Cannabinoids suppress acute and anticipatory nausea in preclinical rat models of conditioned gaping.

The sensation of nausea is one of the most debilitating human experiences. Current antiemetic therapies are effective in reducing vomiting, but are less effective in reducing acute and delayed nausea and are completely ineffective in reducing anticipatory nausea. Recent preclinical evidence using a selective rat model of nausea (conditioned gaping reactions) has revealed that cannabinoids have great promise as treatments for nausea and that their antinausea effects may be mediated by the interoceptive insular cortex.

Suppression of lithium chloride-induced conditioned gaping (a model of nausea-induced behaviour) in rats (using the taste reactivity test) with metoclopramide is enhanced by cannabidiolic acid.

We aimed to determine the potential of various doses of metoclopramide (MCP, a dopamine antagonist) to reduce lithium chloride (LiCl)-induced conditioned gaping (a nausea-induced behaviour) in rats, using the taste reactivity test. We then evaluated whether an ineffective low dose of cannabidiolic acid (CBDA, 0.1 µg/kg, Rock and Parker, 2013), the potent acidic precursor of cannabidiol (CBD, a non-psychoactive component of cannabis) could enhance the anti-nausea effects of an ineffective low dose of MCP. MCP (3.0 mg/kg) reduced conditioned gaping responses. Coadministration of ineffective doses of MCP (0.3 mg/kg) and CBDA (0.1 µg/kg) enhanced the suppression of conditioned gaping, over that of either drug alone, without interfering with conditioned taste avoidance. MCP dose-dependently reduced nausea-induced conditioned gaping in rats. As well, the suppression of conditioned gaping was enhanced when ineffective doses of MCP and CBDA were coadministered. These data suggest that CBDA could be a powerful adjunct treatment to anti-emetic regimens for chemotherapy-induced nausea.

Anandamide transport inhibition by ARN272 attenuates nausea-induced behaviour in rats, and vomiting in shrews (Suncus murinus).

BACKGROUND AND PURPOSE: To understand how anandamide transport inhibition impacts the regulation of nausea and vomiting and the receptor level mechanism of action involved. In light of recent characterization of an anandamide transporter, fatty acid amide hydrolase-1-like anandamide transporter, to provide behavioural support for anandamide cellular reuptake as a facilitated transport process. EXPERIMENTAL APPROACH: The systemic administration of the anandamide transport inhibitor ARN272 ([(4-(5-(4-hydroxy-phenyl)-3,4-diaza-bicyclo[4.4.0]deca-1(6),2,4,7,9-pentaen-2-ylamino)-phenyl)-phenylamino-methanone]) was used to evaluate the prevention of LiCl-induced nausea-induced behaviour (conditioned gaping) in rats, and LiCl-induced emesis in shrews (Suncus murinus). The mechanism of how prolonging anandamide availability acts to regulate nausea in rats was explored by the antagonism of cannabinoid 1 (CB1) receptors with the systemic co-administration of SR141716. KEY RESULTS: The systemic administration of ARN272 produced a dose-dependent suppression of nausea-induced conditioned gaping in rats, and produced a dose-dependent reduction of vomiting in shrews. The systemic co-administration of SR141716 with ARN272 (at 3.0 mg·kg(-1)) in rats produced a complete reversal of ARN272-suppressed gaping at 1.0 mg·kg(-1). SR141716 alone did not differ from the vehicle solution. CONCLUSIONS AND IMPLICATIONS: These results suggest that anandamide transport inhibition by the compound ARN272 tonically activates CB1 receptors and as such produces a type of indirect agonism to regulate toxin-induced nausea and vomiting. The results also provide behavioural evidence in support of a facilitated transport mechanism used in the cellular reuptake of anandamide.

2-arachidonoylglycerol interferes with lithium-induced vomiting in the house musk shrew, Suncus murinus.

