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Cannabinoid 2 (CB2) receptor agonism reduces lithium chloride-induced vomiting in Suncus murinus and nausea-induced conditioned gaping in rats
European Journal of Pharmacology 786 (2016) 94–99
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European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar
Behavioural pharmacology
Cannabinoid 2 (CB2) receptor agonism reduces lithium chlorideinduced vomiting in Suncus murinus and nausea-induced conditioned gaping in rats Erin M. Rock a, Nathalie Boulet a, Cheryl L. Limebeer a, Raphael Mechoulam b, Linda A. Parker a,n a b
Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, Canada Institute of Drug Research, Hebrew University of Jerusalem, Jerusalem, Israel
art ic l e i nf o
a b s t r a c t
Article history: Received 16 November 2015 Received in revised form 20 May 2016 Accepted 1 June 2016 Available online 2 June 2016
We aimed to investigate the potential anti-emetic and anti-nausea properties of targeting the cannabinoid 2 (CB2) receptor. We investigated the effect of the selective CB2 agonist, HU-308, on lithium chloride- (LiCl) induced vomiting in Suncus murinus (S. murinus) and conditioned gaping (nausea-induced behaviour) in rats. Additionally, we determined whether these effects could be prevented by pretreatment with AM630 (a selective CB2 receptor antagonist/inverse agonist). In S. murinus, HU-308 (2.5, 5 mg/kg, i.p.) reduced, but did not completely block, LiCl-induced vomiting; an effect that was prevented with AM630. In rats, HU-308 (5 mg/kg, i.p.) suppressed, but did not completely block, LiClinduced conditioned gaping to a flavour; an effect that was prevented by AM630. These findings are the first to demonstrate the ability of a selective CB2 receptor agonist to reduce nausea in animal models, indicating that targeting the CB2 receptor may be an effective strategy, devoid of psychoactive effects, for managing toxin-induced nausea and vomiting. & 2016 Elsevier B.V. All rights reserved.
Keywords: CB2 receptor HU-308 AM630 Acute nausea Vomiting Conditioned gaping Chemical compounds studied in this article: HU-308 (PubChem CID: 9844711) AM630 (PubChem CID: 4302963) Lithium chloride (PubChem CID: 433294)
1. Introduction Nausea continues to be a distressing side effect of chemotherapy treatment. While acute vomiting is relatively well managed by 5-hydroxytryptamine 3 (5-HT3) receptor antagonists (such as ondansetron; Navari, 2009), and delayed vomiting is relatively well managed by the Neurokinin 1 receptor antagonists (such as aprepitant; e.g. Tatsushima et al., 2011), nausea is still problematic, indicating that other pharmacological avenues need to be explored (see Sharkey et al., 2014). When assessing 5-HT3 receptor antagonists for the alleviation of acute emesis in human patients, complete response (no emetic episodes, no rescue medications, no nausea) is often the primary outcome assessed, making it difficult to dissociate the prevalence of vomiting versus nausea. Nevertheless, in a more recent study, Sepúlveda-Vildósola et al. (2008) reported that treatment with a 5-HT3 receptor antagonist resulted in complete acute emesis control in 72% of patients, but acute n
Corresponding author. E-mail address: [email protected] (L.A. Parker).
http://dx.doi.org/10.1016/j.ejphar.2016.06.001 0014-2999/& 2016 Elsevier B.V. All rights reserved.
nausea was completely controlled in only 38% of patients; highlighting the utility of 5-HT3 receptor antagonists in treating acute emesis (but not acute nausea). Furthermore, treatment with a Neurokinin 1 receptor antagonist resulted in acute emetic control in only 37% of patients, and was less effective in reducing acute nausea than a 5-HT3 receptor antagonist (Cocquyt et al., 2001). Interestingly, treatment with a Neurokinin 1 receptor antagonist resulted in delayed emetic control in 72% of patients, but was more effective than a 5-HT3 receptor antagonist in reducing delayed nausea (Cocquyt et al., 2001). These recent findings suggest that acute emesis and nausea differ from delayed emesis and nausea due to their differential response to these treatments. Although the neural mechanisms of nausea are not well understood, the emetic reflex has been well characterized using animal models such as the ferret and the shrew (e.g. Hornby, 2001). Reliable pre-clinical animal models are also necessary to assess the efficacy of anti-nausea drugs. One pre-clinical model that has been used to assess the anti-nausea effect of compounds is conditioned gaping in the rat. Although rats do not vomit, they display a conditioned gaping response (wide opening of the mouth exposing the lower incisors) when they re-encounter a flavour or a
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context that has previously been paired with an emetic agent (that is an agent that produces vomiting in species capable of vomiting). Conditioned gaping in the rat is only produced by emetic agents and typical anti-emetic agents interfere with the establishment of conditioned gaping (see Parker, 2014). This conditioned gaping response requires similar orofacial muscular responses as those required for the vomiting response in emetic species (Travers and Norgren, 1986). As well, the rat detects emetic toxins (such as cisplatin) in the gut in a similar way as ferrets which are capable of vomiting; with cisplatin causing 5-HT release from enteroendocrine cells in the gut, activating 5-HT3 receptors on vagal afferent fibers (Endo et al., 1995; Hillsley and Grundy, 1998; Horn et al., 2004). In both species, 5-HT3 receptor antagonism can block this vagal activation (Endo et al., 1995; Horn et al., 2004). In addition, the area postrema detects blood-borne toxins in the rat, as well as emetic species (Bernstein et al., 1992; Eckel and Ossenkopp, 1996), indicating that although the detection mechanism for vomiting is present in the rat, the motor output is not (Horn et al., 2004; 2013). Cannabinoids, compounds derived from the Cannabis sativa plant, have been shown to reduce nausea and vomiting in animal models (Sharkey et al., 2014; Parker et al., 2011). The endogenous cannabinoid system is comprised of two cannabinoid receptors (cannabinoid 1, CB1 and cannabinoid 2, CB2) possessing distinct physiological properties that have been identified and well characterized. Although agonists of the CB1 receptor produce psychoactive effects limiting their therapeutic potential, agonists of the CB2 receptor are devoid of psychoactivity (see Pacher and Mechoulam, 2011). The CB1 receptor is highly expressed in the central nervous system, while the CB2 receptor has been identified outside of the central nervous system and was once thought to be solely associated with immune tissues. Recent evidence however, indicates that CB2 receptors are also located centrally in regions such as the brainstem, cortex and cerebellum (Onaivi et al., 2006; Van Sickle et al., 2005). Of most relevance, Van Sickle et al. (2005) reported the expression of CB2 receptor messenger ribonucleic acid expression and protein localization in the rat brainstem regions of the dorsal motor nuclei. Δ9-Tetrahydrocannabinol (THC, the psychoactive component of cannabis) exerts its anti-emetic effects in ferrets via activation of CB1 receptors in the dorsal vagal complex (Van Sickle et al., 2003). In addition, Van Sickle et al. (2005) demonstrated the anti-emetic role of the CB2 receptor in morphine-6-glucuronide- (M6G) induced emesis. Administration of the endogenous cannabinoids, 2-Arachidonoylglycerol or anandamide, dose-dependently reduced emesis in ferrets. The anti-emetic effects of anandamide were blocked by the CB1 receptor antagonist, AM251, but not by the CB2 receptor antagonist/inverse agonist, AM630 (4- [4- (1, 1dimethylheptyl)- 2, 6- dimethoxyphenyl]- 6, 6- dimethyl- bicyclo [3.1.1]hept- 2- ene- 2- methanol). In contrast, the anti-emetic effects of 2-Arachidonoylglycerol (2-AG) were blocked by AM251 or AM630, indicating the functional role of the CB2 receptor in the anti-emetic effects of 2-AG (Van Sickle et al., 2005). However, there is also evidence that the CB2 receptor antagonist SR144528 did not block WIN55,212-2- or CP55,940-induced suppression of cisplatin- or radiation- induced vomiting in the least shrew (Darmani, 2001; Darmani et al., 2003, 2007), nor did the CB2 receptor antagonist AM630 block WIN55,212-2-induced suppression of opioid-induced vomiting in the ferret (Simoneau et al., 2001). Therefore, the evidence is mixed regarding the potential of CB2 agonism to produce an anti-emetic effect. As the CB1 receptor mediates the psychoactive effects of cannabinoids, selective CB2 receptor activation has the potential to exert its physiological effects, in the absence of psychoactivity. Therefore, it is of interest to determine if selective CB2 receptor agonists have anti-emetic and anti-nausea potential.
