Evaluation of Sex Differences in the Potential of Δ-Tetrahydrocannabinol, Cannabidiol, Cannabidiolic Acid, and Oleoyl Alanine to Reduce Nausea-Induced Conditioned Gaping Reactions in Sprague-Dawley Rats.

Cancer patients report nausea as a side effect of their chemotherapy treatment. Using the pre-clinical rodent model of acute nausea-lithium chloride (LiCl)-induced conditioned gaping-our group has demonstrated that exogenous cannabinoids may have antinausea potential. With the goal of evaluating the role of sex as a factor in pre-clinical research, we first compared the conditioned gaping reactions produced by varying doses of LiCl in male and female rats using the taste reactivity test (Experiment 1).

Short communication: Tissue distribution of major cannabinoids following intraperitoneal injection in male rats.

Currently, peripheral tissue distribution of cannabinoids after treatment is poorly understood. This pilot study sought to examine the early tissue distribution of major cannabinoids 30 minutes following an intraperitoneal injection of vehicle (1:9 Tween 80/SAL), and doses of THC (1 mg/kg) and CBD (5 mg/kg) that are feasible for human consumption in serum, adipose, brain, lung, liver, jejunum, and muscle of male Sprague-Dawley rats. The jejunum and adipose were most enriched in THC.

Effect of oleoyl glycine and oleoyl alanine on lithium chloride induced nausea in rats and vomiting in shrews.

Rationale: The fatty acid amide oleoyl glycine (OlGly) and its more stable methylated form oleoyl alanine (OlAla) reduce naloxone-precipitated morphine withdrawal (MWD)-induced conditioned gaping (nausea) responses in rats. In addition, OlGly has been shown to reduce lithium chloride (LiCl)-induced conditioned gaping in rats and vomiting in Suncus murinus (house musk shrews).

Objectives: Here, we compared the potential of these fatty acid amides to maintain their anti-nausea/anti-emetic effect over a delay.

Spontaneous and Naloxone-Precipitated Withdrawal Behaviors From Chronic Opiates are Accompanied by Changes in -Oleoylglycine and -Oleoylalanine Levels in the Brain and Ameliorated by Treatment With These Mediators.

The endocannabinoidome mediators, -Oleoylglycine (OlGly) and -Oleoylalanine (OlAla), have been shown to reduce acute naloxone-precipitated morphine withdrawal affective and somatic responses. To determine the role and mechanism of action of OlGly and OlAla in withdrawal responses from chronic exposure to opiates in male Sprague-Dawley rats. Opiate withdrawal was produced: 1) spontaneously 24 h following chronic exposure to escalating doses of morphine over 14 days (Experiments 1 and 2) and steady-state exposure to heroin by minipumps for 12 days (Experiment 3), 2) by naloxone injection during steady-state heroin exposure (Experiment 4), 3) by naloxone injection during operant heroin self-administration (Experiment 5).

Effects of inescapable stress on responses to social incentive stimuli and modulation by escitalopram.

Rationale: Stress is a well-known risk factor for anhedonia, and its impacts on social reward functions may be mitigated by its controllability. Moreover, there are questions about the effectiveness of selective serotonin reuptake inhibitors (SSRIs) on improving social hedonic functioning deficits characteristic of major depression.

Objectives: The current study in male Sprague-Dawley rats investigated the effects of uncontrollable stress on responses to social incentive stimuli and possible modulation by the SSRI escitalopram (ESC).

Therapeutic Potential of Cannabidiol, Cannabidiolic Acid, and Cannabidiolic Acid Methyl Ester as Treatments for Nausea and Vomiting.

Nausea and vomiting are the most distressing symptoms reported by oncology patients undergoing anticancer treatment. With the currently available treatments, vomiting and especially nausea remain problematic, highlighting the need for alternative treatments. Here we review and evidence for the effectiveness of the nonpsychoactive cannabinoid cannabidiol (CBD) in managing nausea and vomiting.

Cannabidiol Interferes with Establishment of Δ-Tetrahydrocannabinol-Induced Nausea Through a 5-HT Mechanism.

Cannabinoid hyperemesis syndrome (CHS) is characterized by intense nausea and vomiting brought on by the use of high-dose Δ-tetrahydrocannabinol (THC), the main psychotropic compound in cannabis. Cannabidiol (CBD), a nonpsychotropic compound found in cannabis, has been shown to interfere with some acute aversive effects of THC. In this study, we evaluated if CBD would interfere with THC-induced nausea through a 5-HT receptor mechanism as it has been shown to interfere with nausea produced by lithium chloride (LiCl).

High fructose corn syrup alters behavioural and neurobiological responses to oxycodone in rats.

There are indications that sugars in the diet can play a role in vulnerability to opioid abuse. The current study examined a range of neuro-behavioural interactions between oxycodone (OXY) and high fructose corn syrup (HFCS). Male Sprague-Dawley rats had access to HFCS (0 or 50%) over 26 days in their home cages and were subsequently tested on place conditioning induced by 0, 0.

Oleoylglycine and -Oleoylalanine Do Not Modify Tolerance to Nociception, Hyperthermia, and Suppression of Activity Produced by Morphine.

