Erin M. Rock

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 (Δ9‐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.

Cannabidiol, a non‐psychotropic component of cannabis, attenuates vomiting and nausea‐like behaviour via indirect agonism of 5‐HT1A somatodendritic autoreceptors in the dorsal raphe nucleus

BACKGROUND AND PURPOSE To evaluate the hypothesis that activation of somatodendritic 5‐HT1A autoreceptors in the dorsal raphe nucleus (DRN) produces the anti‐emetic/anti‐nausea effects of cannabidiol (CBD), a primary non‐psychoactive cannabinoid found in cannabis.

Cannabidiolic acid prevents vomiting in Suncus murinus and nausea‐induced behaviour in rats by enhancing 5‐HT1A receptor activation

To evaluate the ability of cannabidiolic acid (CBDA) to reduce nausea and vomiting and enhance 5‐HT1A receptor activation in animal models.

The FAAH inhibitor URB-597 interferes with cisplatin- and nicotine-induced vomiting in the Suncus murinus (house musk shrew).

Considerable evidence implicates the endocannabinoid system as a neuromodulator of nausea and vomiting. The action of anandamide (AEA) can be prolonged by inhibiting its degradation, through the use of URB597 (URB), a Fatty Acid Amide Hydrolase (FAAH) enzyme inhibitor. Here we present evidence that the FAAH inhibitor, URB, interferes with cisplatin- and nicotine-induced vomiting in the Suncus murinus. In Experiment 1, shrews were injected with URB (0.9 mg/kg) or vehicle 120 min prior to the behavioral testing. They received a second injection of AEA (5 mg/kg) or vehicle 15 min prior to being injected with cisplatin (20 mg/kg) or saline and the number of vomiting episodes were counted for 60 min. In Experiment 2, shrews were injected with vehicle or URB (0.9 mg/kg) 120 min prior to receiving an injection of nicotine (5 mg/kg) or saline and the number of vomiting episodes were counted for 15 min. Experiment 3 evaluated the potential of the CB(1) antagonist, SR141716, to reverse the effect of URB on nicotine-induced vomiting. URB attenuated vomiting produced by cisplatin and nicotine and the combination of URB+AEA suppressed vomiting produced by cisplatin. The effect of URB on nicotine-induced vomiting was reversed by SR141716. These data suggest that the EC system plays a tonic role in the regulation of toxin-induced vomiting.

Inhibition of monoacylglycerol lipase attenuates vomiting in Suncus murinus and 2-arachidonoyl glycerol attenuates nausea in rats

BACKGROUND AND PURPOSE To evaluate the role of 2‐arachidonoyl glycerol (2AG) in the regulation of nausea and vomiting using animal models of vomiting and of nausea‐like behaviour (conditioned gaping).

The anti-nausea effects of CB1 agonists are mediated by an action at the visceral insular cortex

BACKGROUND AND PURPOSE Conditioned gaping reactions reflect nausea‐induced behaviour in rats. Cannabinoid 1 receptor (CB1) agonists interfere with the establishment of nausea‐induced conditioned gaping; however, it is not known if their effects are mediated by an action at peripheral or central CB1 receptors.

Effect of chronic exposure to rimonabant and phytocannabinoids on anxiety-like behavior and saccharin palatability.

The acute effects of cannabinoid compounds have been investigated in animal models of anxiety-like behavior and palatability processing. However, the chronic effects of cannabinoids in such models are poorly understood. Experiment 1 compared the effects of both acute and chronic (14 days) exposure to the CB(1) receptor inverse agonist/antagonist, rimonabant, and the cannabis-derived CB(1) receptor neutral antagonist, tetrahydrocannabivarin (THCV), on: 1) time spent in the open, lit box in the Light-Dark (LD) immersion model of anxiety-like behavior and 2) saccharin hedonic reactions in the taste reactivity (TR) test of palatability processing. Experiment 2 compared the effects of chronic administration of cannabis-derived Δ(9)-tetrahydrocannabinol (Δ(9)-THC), cannabidiol (CBD) and cannabigerol (CBG) in these models. Tests were administered on Days 1, 7 and 14 of drug administration. In Experiment 1, rimonabant, but not THCV, produced an anxiogenic-like reaction in the LD immersion test and reduced saccharin palatability in the TR test; both of these effects occurred acutely and were not enhanced by chronic exposure. In Experiment 2, Δ(9)-THC also produced an acute anxiogenic-like reaction in the LD immersion test, without enhancement by chronic exposure. However, Δ(9)-THC enhanced saccharin palatability in the TR test on Day 1 of drug exposure only. CBD and CBG did not modify anxiety-like responding, but CBG produced a weak enhancement of saccharin palatability on Day 1 only. The results suggest that the anxiogenic-like reactions and the suppression of hedonic responding produced by rimonabant, are mediated by inverse agonism of the CB(1) receptor and these effects are not enhanced with chronic exposure.

Tetrahydrocannabinolic acid reduces nausea-induced conditioned gaping in rats and vomiting in Suncus murinus

We evaluated the anti‐emetic and anti‐nausea properties of the acid precursor of Δ9‐tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), and determined its mechanism of action in these animal models.

Effect of low doses of cannabidiolic acid and ondansetron on LiCl‐induced conditioned gaping (a model of nausea‐induced behaviour) in rats

To determine the minimally effective dose of cannabidiolic acid (CBDA) that effectively reduces lithium chloride (LiCl)‐induced conditioned gaping reactions (nausea‐induced behaviour) in rats and to determine if these low systemic doses of CBDA (5–0.1 μg·kg−1) relative to those of CBD could potentiate the anti‐nausea effects of the classic 5‐hydroxytryptamine 3 (5‐HT3) receptor antagonist, ondansetron (OND).

Potential of the rat model of conditioned gaping to detect nausea produced by rolipram, a phosphodiesterase-4 (PDE4) inhibitor.

Rolipram, a phosphodiesterase-4 (PDE4) inhibitor, is of current interest as a cognitive enhancer and as a treatment for inflammatory diseases. Originally developed as an anti-depressant, roliprams efficacy was limited due to its side effects of nausea and vomiting. The experiments reported here evaluated the potential of rolipram to produce conditioned gaping (a selective measure of nausea in rats) to a flavor in the taste reactivity test (Experiment 1) and to a context (Experiment 2). In Experiment 1, rats were intra-orally infused with 17% sucrose solution prior to being injected with rolipram (Vehicle, 0.03, 0.1 or 0.3 mg/kg). Following 3 conditioning trials, rats conditioned with 0.3 mg/kg rolipram displayed conditioned gaping reactions during the infusion of sucrose. In Experiment 2, rats received 4 conditioning trials in which they were injected with 0.3 mg/kg rolipram and placed into a distinctive chamber. At test, when returned to the chamber rats displayed conditioned gaping. These results demonstrate the ability of the conditioned gaping model to detect the nauseating properties of a rolipram-paired flavor (Experiment 1) and rolipram-paired context (Experiment 2), further validating the potential use of the conditioned gaping model as a pre-clinical screening tool to evaluate the side effect of nausea produced by newly developed drugs.