The role of the endocannabinoid system in vomiting has been previously studied using several animal species. These investigations have clearly demonstrated an anti-emetic role for the eCB, anandamide, in these animal models; however, research concerning the role of 2-arhachidonoylglycerol (2AG) has been less clear. The aim of the present study was to assess the effects of exogenous 2AG administration in the house musk shrew, Suncus murinus. In Experiment 1, shrews were injected with vehicle or 2AG (1, 2, 5, 10 mg/kg) 15 min prior to behavioral testing in which the frequency of vomiting episodes was observed. In Experiment 2, shrews were pre-treated with 2AG (2, 5 mg/kg) prior to being administered the emetic drug, lithium chloride (LiCl). It was found that 2AG alone did not induce emesis, but interfered with vomiting in response to LiCl administration. The anti-emetic effects of 2AG in Suncus murinus do not appear to be mediated by CB1 receptors, as concomitant pretreatment with the CB1 receptor antagonist, SR141716, did not reverse the suppressive effects of 2AG. These results confirm that manipulations that increase levels of 2AG exert anti-emetic effects in the house musk shrew.

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

BACKGROUND AND PURPOSE: We evaluated the anti-emetic and anti-nausea properties of the acid precursor of Δ(9) -tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THCA), and determined its mechanism of action in these animal models. EXPERIMENTAL APPROACH: We investigated the effect of THCA on lithium chloride- (LiCl) induced conditioned gaping (nausea-induced behaviour) to a flavour, and context (a model of anticipatory nausea) in rats, and on LiCl-induced vomiting in Suncus murinus. Furthermore, we investigated THCA's ability to induce hypothermia and suppress locomotion [rodent tasks to assess cannabinoid1 (CB1 ) receptor agonist-like activity], and measured plasma and brain THCA and THC levels. We also determined whether THCA's effect could be blocked by pretreatment with SR141716 (SR, a CB1 receptor antagonist). KEY RESULTS: In rats, THCA (0.05 and/or 0.5 mg·kg(-1) ) suppressed LiCl-induced conditioned gaping to a flavour and context; the latter effect blocked by the CB1 receptor antagonist, SR, but not by the 5-hydroxytryptamine-1A receptor antagonist, WAY100635. In S. murinus, THCA (0.05 and 0.5 mg·kg(-1) ) reduced LiCl-induced vomiting, an effect that was reversed with SR. A comparatively low dose of THC (0.05 mg·kg(-1) ) did not suppress conditioned gaping to a LiCl-paired flavour or context. THCA did not induce hypothermia or reduce locomotion, indicating non-CB1 agonist-like effects. THCA, but not THC was detected in plasma samples. CONCLUSIONS AND IMPLICATIONS: THCA potently reduced conditioned gaping in rats and vomiting in S. murinus, effects that were blocked by SR. These data suggest that THCA may be a more potent alternative to THC in the treatment of nausea and vomiting.

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

BACKGROUND AND PURPOSE: 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). EXPERIMENTAL APPROACH: We investigated the efficacy of low doses of CBDA to suppress acute nausea, assessed by the establishment of conditioned gaping to a LiCl-paired flavour in rats. The potential of threshold and subthreshold doses of CBDA to enhance the reduction of nausea-induced conditioned gaping by OND were then determined. KEY RESULTS: CBDA (at doses as low as 0.5 µg·kg⁻¹) suppressed nausea-induced conditioned gaping to a flavour. A low dose of OND (1.0 µg·kg⁻¹) alone reduced nausea-induced conditioned gaping, but when it was combined with a subthreshold dose of CBDA (0.1 µg·kg⁻¹) there was an enhancement in the suppression of LiCl-induced conditioned gaping. CONCLUSIONS AND IMPLICATIONS: CBDA potently reduced conditioned gaping in rats, even at low doses and enhanced the anti-nausea effect of a low dose of OND. These findings suggest that combining low doses of CBDA and OND will more effectively treat acute nausea in chemotherapy patients.