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1.1. Objective The purpose of the current study was to investigate the potential of the selective CB2 receptor agonist, HU-308 (4- [4- (1, 1dimethylheptyl)-2, 6- dimethoxyphenyl]-6, 6- dimethyl- bicyclo [3.1.1]hept- 2- ene- 2- methanol, Hanus et al., 1999) to interfere with LiCl-induced vomiting in S. murinus and conditioned gaping in rats. In addition, the CB2 receptor mediation of HU-308's antiemetic and anti-nausea effects was investigated via pretreatment with the selective CB2 receptor antagonist/inverse agonist AM630 (Hosohata et al., 1997; Ross et al., 1999).
2. Materials and methods 2.1. Animals All animal procedures complied with the Canadian Council on Animal Care and were approved by the Institutional Animal Care Committee (accredited by the Canadian Council on Animal Care). The shrews were bred and raised in the University of Guelph colony and ranged from 49 to 193 days old at the time of testing. Naive male (n ¼19) and female (n ¼20) S. murinus (house musk shrews) were individually housed in opaque white mouse cages in the colony room at an ambient temperature of 21 °C on a 10/14 h light-dark schedule (lights off at 7 PM). Shrews were tested in their light cycle. They were provided with an open ended plastic cylinder (4 8 cm) containing enviro-paper, maintained on Medical/Royal Canine Feline Maintenance mixed with Harlan Ferret dry chow and had ad libitum access to water. All shrews were weaned at 25-30 days of age. Both male and female shrews are used in these emesis studies as no sex differences were observed for vomiting behaviour. Naïve male Sprague-Dawley rats (N ¼ 73), weighing between 258 and 353 g on the day of conditioning, obtained from Charles River Laboratories (St Constant, Quebec) were used for assessment of anti-nausea-like behaviour. The rats were housed singly in opaque plastic shoebox cages (48 26 20 cm), containing bed-ocob bedding from Harlan Laboratories, Inc. (Mississauga, Ontario), a brown paper towel and Crink-l'Nest™ from The Andersons, Inc. (Maumee, Ohio). Additionally, the rats were provided with a soft white plastic container that was 14 cm long and 12 cm in diameter. The colony room was kept at an ambient temperature of 21 °C with a 12/12 h light-dark schedule (lights off at 8 am). The rats were tested in their dark cycle; they were removed from the dark housing area and tested in the dimly lit taste reactivity chambers. The rats were maintained on food (Highland Rat Chow [8640]) and water ad-libitum. 2.2. Experimental procedures 2.2.1. Effect of HU-308 on LiCl-induced vomiting in S. murinus On the test day shrews were individually transferred from the colony room (University of Guelph colony) to an empty cage in the experimental room that contained four mealworms. After 15 min they were injected with vehicle (VEH; consisting of 1:9 Tween80: Saline, 1 ml/kg) or AM630 (3 mg/kg i.p.) followed 15 min later by an injection of VEH or HU-308 (1, 2.5, 5, 10, 20, 40 mg/kg, i.p.). Thirty min following the two pretreatment injections the shrews were injected with LiCl and put into an observation chamber for 45 min. The Plexiglas observation chambers (22.5 26 20 cm) were placed on a table with a clear glass top. A mirror at a 450 angle beneath the chamber facilitated viewing of the ventral surface of each shrew and hence of all vomiting episodes (oral expulsion of gastric contents). An observer blind to the experimental conditions counted the frequency of vomiting episodes. The
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groups were as follows: VEH-VEH (n ¼6, 4 Females [F], 2 Males [M]), VEH-HU-308 1 mg/kg (n ¼ 4, 2 F, 2 M), VEH-HU-308 2.5 mg/ kg (n ¼4, 2 F, 2 M, VEH-HU-308 5 mg/kg (n ¼5, 2 F, 3 M), VEH-HU308 10 mg/kg (n¼ 4, 2 F, 2 M), VEH-HU-308 20 mg/kg (n ¼ 4, 2 F, 2 M), VEH-HU-308 40 mg/kg (n ¼ 4, 1 F, 3 M), AM630-VEH (n ¼4, 2 F, 2 M), AM630-HU-308 5 mg/kg (n ¼4, 3 F, 1 M). 2.2.2. Effect of HU-308 on LiCl-induced conditioned gaping in rats All rats were surgically implanted with an intraoral cannula under isoflurane anaesthesia according to the procedures described by Limebeer et al. (2010). Following three days recovery from surgery, the rats were adapted to the taste reactivity (TR) chambers and infusion procedure. They were placed in the TR chamber with their cannula attached to an infusion pump (Model KDS100, KD Scientific, Holliston, MA, USA) and water was infused into their intraoral cannula for 2 min at a rate of 1 ml/min. The TR chambers were made of clear Plexiglas (22.5 26 20 cm) that sat on a table with a clear glass top. A mirror beneath the chamber on a 45° angle (illuminated by two 25 W lights on either side, but no overhead light in the room) facilitated viewing of the ventral surface of the rat to observe orofacial responses. On the next day, the rats received a conditioning trial in which they were administered a pretreatment injection of VEH or AM630 (1 mg/kg). Fifteen min later, the rats were injected with either VEH or HU-308 (1, 2.5, 5, 10 mg/kg). Thirty min following the two pretreatment injections the rats were individually placed in the TR chamber and intraorally infused with 0.1% saccharin solution for 2 min at the rate of 1 ml/min while the orofacial responses were video recorded (Sony DCR-HC48, Henry's Cameras, Waterloo, ON, Canada) for subsequent scoring of gaping responses (large openings of the mouth and jaw, with lower incisors exposed; at ½ speed) by a rater blind to the experimental conditions using ‘The Observer’ (version XT 7, Noldus Information Technology Inc., Leesburg, VA, USA). The number of gaping responses was recorded over the 2 min test session. Immediately after the saccharin infusion, all rats were injected with 20 ml/kg of 0.15 M LiCl and returned to their home cage. The groups were as follows: VEH-VEH (n ¼11), VEH-HU-308 1 mg/kg (n ¼7), VEH-HU-308 2.5 mg/kg (n ¼9), VEH-HU-308 5 mg/kg (n¼ 12), VEH-HU-308 10 mg/kg (n ¼7), AM630-VEH (n ¼8), AM630-HU-308 5 mg/kg (n ¼11). Seventy-two h following conditioning a drug-free test was conducted. Rats were brought individually to the TR chamber where they were intraorally infused with 0.1% saccharin solution for 2 min at the rate of 1 ml/min while the orofacial responses were video recorded for later scoring. At the end of the saccharin infusion rats were returned to their home cages. To determine if the pretreatments interfered with learning per se, conditioned taste avoidance was assessed in a single bottle test. Rats were water-restricted at 4:00 PM following the taste reactivity test. The following morning, a single bottle containing 0.1% saccharin was placed on the cage at 9:00 AM. Measures of saccharin consumption were taken at 30, 120, and 360 min. To assess the amount of saccharin consumed by naïve rats, an additional group of rats were pretreated with VEH-VEH-Saline (n ¼8).
