Tramer MR, Carroll D, Campbell FA, Reynolds DJM, Moore RA, McQuay HJ. Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ. 2001; 323 :1–8. [PMC free article] [PubMed] [Google Scholar]
  • Travers JB, Norgren R. Electromyographic analysis of the ingestion and rejection of sapid stimuli in the rat. Behav Neurosci. 1986; 100 :544–555. [PubMed] [Google Scholar]
  • Tsukada H, Hirose T, Yokoyama A, Kurita Y. Randomized comparison of ondansetron plus dexamethasone with desamethasone alone for the control of delayed cisplatin-induced emesis. Eur J Cancer. 2001; 37 :2398–2404. [PubMed] [Google Scholar]
  • Tuerke KJ, Limebeer CL, Lester J, Chambers J, Fletcher PJ, Parker LA. Depletion of serotonin in the insular cortex by 5,7-Dihydroxytrptamine (5,7-DHT) lesions attenuates conditioned nauea in rats. 2010. Poster presented at the Society for Neuroscience meetings, San Diego.
  • Ueno S, Matsuki N, Saito H. Suncus murinus: a new experimental model in emesis research. Life Sci. 1987; 43 :513–518. [PubMed] [Google Scholar]
  • Ungerleider JT, Andrysiak TA, Fairbanks LA, Tesler AS, Parker RG. Tetrahydrocannabinol vs. prochlorperazine. The effects of two antiemetics on patients undergoing radiotherapy. Radiology. 1984; 150 :598–599. [PubMed] [Google Scholar]
  • Van Belle S, Lichinitser M, Navari R, Garin AM, Decramer ML, Riviere A, et al. Prevention of cisplatin-induced acute and delayed emesis by the selective neurokinin-1 antagonists, L-758,298 and MK869. Cancer. 2002; 94 :3032–3041. [PubMed] [Google Scholar]
  • Van der Stelt M, DiMarzo V. Endovanilloids. Putative endogenous ligands of transient receptor potential vanilloid 1 channels. Eur J Biochem. 2004; 271 :1827–1834. [PubMed] [Google Scholar]
  • Van Sickle MD, Oland LD, HO W, Hillard CJ, Mackie K, Davison JS, et al. Cannabinoids inhibit emesis through CB1 receptors in the brainstem of the ferret. Gastroenterology. 2001; 121 :767–774. [PubMed] [Google Scholar]
  • Van Sickle MD, Oland LD, Mackie K, Davison JS, Sharkey KA. Δ 9 -Tetrahydrocannabinol selectively acts on CB1 receptors in specific regions of dorsal vagal complex to inhibit emesis in ferrets. Am J Physiol Gastrointest Liver Physiol. 2003; 285 :G566–G576. [PubMed] [Google Scholar]
  • Van Sickle MD, Cuncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, et al. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science. 2005; 310 :329–332. [PubMed] [Google Scholar]
  • Wang Y, Ray AP, McClanahan BA, Darmani NA. The antiemetic interaction of Δ 9 -tetrahydrocannabinol when combined with tropisetron or dexamethasone in the least shrew. Pharmacol Biochem Behav. 2009; 91 :367–373. [PMC free article] [PubMed] [Google Scholar]
  • Wegener G, Smith DF, Rosenberg R. 5-HT1A receptors in lithium-induced conditioned taste aversion. Psychopharmacol. 1997; 133 :51–54. [PubMed] [Google Scholar]
  • Wise R, Yokel P, DeWit H. Both positive reinforcement and conditioned aversion from amphetamine and from apomorphine in rats. Science. 1976; 191 :1273–1274. [PubMed] [Google Scholar]
  • Wolff MC, Leander JD. Antiemetic effects of 5-HT1A agonists in the pigeon. Pharmacol Biochem Behav. 1994; 49 :385–391. [PubMed] [Google Scholar]
  • Wolff MC, Leander JD. Comparison of the antiemetic effects of a 5-HT1A agonist, LY228729, and 5-HT3 antagonists in the pigeon. Pharmacol Biochem Behav. 1995; 52 :571–575. [PubMed] [Google Scholar]
  • Wolff MC, Leander JD. Effects of a 5-HT1A receptor agonist on acute and delayed cyclophosphamide-induced vomiting. Eur J Pharmacol. 1997; 340 :217–220. [PubMed] [Google Scholar]
  • Yamakuni H, Sawai-Nakayama H, Imazumi K, Maeda Y, Matsuo M, Manda T, et al. Resiniferatoxin antagonizes cisplatin-induced emesis in dogs and ferrets. Eur J Pharmacol. 2002; 442 :273–278. [PubMed] [Google Scholar]
  • Yang KH, Galadari S, Isaev D, Petroianu G, Shippenberg TS, Oz M. The nonpsychoactive cannabinoid cannabidiol inhibits 5-Hydroxytryptamine3A receptor-mediated currents in Xenopus laevis Oocytes. J Pharmacol Exp Therap. 2010; 333 :547–554. [PMC free article] [PubMed] [Google Scholar]
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Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

How to Take CBD Oil for Nausea

This article was co-authored by Aimée Shunney, ND and by wikiHow staff writer, Megaera Lorenz, PhD. Dr. Aimée Gould Shunney is a Licensed Naturopathic Doctor at Santa Cruz Integrative Medicine in Santa Cruz, California where she specializes in women’s health and hormone balancing. She also consults with various companies in the natural products industry including CV Sciences, makers of PlusCBD Oil. Dr. Aimée educates consumers, retailers, and healthcare providers about CBD oil through written articles, webinars, podcasts, and conferences nationwide. Her work has been featured at the American Academy for Anti-Aging Medicine, the American Association of Naturopathic Physicians Conference, and on Fox News. She earned her ND from the National College of Naturopathic Medicine in 2001.

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CBD oil, or cannabidiol, is a natural compound found in marijuana and another related plant, hemp. Unlike THC, another compound in the marijuana plant, CBD doesn’t cause a “high.” However, it may help reduce nausea and other unpleasant symptoms, like pain and anxiety. If you have nausea due to a medical condition or a medication you’re taking, such as chemotherapy drugs, talk to your doctor about using CBD to get relief.

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