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

BACKGROUND AND PURPOSE: To evaluate the ability of cannabidiolic acid (CBDA) to reduce nausea and vomiting and enhance 5-HT(1A) receptor activation in animal models. EXPERIMENTAL APPROACH: We investigated the effect of CBDA on (i) lithium chloride (LiCl)-induced conditioned gaping to a flavour (nausea-induced behaviour) or a context (model of anticipatory nausea) in rats; (ii) saccharin palatability in rats; (iii) motion-, LiCl- or cisplatin-induced vomiting in house musk shrews (Suncus murinus); and (iv) rat brainstem 5-HT(1A) receptor activation by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and mouse whole brain CB(1) receptor activation by CP55940, using [³5S]GTPγS-binding assays. KEY RESULTS: In shrews, CBDA (0.1 and/or 0.5 mg·kg⁻¹ i.p.) reduced toxin- and motion-induced vomiting, and increased the onset latency of the first motion-induced emetic episode. In rats, CBDA (0.01 and 0.1 mg·kg⁻¹ i.p.) suppressed LiCl- and context-induced conditioned gaping, effects that were blocked by the 5-HT(1A) receptor antagonist, WAY100635 (0.1 mg·kg⁻¹ i.p.), and, at 0.01 mg·kg⁻¹ i.p., enhanced saccharin palatability. CBDA-induced suppression of LiCl-induced conditioned gaping was unaffected by the CB1 receptor antagonist, SR141716A (1 mg·kg⁻¹ i.p.). In vitro, CBDA (0.1-100 nM) increased the E(max) of 8-OH-DPAT. CONCLUSIONS AND IMPLICATIONS: Compared with cannabidiol, CBDA displays significantly greater potency at inhibiting vomiting in shrews and nausea in rats, and at enhancing 5-HT(1A) receptor activation, an action that accounts for its ability to attenuate conditioned gaping in rats. Consequently, CBDA shows promise as a treatment for nausea and vomiting, including anticipatory nausea for which no specific therapy is currently available.

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 (CB(1) ) 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 CB(1) receptors. EXPERIMENTAL APPROACH: We utilized the conditioned gaping model of nausea to evaluate the effect of peripheral and central administration of the peripherally restricted CB(1) agonist, CB13, on the establishment of LiCl-induced gaping in rats. We further evaluated the ability of HU-210 administered to the gustatory insular cortex (GIC) or visceral insular cortex (VIC) to interfere with LiCl-induced conditioned gaping and determined if this effect was mediated by CB(1) receptors. KEY RESULTS: Central, but not peripheral, CB13 suppressed LiCl-induced conditioned gaping. Central administration of the potent CB(1) agonist, HU-210, delivered to the VIC, but not the GIC, suppressed the establishment of LiCl-induced gaping reactions, but not LiCl-induced suppression of hedonic reactions or conditioned taste avoidance. This pattern of results suggests that HU-210 delivered to the VIC prevented LiCl-induced nausea, but not learning per se. The suppression of LiCl-induced conditioned gaping by HU-210 was mediated by CB(1) receptors because it was prevented by co-administration of CB(1) antagonist/inverse agonist, AM-251, into the VIC. A high dose of AM-251 (20 µg) administered alone into the VIC did not produce conditioned gaping reactions. CONCLUSIONS AND IMPLICATIONS: The nausea-relieving effects of CB(1) agonists, but not the nausea-inducing effects of CB(1) inverse agonists, are mediated, at least in part, by their action at the VIC in rats.

Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT(1A) somatodendritic autoreceptors in the dorsal raphe nucleus.

BACKGROUND AND PURPOSE: To evaluate the hypothesis that activation of somatodendritic 5-HT(1A) 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. EXPERIMENTAL APPROACH: The potential of systemic and intra-DRN administration of 5-HT(1A) receptor antagonists, WAY100135 or WAY100635, to prevent the anti-emetic effect of CBD in shrews (Suncus murinus) and the anti-nausea-like effects of CBD (conditioned gaping) in rats were evaluated. Also, the ability of intra-DRN administration of CBD to produce anti-nausea-like effects (and reversal by systemic WAY100635) was assessed. In vitro studies evaluated the potential of CBD to directly target 5-HT(1A) receptors and to modify the ability of the 5-HT(1A) agonist, 8-OH-DPAT, to stimulate [(35) S]GTPγS binding in rat brainstem membranes. KEY RESULTS: CBD suppressed nicotine-, lithium chloride (LiCl)- and cisplatin (20 mg·kg(-1) , but not 40 mg·kg(-1) )-induced vomiting in the S. murinus and LiCl-induced conditioned gaping in rats. Anti-emetic and anti-nausea-like effects of CBD were suppressed by WAY100135 and the latter by WAY100635. When administered to the DRN: (i) WAY100635 reversed anti-nausea-like effects of systemic CBD, and (ii) CBD suppressed nausea-like effects, an effect that was reversed by systemic WAY100635. CBD also displayed significant potency (in a bell-shaped dose-response curve) at enhancing the ability of 8-OH-DPAT to stimulate [(35) S]GTPγS binding to rat brainstem membranes in vitro. Systemically administered CBD and 8-OH-DPAT synergistically suppressed LiCl-induced conditioned gaping. CONCLUSIONS AND IMPLICATIONS: These results suggest that CBD produced its anti-emetic/anti-nausea effects by indirect activation of the somatodendritic 5-HT(1A) autoreceptors in the DRN. LINKED ARTICLES: This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.