1 or 40 mg/ml (1, 40 mg/kg, respectively), or at a volume of 0.5, 1, 2, 4 ml/kg at a concentration of 5 mg/ml (2.5, 5, 10, 20 mg/kg, respectively). In rats, HU-308 was administered i.p. at a volume of 1 ml/kg at a concentration of 1, 5 or 10 mg/ml (1, 5, 10 mg/kg, respectively, or at a volume of 0.5 ml/kg at a concentration of 5 mg/ml (2.5 mg/kg). AM630 was administered i.p. at a volume of 3 ml/kg at a concentration of 1 mg/ml (3 mg/kg) in shrews and i.p. at a volume of 1 ml/kg at a concentration of 1 mg/ml (1 mg/kg) in rats. The AM630 dose of 1 mg/kg in rats were chosen based on previous studies (e.g. Tang et al., 2016; Wang et al., 2015). 2.4. Statistical methods The number of vomiting responses (total number of vomiting responses with expulsion of gastric contents) for the shrews and the number of gapes during the TR test (total of wide openings of the mouth over the 2 min test period) for the rats was entered into an Independent Samples Kruskal-Wallis test with subsequent pairwise comparisons tests. The ml saccharin consumed at each test interval during the conditioned taste avoidance test for each group of rats was entered into a mixed-factors Analysis of Variance (ANOVA) with subsequent Bonferroni post-hoc comparison tests. For all analyses, P values o0.05 were taken as significant.
3. Results 3.1. HU-308 reduces LiCl-induced vomiting in S. murinus; a CB2 receptor mediated effect HU-308 (2.5, 5 but not 1, 10, 20 or 40 mg/kg) reduced LiCl-induced vomiting in shrews, an effect that was prevented by the CB2 antagonist AM630 (Fig. 1). A Kruskal-Wallis test of the number vomits displayed by the various groups was significant, H(8) ¼ 29.3; Po 0.001). Subsequent pairwise comparison tests revealed that those shrews given LiCl after pretreatment with VEH-HU-308 (2.5, 5 mg/kg) vomited significantly less than VEH-VEH pretreated controls (P'so 0.02). As well, Group AM630-HU-308 5 mg/kg did
2.3. Drugs and materials LiCl (Sigma) was prepared in a 0.15 M solution with sterile water and was administered intraperitoneally (i.p.) for shrews at a volume of 60 ml/kg (390 mg/kg dose), and i.p. at a volume of 20 ml/kg (127.2 mg/kg) for rats. HU-308 and AM630 were prepared in a vehicle that consisted of 1:9 Tween80:Saline. First the drugs were dissolved in ethanol (EtOH) and then Tween80 (Sigma) was added to the solution. Then the EtOH was evaporated using a nitrogen stream and then saline was added. In shrews, HU-308 was administered i.p. at a volume of 1 ml/kg at a concentration of
Fig. 1. Effect of HU-308 (1, 2.5, 5, 10, 20, 40 mg/kg, i.p.) or VEH administered i.p. 30 min prior to LiCl administration. Additional groups were also given AM630 (3 mg/kg, i.p.) 15 min prior to VEH or HU-308 (5 mg/kg). The number of emetic episodes in shrews treated with LiCl was measured. Each bar represents the mean7 S.E.M. (n¼ 4–6). The numbers in parentheses indicate n/group that displayed emetic behaviour. The asterisks indicate a significant difference from the VEH-VEH pretreated control animals (**Po 0.01, *P o 0.05).
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Fig. 2. Effect of HU-308 (1, 2.5, 5, 10 mg/kg, i.p.), or VEH administered 30 min prior to LiCl. Additional groups were also given AM630 (1 mg/kg, i.p.) 15 min prior to VEH or HU308 (5 mg/kg) and LiCl. (A) The mean number of conditioned gaping responses was measured during the test trial. Each bar represents the mean7S.E.M. (n¼7–12). The numbers in parentheses indicate n/group that displayed at least one conditioned gaping response. The asterisks indicate a significant difference from the VEH-VEH pretreated control animals (**Po0.01, *Po0.05). The number signs represent a significant difference from the VEH-HU-308 5 mg/kg group (#Po0.05). (B) The mean cumulative amount of saccharin solution consumed (ml7SEM) during a one-bottle consumption test was measured at 30, 120 and 360 min after introduction of the bottle to fluid-restricted rats. A naïve group of rats (not LiCl-treated) was also added (denoted VEH-VEH-Saline). The asterisks indicate a significant difference from all other groups (**Po0.01).
not significantly differ from VEH-VEH (P 40.05), indicating that administration of AM630 blocked the suppressive effect of HU-308 (5 mg/kg) on vomiting. Furthermore, Group AM630-VEH did not significantly differ from Group VEH-VEH (P 40.05), indicating that administration of AM630 alone had no effect. When administered alone, VEH, HU-308 and AM630 did not produce vomiting during the pretreatment period before administration of LiCl in these animals (data not shown). In addition, no sex differences in vomiting were observed (data not shown). The incidence of vomiting was 100% for all groups, except for Group VEH-HU-308 (5 mg/kg), for which the incidence of vomiting was 80%; therefore, HU-308 did not completely block LiCl-induced vomiting. 3.2. HU-308 suppresses LiCl-induced conditioned gaping to a flavour in rats; a CB2 receptor mediated effect HU-308 suppressed LiCl-induced gaping in rats, an effect that was prevented by pretreatment with AM630 (Fig. 2(A)). A KruskalWallis test of the number of gapes revealed a significant effect of pretreatment group H(6)¼ 21.8; P ¼0.001). Subsequent pairwise comparison tests revealed that 5 mg/kg HU-308 significantly (P ¼0.007) reduced LiCl-induced gaping relative to the VEH-VEH pretreated controls. In addition those rats in pretreatment group AM630-HU-308 5 mg/kg gaped significantly more than rats in pretreatment group VEH-HU-308 5 mg/kg (P ¼0.03), suggesting a CB2 mediated effect. The number of rats that displayed at least one gaping reaction at test is indicated in parenthesis above each bar in Fig. 2(A). As is apparent, only in the group pretreated with 5 mg/ kg HU308 (Group VEH- HU-308 5 mg/kg) did fewer than 42% of the rats display even a single gape at test. The mean amounts of saccharin consumed during the conditioned taste avoidance test at 30, 120, and 360 min are presented in Fig. 2(B). A 8 3 mixed factors ANOVA revealed a significant effect of time of test, F(2,130) ¼289.3, P o0.001, indicating that as time passed, all rats consumed more saccharin. In addition, there was a significant effect of group, F(7,65) ¼4.6, Po0.001.
Subsequent Bonferroni post-hoc comparsion tests revealed that group VEH-VEH-Saline drank significantly more saccharin than all other groups (treated with LiCl), P o0.001. There were no other significant differences between groups, indicating that pretreatment with either HU-308 or AM630 did not interfere with learning per se.
4. Discussion HU-308 (2.5, 5 mg/kg) reduced, but did not completely block, LiCl-induced vomiting in S. murinus. Furthermore, HU-308 (5 mg/ kg) was also effective in reducing, but not completely blocking, LiCl-induced conditioned gaping in rats. The suppressive effects of HU-308 (5 mg/kg) on both vomiting in shrews and conditioned gaping in rats were prevented by AM630 administration, indicating that both effects were mediated by a CB2 receptor mechanism of action. To our knowledge, the studies presented here are the first demonstration of the anti-nausea effect of direct CB2 receptor agonism in animal models. In addition, they further characterize the anti-emetic role of the CB2 receptor, as initially explored by Van Sickle et al. (2005). Indeed Van Sickle et al. (2005) reported that the anti-emetic actions of 2-AG and the endocannabinoid transport inhibitor, VDM11, were blocked by both CB1 and CB2 antagonists, establishing a role for the potential anti-emetic effects of CB2 agonists. Our finding that HU-308 reduced LiCl-induced emesis in the Suncus murinus is in contrast to results reported by Van Sickle et al. (2005) who observed no anti-emetic effect in ferrets pretreated with the CB2 receptor agonists AM1241 (1 or 2 mg/kg) or JWH 133 (1 or 5 mg/kg) before M6G (0.05 mg/kg, subcutaneously, s.c.). This inconsistency in results could be due to the emetogenic properties of differing agents (M6G versus LiCl). For example granisetron (1 mg/kg, s.c., a 5-HT3 receptor antagonist) failed to reduce emesis in ferrets treated with M6G (0.05 mg/kg, s.c.) (Thompson et al., 1992), even though the dose of granisetron used was in excess of
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that necessary to reduce radiation- and cytotoxic-induced emesis in ferrets (Bermudez et al., 1988). In contrast, the lesser potent (Andrews et al., 1993) 5-HT3 receptor antagonist ondansetron (0.2– 3 mg/kg, i.p.) effectively reduced cisplatin-induced emesis in S. murinus (Kwiatkowska et al., 2004). These findings indicate that M6G may be more emetogenic in ferrets than other toxins such as cisplatin or LiCl in ferrets or S. murinus, and could therefore account for the ineffectiveness of CB2 receptor agonists in reducing M6G-induced emesis. HU-308 at doses of 2.5 and 5 mg/kg (but not doses of 1 and 10, 20, 40 mg/kg), reduced LiCl-induced vomiting in shrews. Such dose dependent, biphasic, effects are typical in many in vivo studies with cannabinoids. For example, activation of CB1 cannabinoid receptors at low doses has been shown to reduce anxiety-like behaviors in mice (e.g. Patel and Hillard, 2006), while higher doses of cannabinoid compounds induce anxiogenic-like effects (Viveros et al., 2005). Such a dose response curve is also seen in conditioned gaping with cannabidiolic acid, the precursor of cannabidiol. For example, at low doses (0.05 mg/kg) and high doses (5 mg/ kg), cannabidiolic acid is ineffective in suppressing LiCl-induced vomiting in S. murinus while moderate doses (0.1, 0.5 mg/kg) suppressed LiCl-induced vomiting (Bolognini et al., 2013). No pretreatments modified the strength of conditioned taste avoidance in rats, indicating that the interference with conditioned gaping by HU-308 was not the result of interference with learning per se. Anti-emetic treatments prevent nausea-induced conditioned gaping reactions, but spare conditioned avoidance, indicating that conditioned avoidance does not reflect conditioned nausea, as does conditioned gaping reactions (see Parker, 2014). Indeed, other anti-emetic cannabinoid treatments such as Δ9tetrahydrocannabinol (Limebeer and Parker, 1999; Parker et al., 2003), HU-210 (Parker et al., 2003), cannabidiol (Rock et al., 2012), FAAH inhibitors (Cross-Mellor et al., 2007; Rock et al., 2015) and MAGL inhibitors (Parker et al., 2014; Sticht et al., 2015) have also been reported to selectively interfere with the establishment of LiCl-induced conditioned gaping reactions, but not conditioned taste avoidance. Conditioned taste avoidance seems to be mediated by a different mechanism (potentially conditioned fear rather than nausea) than conditioned gaping reactions (for review see Parker et al., 2008, 2009; Parker, 2014). The localization of CB2 receptors in the brainstem (Van Sickle et al., 2005) makes this location the likely brain region to regulate the anti-emetic effects of HU-308 in shrews. In addition to their location in brainstem structures, Gong et al. (2006) also identified CB2 immunoreactive fibers and nerve terminals at the level of the visceral insular cortex (VIC). Our group has accumulating evidence to suggest that the VIC plays a critical role during acute nauseainduced conditioned gaping in rats (Limebeer et al., 2012; Tuerke et al., 2012). Therefore, it is possible that CB2 receptors in this area may be mediating the anti-nausea effect of HU-308 in rats; however, there have been no reports of localization of CB2 receptors in the VIC. Further study of intra-VIC delivery of HU-308 on the establishment of conditioned gaping in rats is warranted. In summary, this is the first demonstration of anti-emetic and anti-nausea effects of selective CB2 receptor agonism in animal models. Additionally, the selective CB2 receptor antagonist/inverse agonist AM630 blocked these effects, further indicating a CB2 receptor mechanism of action. As CB2 receptor activation is devoid of the psychoactive effects seen with CB1 receptor agonists, selective CB2 receptor activation may be a desirable therapeutic option to manage toxin-induced vomiting and/or nausea. However, the failure of a wide range of doses of HU-308 to completely block LiCl-induced vomiting in the Suncus murinus and LiCl-induced gaping in the rat, suggests that CB2 agonism may reduce but not completely prevent nausea and vomiting.
Acknowledgements This research was supported by a Grant from Natural Sciences and Engineering Research Council of Canada (NSERC-92057) to LAP.