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.

To know that we know what we know: perceived knowledge and adolescent sexual risk behavior.

STUDY OBJECTIVE: To examine the relationship between perceived knowledge about sex and adolescent sexual behaviors. DESIGN: Secondary analysis of the 2001 Minnesota Student Survey. Bivariate and multivariate relationships between perceived knowledge about sex and sexual behaviors were examined. SETTING: Minnesota. PARTICIPANTS: 83,481 9(th) and 12(th) grade public school students. MAIN OUTCOME MEASURES: Students' report of sexual experience and sexual behaviors. RESULTS: Students with low perceived knowledge were less likely to be sexually experienced (OR=0.22, CI=0.17-0.29, females, OR=0.70, CI=0.59-0.82, males, P=0.00). Among sexually active students, those with low perceived knowledge also had significantly higher odds of engaging in risky sexual behaviors. Sexually experienced females with low perceived knowledge were more likely to report not talking with their partners about STIs (OR=1.83, CI=1.1-3.16, P=0.02), a history of pregnancy (OR=2.87, CI=1.59-5.18, P=0.00), and had higher numbers of male (P=0.03) and female (P=0.00) sexual partners. Sexually experienced males with low perceived knowledge were more likely to report not talking with their partners about pregnancy (OR=1.43, CI=1.11-1.84, P=0.01), pregnancy involvement (OR=2.22, CI=1.65-2.95, P=0.00), inconsistent use of birth control (OR=1.30, CI= 1.01-1.68, P=0.04), inconsistent use of condoms (OR=1.79, CI=1.38-2.32, P=0.00), not using a condom at last intercourse (OR=1.58, CI=1.22-2.04, P=0.00), and had a higher numbers of male (P=0.00) and female (P=0.00) sexual partners. CONCLUSIONS: Perceived knowledge may be a salient antecedent of adolescent sexual risk behavior. Health care providers and programs should incorporate the construct of perceived knowledge into their assessments of and interventions targeted at adolescents.

Physician knowledge and attitudes of Minnesota laws concerning adolescent health care.

STUDY OBJECTIVE: To determine physicians' knowledge and attitudes of medico-legal issues affecting adolescent health care. DESIGN, SETTING, PARTICIPANTS: A cross-sectional, mailed survey was distributed to 900 randomly selected primary care physicians in Minnesota, and all eligible physicians in Olmsted County. INTERVENTIONS: Physicians were mailed a survey with questions concerning Minnesota consent and confidentiality laws. MAIN OUTCOME MEASURES: Physician knowledge and attitudes of consent and confidentiality laws. RESULTS: A total of 317 (26%) surveys were returned. Olmsted county physicians achieved a median score of 37.5% and non-Olmsted physicians achieved a median score of 50% correct on a test of knowledge. Using a scoring scale where -1 signified "a bad law," 0 signified "neither a good nor bad law," and +1 signified "a good law," attitude regarding the laws was a median of +0.5 for both groups. In all, 41.1% of Olmsted physicians and 51.7% of non-Olmsted physicians felt that the laws had affected them or their practice. Olmsted physicians were compared to a cohort of Olmsted parents previously reported, with statistically significant differences noted. CONCLUSIONS: Results suggest that primary care physicians are not knowledgeable of Minnesota laws affecting adolescent health care. Opinion of these laws was positive, with notable exceptions. Physicians lack a sense of impact of laws affecting adolescent health care. Physicians were more knowledgeable and felt more positively about the laws than did parents of adolescents. Lack of knowledge and the presence of certain attitudes identify areas where physicians could benefit from greater understanding.