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HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor. Proc. Natl. Acad. Sci. USA 96, 14228–14233. Hillsley, K., Grundy, D., 1998. Serotonin and cholecystokinin activate different populations of rat mesenteric vagal afferents. Neurosci. Lett. 255, 63–66. Horn, C.C., Kimball, B.A., Wang, H., Kaus, J., Dienel, S., Nagy, A., Gathright, G.R., Yates, B.J., Andrews, P.L.R., 2013. Why can’t rodents vomit? A comparative behavioral, anatomical, and physiological study. PLoS One 8, 1–16. Horn, C.C., Richardson, E.J., Andrews, P.L., Friedman, M.L., 2004. Differential effects on gastrointestinal and hepatic vagal afferent fibers in the rat by the anticancer agent cisplatin. Auton. Neurosci. 115, 74–81. Hornby, P.J., 2001. Central neurocircuitry associated with emesis. Am. J. Med 111 (Suppl 8A), 106S–112S. Hosohata, K., Quock, R.M., Hosohata, Y., Burkey, T.H., Makriyannis, A., Consroe, P., et al., 1997. 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Contents lists available at ScienceDirect
European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar
Behavioural pharmacology
Cannabinoid 2 (CB2) receptor agonism reduces lithium chlorideinduced vomiting in Suncus murinus and nausea-induced conditioned gaping in rats Erin M. Rock a, Nathalie Boulet a, Cheryl L. Limebeer a, Raphael Mechoulam b, Linda A. Parker a,n a b
Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, Canada Institute of Drug Research, Hebrew University of Jerusalem, Jerusalem, Israel
art ic l e i nf o
a b s t r a c t
Article history: Received 16 November 2015 Received in revised form 20 May 2016 Accepted 1 June 2016 Available online 2 June 2016
We aimed to investigate the potential anti-emetic and anti-nausea properties of targeting the cannabinoid 2 (CB2) receptor. We investigated the effect of the selective CB2 agonist, HU-308, on lithium chloride- (LiCl) induced vomiting in Suncus murinus (S. murinus) and conditioned gaping (nausea-induced behaviour) in rats. Additionally, we determined whether these effects could be prevented by pretreatment with AM630 (a selective CB2 receptor antagonist/inverse agonist). In S. murinus, HU-308 (2.5, 5 mg/kg, i.p.) reduced, but did not completely block, LiCl-induced vomiting; an effect that was prevented with AM630. In rats, HU-308 (5 mg/kg, i.p.) suppressed, but did not completely block, LiClinduced conditioned gaping to a flavour; an effect that was prevented by AM630. These findings are the first to demonstrate the ability of a selective CB2 receptor agonist to reduce nausea in animal models, indicating that targeting the CB2 receptor may be an effective strategy, devoid of psychoactive effects, for managing toxin-induced nausea and vomiting. & 2016 Elsevier B.V. All rights reserved.
Keywords: CB2 receptor HU-308 AM630 Acute nausea Vomiting Conditioned gaping Chemical compounds studied in this article: HU-308 (PubChem CID: 9844711) AM630 (PubChem CID: 4302963) Lithium chloride (PubChem CID: 433294)
1. Introduction Nausea continues to be a distressing side effect of chemotherapy treatment. While acute vomiting is relatively well managed by 5-hydroxytryptamine 3 (5-HT3) receptor antagonists (such as ondansetron; Navari, 2009), and delayed vomiting is relatively well managed by the Neurokinin 1 receptor antagonists (such as aprepitant; e.g. Tatsushima et al., 2011), nausea is still problematic, indicating that other pharmacological avenues need to be explored (see Sharkey et al., 2014). When assessing 5-HT3 receptor antagonists for the alleviation of acute emesis in human patients, complete response (no emetic episodes, no rescue medications, no nausea) is often the primary outcome assessed, making it difficult to dissociate the prevalence of vomiting versus nausea. Nevertheless, in a more recent study, Sepúlveda-Vildósola et al. (2008) reported that treatment with a 5-HT3 receptor antagonist resulted in complete acute emesis control in 72% of patients, but acute n
Corresponding author. E-mail address: [email protected] (L.A. Parker).
http://dx.doi.org/10.1016/j.ejphar.2016.06.001 0014-2999/& 2016 Elsevier B.V. All rights reserved.
nausea was completely controlled in only 38% of patients; highlighting the utility of 5-HT3 receptor antagonists in treating acute emesis (but not acute nausea). Furthermore, treatment with a Neurokinin 1 receptor antagonist resulted in acute emetic control in only 37% of patients, and was less effective in reducing acute nausea than a 5-HT3 receptor antagonist (Cocquyt et al., 2001). Interestingly, treatment with a Neurokinin 1 receptor antagonist resulted in delayed emetic control in 72% of patients, but was more effective than a 5-HT3 receptor antagonist in reducing delayed nausea (Cocquyt et al., 2001). These recent findings suggest that acute emesis and nausea differ from delayed emesis and nausea due to their differential response to these treatments. Although the neural mechanisms of nausea are not well understood, the emetic reflex has been well characterized using animal models such as the ferret and the shrew (e.g. Hornby, 2001). Reliable pre-clinical animal models are also necessary to assess the efficacy of anti-nausea drugs. One pre-clinical model that has been used to assess the anti-nausea effect of compounds is conditioned gaping in the rat. Although rats do not vomit, they display a conditioned gaping response (wide opening of the mouth exposing the lower incisors) when they re-encounter a flavour or a
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context that has previously been paired with an emetic agent (that is an agent that produces vomiting in species capable of vomiting). Conditioned gaping in the rat is only produced by emetic agents and typical anti-emetic agents interfere with the establishment of conditioned gaping (see Parker, 2014). This conditioned gaping response requires similar orofacial muscular responses as those required for the vomiting response in emetic species (Travers and Norgren, 1986). As well, the rat detects emetic toxins (such as cisplatin) in the gut in a similar way as ferrets which are capable of vomiting; with cisplatin causing 5-HT release from enteroendocrine cells in the gut, activating 5-HT3 receptors on vagal afferent fibers (Endo et al., 1995; Hillsley and Grundy, 1998; Horn et al., 2004). In both species, 5-HT3 receptor antagonism can block this vagal activation (Endo et al., 1995; Horn et al., 2004). In addition, the area postrema detects blood-borne toxins in the rat, as well as emetic species (Bernstein et al., 1992; Eckel and Ossenkopp, 1996), indicating that although the detection mechanism for vomiting is present in the rat, the motor output is not (Horn et al., 2004; 2013). Cannabinoids, compounds derived from the Cannabis sativa plant, have been shown to reduce nausea and vomiting in animal models (Sharkey et al., 2014; Parker et al., 2011). The endogenous cannabinoid system is comprised of two cannabinoid receptors (cannabinoid 1, CB1 and cannabinoid 2, CB2) possessing distinct physiological properties that have been identified and well characterized. Although agonists of the CB1 receptor produce psychoactive effects limiting their therapeutic potential, agonists of the CB2 receptor are devoid of psychoactivity (see Pacher and Mechoulam, 2011). The CB1 receptor is highly expressed in the central nervous system, while the CB2 receptor has been identified outside of the central nervous system and was once thought to be solely associated with immune tissues. Recent evidence however, indicates that CB2 receptors are also located centrally in regions such as the brainstem, cortex and cerebellum (Onaivi et al., 2006; Van Sickle et al., 2005). Of most relevance, Van Sickle et al. (2005) reported the expression of CB2 receptor messenger ribonucleic acid expression and protein localization in the rat brainstem regions of the dorsal motor nuclei. Δ9-Tetrahydrocannabinol (THC, the psychoactive component of cannabis) exerts its anti-emetic effects in ferrets via activation of CB1 receptors in the dorsal vagal complex (Van Sickle et al., 2003). In addition, Van Sickle et al. (2005) demonstrated the anti-emetic role of the CB2 receptor in morphine-6-glucuronide- (M6G) induced emesis. Administration of the endogenous cannabinoids, 2-Arachidonoylglycerol or anandamide, dose-dependently reduced emesis in ferrets. The anti-emetic effects of anandamide were blocked by the CB1 receptor antagonist, AM251, but not by the CB2 receptor antagonist/inverse agonist, AM630 (4- [4- (1, 1dimethylheptyl)- 2, 6- dimethoxyphenyl]- 6, 6- dimethyl- bicyclo [3.1.1]hept- 2- ene- 2- methanol). In contrast, the anti-emetic effects of 2-Arachidonoylglycerol (2-AG) were blocked by AM251 or AM630, indicating the functional role of the CB2 receptor in the anti-emetic effects of 2-AG (Van Sickle et al., 2005). However, there is also evidence that the CB2 receptor antagonist SR144528 did not block WIN55,212-2- or CP55,940-induced suppression of cisplatin- or radiation- induced vomiting in the least shrew (Darmani, 2001; Darmani et al., 2003, 2007), nor did the CB2 receptor antagonist AM630 block WIN55,212-2-induced suppression of opioid-induced vomiting in the ferret (Simoneau et al., 2001). Therefore, the evidence is mixed regarding the potential of CB2 agonism to produce an anti-emetic effect. As the CB1 receptor mediates the psychoactive effects of cannabinoids, selective CB2 receptor activation has the potential to exert its physiological effects, in the absence of psychoactivity. Therefore, it is of interest to determine if selective CB2 receptor agonists have anti-emetic and anti-nausea potential.
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1.1. Objective The purpose of the current study was to investigate the potential of the selective CB2 receptor agonist, HU-308 (4- [4- (1, 1dimethylheptyl)-2, 6- dimethoxyphenyl]-6, 6- dimethyl- bicyclo [3.1.1]hept- 2- ene- 2- methanol, Hanus et al., 1999) to interfere with LiCl-induced vomiting in S. murinus and conditioned gaping in rats. In addition, the CB2 receptor mediation of HU-308's antiemetic and anti-nausea effects was investigated via pretreatment with the selective CB2 receptor antagonist/inverse agonist AM630 (Hosohata et al., 1997; Ross et al., 1999).
2. Materials and methods 2.1. Animals All animal procedures complied with the Canadian Council on Animal Care and were approved by the Institutional Animal Care Committee (accredited by the Canadian Council on Animal Care). The shrews were bred and raised in the University of Guelph colony and ranged from 49 to 193 days old at the time of testing. Naive male (n ¼19) and female (n ¼20) S. murinus (house musk shrews) were individually housed in opaque white mouse cages in the colony room at an ambient temperature of 21 °C on a 10/14 h light-dark schedule (lights off at 7 PM). Shrews were tested in their light cycle. They were provided with an open ended plastic cylinder (4 8 cm) containing enviro-paper, maintained on Medical/Royal Canine Feline Maintenance mixed with Harlan Ferret dry chow and had ad libitum access to water. All shrews were weaned at 25-30 days of age. Both male and female shrews are used in these emesis studies as no sex differences were observed for vomiting behaviour. Naïve male Sprague-Dawley rats (N ¼ 73), weighing between 258 and 353 g on the day of conditioning, obtained from Charles River Laboratories (St Constant, Quebec) were used for assessment of anti-nausea-like behaviour. The rats were housed singly in opaque plastic shoebox cages (48 26 20 cm), containing bed-ocob bedding from Harlan Laboratories, Inc. (Mississauga, Ontario), a brown paper towel and Crink-l'Nest™ from The Andersons, Inc. (Maumee, Ohio). Additionally, the rats were provided with a soft white plastic container that was 14 cm long and 12 cm in diameter. The colony room was kept at an ambient temperature of 21 °C with a 12/12 h light-dark schedule (lights off at 8 am). The rats were tested in their dark cycle; they were removed from the dark housing area and tested in the dimly lit taste reactivity chambers. The rats were maintained on food (Highland Rat Chow [8640]) and water ad-libitum. 2.2. Experimental procedures 2.2.1. Effect of HU-308 on LiCl-induced vomiting in S. murinus On the test day shrews were individually transferred from the colony room (University of Guelph colony) to an empty cage in the experimental room that contained four mealworms. After 15 min they were injected with vehicle (VEH; consisting of 1:9 Tween80: Saline, 1 ml/kg) or AM630 (3 mg/kg i.p.) followed 15 min later by an injection of VEH or HU-308 (1, 2.5, 5, 10, 20, 40 mg/kg, i.p.). Thirty min following the two pretreatment injections the shrews were injected with LiCl and put into an observation chamber for 45 min. The Plexiglas observation chambers (22.5 26 20 cm) were placed on a table with a clear glass top. A mirror at a 450 angle beneath the chamber facilitated viewing of the ventral surface of each shrew and hence of all vomiting episodes (oral expulsion of gastric contents). An observer blind to the experimental conditions counted the frequency of vomiting episodes. The
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groups were as follows: VEH-VEH (n ¼6, 4 Females [F], 2 Males [M]), VEH-HU-308 1 mg/kg (n ¼ 4, 2 F, 2 M), VEH-HU-308 2.5 mg/ kg (n ¼4, 2 F, 2 M, VEH-HU-308 5 mg/kg (n ¼5, 2 F, 3 M), VEH-HU308 10 mg/kg (n¼ 4, 2 F, 2 M), VEH-HU-308 20 mg/kg (n ¼ 4, 2 F, 2 M), VEH-HU-308 40 mg/kg (n ¼ 4, 1 F, 3 M), AM630-VEH (n ¼4, 2 F, 2 M), AM630-HU-308 5 mg/kg (n ¼4, 3 F, 1 M). 2.2.2. Effect of HU-308 on LiCl-induced conditioned gaping in rats All rats were surgically implanted with an intraoral cannula under isoflurane anaesthesia according to the procedures described by Limebeer et al. (2010). Following three days recovery from surgery, the rats were adapted to the taste reactivity (TR) chambers and infusion procedure. They were placed in the TR chamber with their cannula attached to an infusion pump (Model KDS100, KD Scientific, Holliston, MA, USA) and water was infused into their intraoral cannula for 2 min at a rate of 1 ml/min. The TR chambers were made of clear Plexiglas (22.5 26 20 cm) that sat on a table with a clear glass top. A mirror beneath the chamber on a 45° angle (illuminated by two 25 W lights on either side, but no overhead light in the room) facilitated viewing of the ventral surface of the rat to observe orofacial responses. On the next day, the rats received a conditioning trial in which they were administered a pretreatment injection of VEH or AM630 (1 mg/kg). Fifteen min later, the rats were injected with either VEH or HU-308 (1, 2.5, 5, 10 mg/kg). Thirty min following the two pretreatment injections the rats were individually placed in the TR chamber and intraorally infused with 0.1% saccharin solution for 2 min at the rate of 1 ml/min while the orofacial responses were video recorded (Sony DCR-HC48, Henry's Cameras, Waterloo, ON, Canada) for subsequent scoring of gaping responses (large openings of the mouth and jaw, with lower incisors exposed; at ½ speed) by a rater blind to the experimental conditions using ‘The Observer’ (version XT 7, Noldus Information Technology Inc., Leesburg, VA, USA). The number of gaping responses was recorded over the 2 min test session. Immediately after the saccharin infusion, all rats were injected with 20 ml/kg of 0.15 M LiCl and returned to their home cage. The groups were as follows: VEH-VEH (n ¼11), VEH-HU-308 1 mg/kg (n ¼7), VEH-HU-308 2.5 mg/kg (n ¼9), VEH-HU-308 5 mg/kg (n¼ 12), VEH-HU-308 10 mg/kg (n ¼7), AM630-VEH (n ¼8), AM630-HU-308 5 mg/kg (n ¼11). Seventy-two h following conditioning a drug-free test was conducted. Rats were brought individually to the TR chamber where they were intraorally infused with 0.1% saccharin solution for 2 min at the rate of 1 ml/min while the orofacial responses were video recorded for later scoring. At the end of the saccharin infusion rats were returned to their home cages. To determine if the pretreatments interfered with learning per se, conditioned taste avoidance was assessed in a single bottle test. Rats were water-restricted at 4:00 PM following the taste reactivity test. The following morning, a single bottle containing 0.1% saccharin was placed on the cage at 9:00 AM. Measures of saccharin consumption were taken at 30, 120, and 360 min. To assess the amount of saccharin consumed by naïve rats, an additional group of rats were pretreated with VEH-VEH-Saline (n ¼8).
1 or 40 mg/ml (1, 40 mg/kg, respectively), or at a volume of 0.5, 1, 2, 4 ml/kg at a concentration of 5 mg/ml (2.5, 5, 10, 20 mg/kg, respectively). In rats, HU-308 was administered i.p. at a volume of 1 ml/kg at a concentration of 1, 5 or 10 mg/ml (1, 5, 10 mg/kg, respectively, or at a volume of 0.5 ml/kg at a concentration of 5 mg/ml (2.5 mg/kg). AM630 was administered i.p. at a volume of 3 ml/kg at a concentration of 1 mg/ml (3 mg/kg) in shrews and i.p. at a volume of 1 ml/kg at a concentration of 1 mg/ml (1 mg/kg) in rats. The AM630 dose of 1 mg/kg in rats were chosen based on previous studies (e.g. Tang et al., 2016; Wang et al., 2015). 2.4. Statistical methods The number of vomiting responses (total number of vomiting responses with expulsion of gastric contents) for the shrews and the number of gapes during the TR test (total of wide openings of the mouth over the 2 min test period) for the rats was entered into an Independent Samples Kruskal-Wallis test with subsequent pairwise comparisons tests. The ml saccharin consumed at each test interval during the conditioned taste avoidance test for each group of rats was entered into a mixed-factors Analysis of Variance (ANOVA) with subsequent Bonferroni post-hoc comparison tests. For all analyses, P values o0.05 were taken as significant.
3. Results 3.1. HU-308 reduces LiCl-induced vomiting in S. murinus; a CB2 receptor mediated effect HU-308 (2.5, 5 but not 1, 10, 20 or 40 mg/kg) reduced LiCl-induced vomiting in shrews, an effect that was prevented by the CB2 antagonist AM630 (Fig. 1). A Kruskal-Wallis test of the number vomits displayed by the various groups was significant, H(8) ¼ 29.3; Po 0.001). Subsequent pairwise comparison tests revealed that those shrews given LiCl after pretreatment with VEH-HU-308 (2.5, 5 mg/kg) vomited significantly less than VEH-VEH pretreated controls (P'so 0.02). As well, Group AM630-HU-308 5 mg/kg did
2.3. Drugs and materials LiCl (Sigma) was prepared in a 0.15 M solution with sterile water and was administered intraperitoneally (i.p.) for shrews at a volume of 60 ml/kg (390 mg/kg dose), and i.p. at a volume of 20 ml/kg (127.2 mg/kg) for rats. HU-308 and AM630 were prepared in a vehicle that consisted of 1:9 Tween80:Saline. First the drugs were dissolved in ethanol (EtOH) and then Tween80 (Sigma) was added to the solution. Then the EtOH was evaporated using a nitrogen stream and then saline was added. In shrews, HU-308 was administered i.p. at a volume of 1 ml/kg at a concentration of
Fig. 1. Effect of HU-308 (1, 2.5, 5, 10, 20, 40 mg/kg, i.p.) or VEH administered i.p. 30 min prior to LiCl administration. Additional groups were also given AM630 (3 mg/kg, i.p.) 15 min prior to VEH or HU-308 (5 mg/kg). The number of emetic episodes in shrews treated with LiCl was measured. Each bar represents the mean7 S.E.M. (n¼ 4–6). The numbers in parentheses indicate n/group that displayed emetic behaviour. The asterisks indicate a significant difference from the VEH-VEH pretreated control animals (**Po 0.01, *P o 0.05).
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Fig. 2. Effect of HU-308 (1, 2.5, 5, 10 mg/kg, i.p.), or VEH administered 30 min prior to LiCl. Additional groups were also given AM630 (1 mg/kg, i.p.) 15 min prior to VEH or HU308 (5 mg/kg) and LiCl. (A) The mean number of conditioned gaping responses was measured during the test trial. Each bar represents the mean7S.E.M. (n¼7–12). The numbers in parentheses indicate n/group that displayed at least one conditioned gaping response. The asterisks indicate a significant difference from the VEH-VEH pretreated control animals (**Po0.01, *Po0.05). The number signs represent a significant difference from the VEH-HU-308 5 mg/kg group (#Po0.05). (B) The mean cumulative amount of saccharin solution consumed (ml7SEM) during a one-bottle consumption test was measured at 30, 120 and 360 min after introduction of the bottle to fluid-restricted rats. A naïve group of rats (not LiCl-treated) was also added (denoted VEH-VEH-Saline). The asterisks indicate a significant difference from all other groups (**Po0.01).
not significantly differ from VEH-VEH (P 40.05), indicating that administration of AM630 blocked the suppressive effect of HU-308 (5 mg/kg) on vomiting. Furthermore, Group AM630-VEH did not significantly differ from Group VEH-VEH (P 40.05), indicating that administration of AM630 alone had no effect. When administered alone, VEH, HU-308 and AM630 did not produce vomiting during the pretreatment period before administration of LiCl in these animals (data not shown). In addition, no sex differences in vomiting were observed (data not shown). The incidence of vomiting was 100% for all groups, except for Group VEH-HU-308 (5 mg/kg), for which the incidence of vomiting was 80%; therefore, HU-308 did not completely block LiCl-induced vomiting. 3.2. HU-308 suppresses LiCl-induced conditioned gaping to a flavour in rats; a CB2 receptor mediated effect HU-308 suppressed LiCl-induced gaping in rats, an effect that was prevented by pretreatment with AM630 (Fig. 2(A)). A KruskalWallis test of the number of gapes revealed a significant effect of pretreatment group H(6)¼ 21.8; P ¼0.001). Subsequent pairwise comparison tests revealed that 5 mg/kg HU-308 significantly (P ¼0.007) reduced LiCl-induced gaping relative to the VEH-VEH pretreated controls. In addition those rats in pretreatment group AM630-HU-308 5 mg/kg gaped significantly more than rats in pretreatment group VEH-HU-308 5 mg/kg (P ¼0.03), suggesting a CB2 mediated effect. The number of rats that displayed at least one gaping reaction at test is indicated in parenthesis above each bar in Fig. 2(A). As is apparent, only in the group pretreated with 5 mg/ kg HU308 (Group VEH- HU-308 5 mg/kg) did fewer than 42% of the rats display even a single gape at test. The mean amounts of saccharin consumed during the conditioned taste avoidance test at 30, 120, and 360 min are presented in Fig. 2(B). A 8 3 mixed factors ANOVA revealed a significant effect of time of test, F(2,130) ¼289.3, P o0.001, indicating that as time passed, all rats consumed more saccharin. In addition, there was a significant effect of group, F(7,65) ¼4.6, Po0.001.
Subsequent Bonferroni post-hoc comparsion tests revealed that group VEH-VEH-Saline drank significantly more saccharin than all other groups (treated with LiCl), P o0.001. There were no other significant differences between groups, indicating that pretreatment with either HU-308 or AM630 did not interfere with learning per se.
4. Discussion HU-308 (2.5, 5 mg/kg) reduced, but did not completely block, LiCl-induced vomiting in S. murinus. Furthermore, HU-308 (5 mg/ kg) was also effective in reducing, but not completely blocking, LiCl-induced conditioned gaping in rats. The suppressive effects of HU-308 (5 mg/kg) on both vomiting in shrews and conditioned gaping in rats were prevented by AM630 administration, indicating that both effects were mediated by a CB2 receptor mechanism of action. To our knowledge, the studies presented here are the first demonstration of the anti-nausea effect of direct CB2 receptor agonism in animal models. In addition, they further characterize the anti-emetic role of the CB2 receptor, as initially explored by Van Sickle et al. (2005). Indeed Van Sickle et al. (2005) reported that the anti-emetic actions of 2-AG and the endocannabinoid transport inhibitor, VDM11, were blocked by both CB1 and CB2 antagonists, establishing a role for the potential anti-emetic effects of CB2 agonists. Our finding that HU-308 reduced LiCl-induced emesis in the Suncus murinus is in contrast to results reported by Van Sickle et al. (2005) who observed no anti-emetic effect in ferrets pretreated with the CB2 receptor agonists AM1241 (1 or 2 mg/kg) or JWH 133 (1 or 5 mg/kg) before M6G (0.05 mg/kg, subcutaneously, s.c.). This inconsistency in results could be due to the emetogenic properties of differing agents (M6G versus LiCl). For example granisetron (1 mg/kg, s.c., a 5-HT3 receptor antagonist) failed to reduce emesis in ferrets treated with M6G (0.05 mg/kg, s.c.) (Thompson et al., 1992), even though the dose of granisetron used was in excess of
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that necessary to reduce radiation- and cytotoxic-induced emesis in ferrets (Bermudez et al., 1988). In contrast, the lesser potent (Andrews et al., 1993) 5-HT3 receptor antagonist ondansetron (0.2– 3 mg/kg, i.p.) effectively reduced cisplatin-induced emesis in S. murinus (Kwiatkowska et al., 2004). These findings indicate that M6G may be more emetogenic in ferrets than other toxins such as cisplatin or LiCl in ferrets or S. murinus, and could therefore account for the ineffectiveness of CB2 receptor agonists in reducing M6G-induced emesis. HU-308 at doses of 2.5 and 5 mg/kg (but not doses of 1 and 10, 20, 40 mg/kg), reduced LiCl-induced vomiting in shrews. Such dose dependent, biphasic, effects are typical in many in vivo studies with cannabinoids. For example, activation of CB1 cannabinoid receptors at low doses has been shown to reduce anxiety-like behaviors in mice (e.g. Patel and Hillard, 2006), while higher doses of cannabinoid compounds induce anxiogenic-like effects (Viveros et al., 2005). Such a dose response curve is also seen in conditioned gaping with cannabidiolic acid, the precursor of cannabidiol. For example, at low doses (0.05 mg/kg) and high doses (5 mg/ kg), cannabidiolic acid is ineffective in suppressing LiCl-induced vomiting in S. murinus while moderate doses (0.1, 0.5 mg/kg) suppressed LiCl-induced vomiting (Bolognini et al., 2013). No pretreatments modified the strength of conditioned taste avoidance in rats, indicating that the interference with conditioned gaping by HU-308 was not the result of interference with learning per se. Anti-emetic treatments prevent nausea-induced conditioned gaping reactions, but spare conditioned avoidance, indicating that conditioned avoidance does not reflect conditioned nausea, as does conditioned gaping reactions (see Parker, 2014). Indeed, other anti-emetic cannabinoid treatments such as Δ9tetrahydrocannabinol (Limebeer and Parker, 1999; Parker et al., 2003), HU-210 (Parker et al., 2003), cannabidiol (Rock et al., 2012), FAAH inhibitors (Cross-Mellor et al., 2007; Rock et al., 2015) and MAGL inhibitors (Parker et al., 2014; Sticht et al., 2015) have also been reported to selectively interfere with the establishment of LiCl-induced conditioned gaping reactions, but not conditioned taste avoidance. Conditioned taste avoidance seems to be mediated by a different mechanism (potentially conditioned fear rather than nausea) than conditioned gaping reactions (for review see Parker et al., 2008, 2009; Parker, 2014). The localization of CB2 receptors in the brainstem (Van Sickle et al., 2005) makes this location the likely brain region to regulate the anti-emetic effects of HU-308 in shrews. In addition to their location in brainstem structures, Gong et al. (2006) also identified CB2 immunoreactive fibers and nerve terminals at the level of the visceral insular cortex (VIC). Our group has accumulating evidence to suggest that the VIC plays a critical role during acute nauseainduced conditioned gaping in rats (Limebeer et al., 2012; Tuerke et al., 2012). Therefore, it is possible that CB2 receptors in this area may be mediating the anti-nausea effect of HU-308 in rats; however, there have been no reports of localization of CB2 receptors in the VIC. Further study of intra-VIC delivery of HU-308 on the establishment of conditioned gaping in rats is warranted. In summary, this is the first demonstration of anti-emetic and anti-nausea effects of selective CB2 receptor agonism in animal models. Additionally, the selective CB2 receptor antagonist/inverse agonist AM630 blocked these effects, further indicating a CB2 receptor mechanism of action. As CB2 receptor activation is devoid of the psychoactive effects seen with CB1 receptor agonists, selective CB2 receptor activation may be a desirable therapeutic option to manage toxin-induced vomiting and/or nausea. However, the failure of a wide range of doses of HU-308 to completely block LiCl-induced vomiting in the Suncus murinus and LiCl-induced gaping in the rat, suggests that CB2 agonism may reduce but not completely prevent nausea and vomiting.
Acknowledgements This research was supported by a Grant from Natural Sciences and Engineering Research Council of Canada (NSERC-92057) to LAP.
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