The endogenous amide -Oleoylglycine (OlGly) and its analog -Oleoylalanine (OlAla), have been shown to interfere with the affective and somatic responses to acute naloxone-precipitated MWD in male rats. Here we evaluated the potential of a single dose (5 mg/kg, ip) which alleviates withdrawal of these endogenous fatty acid amides to modify tolerance to anti-nociception, hyperthermia, and suppression of locomotion produced by morphine in male Sprague-Dawley rats. Although rats did develop tolerance to the hypolocomotor and analgesic effects of morphine, they did not develop tolerance to the hyperthermic effects of this substance.

Nausea-Induced Conditioned Gaping Reactions in Rats Produced by High-Dose Synthetic Cannabinoid, JWH-018.

Cannabinoid hyperemesis syndrome is becoming a more prominently reported side effect of cannabis containing high-dose Δ-tetrahydrocannabinol (THC) and designer cannabinoid drugs such as "Spice." One active ingredient that has been found in "Spice" is 1-pentyl-3-(1-naphthoyl)indole (JWH-018), a synthetic full agonist of the cannabinoid 1 (CB) receptor. In this study, we evaluated the potential of different doses of JWH-018 to produce conditioned gaping in rats, an index of nausea.

Oleoyl alanine (HU595): a stable monomethylated oleoyl glycine interferes with acute naloxone precipitated morphine withdrawal in male rats.

Rationale: Oleoyl glycine, a little studied fatty acid amide similar in structure to anandamide, interferes with nicotine addiction in mice and acute naloxone-precipitated morphine withdrawal (MWD) in rats. Because endogenous oleoyl glycine is subject to rapid enzymatic deactivation, we evaluated the potential of more stable analogs to interfere with opiate withdrawal.

Objectives: The potential of monomethylated oleoyl glycine (oleoyl alanine, HU595) to interfere with somatic and aversive effects of acute naloxone-precipitated MWD, its duration, and mechanism of action was assessed in male Sprague Dawley rats.

Effects of high fructose corn syrup on ethanol self-administration in rats.

Objective: The addition of sweeteners to alcoholic beverages is thought to facilitate heavy alcohol consumption, and this may be of particular concern when the additive is high fructose corn syrup (HFCS).

Methods: Four experiments in male Sprague-Dawley rats were performed to investigate whether the addition of 25% HFCS to ethanol (5%, 10%, and 20% v/v ethanol) would alter its intraoral operant self-administration, palatability, and sensitivity to food deprivation stress.

Results: As anticipated, HFCS drastically increased ethanol intake, and this effect appeared driven by its caloric value.

Evaluation of repeated or acute treatment with cannabidiol (CBD), cannabidiolic acid (CBDA) or CBDA methyl ester (HU-580) on nausea and/or vomiting in rats and shrews.

Rationale: When acutely administered intraperitoneally, the non-psychoactive cannabinoid cannabidiol (CBD), its acidic precursor cannabidiolic acid (CBDA) and a stable methyl ester of CBDA (HU-580) reduce lithium chloride (LiCl)-induced conditioned gaping in male rats (a selective preclinical model of acute nausea) via activation of the serotonin 1A (5-HT) receptor.

Objectives: To utilise these compounds to manage nausea in the clinic, we must determine if their effectiveness is maintained when injected subcutaneously (s.c) and when repeatedly administered.

Role of the stress response and the endocannabinoid system in Δ-tetrahydrocannabinol (THC)-induced nausea.

Rationale: Dysregulation of the endocannabinoid (eCB) system by high doses of Δ-tetrahydrocannabinol (THC) is hypothesized to generate a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis contributing to cannabinoid hyperemesis syndrome (CHS).

Objectives And Methods: Using the conditioned gaping model of nausea, we aimed to determine if pre-treatments that interfere with stress, or an anti-emetic drug, interfere with THC-induced nausea in male rats. The corticotropin-releasing hormone (CRH) antagonist, antalarmin, was given to inhibit the HPA axis during conditioning.

Effect of combined doses of Δ-tetrahydrocannabinol and cannabidiol or tetrahydrocannabinolic acid and cannabidiolic acid on acute nausea in male Sprague-Dawley rats.

Rationale: This study evaluated the potential of combined cannabis constituents to reduce nausea.

Objectives: Using the lithium chloride (LiCl)-induced conditioned gaping model of nausea in male rats, we aimed to: 1) Determine effective anti-nausea doses of cannabidiol (CBD) 2) Determine effectiveness and the mechanism of action of combined subthreshold doses of CBD and Δ-tetrahydrocannabinol (THC) 3) Determine effective doses of synthetic cannabidiolic acid (CBDA) 4) Determine effective doses of synthetic tetrahydrocannabinolic acid (THCA) 5) Determine the mechanism of action for THCA 6) Determine effectiveness and the mechanism of action of combined subthreshold doses of CBDA and THCA RESULTS: CBD (0.5-5 mg/kg, intraperitoneal [i.

A study of limbic brain derived neurotrophic factor gene expression in male Sprague-Dawley rats trained on a learned helplessness task.

Background: Brain derived neurotrophic factor (BDNF) has been linked to the etiology and pathology of Major Depressive Disorder (MDD). Here, the relationship between learned helplessness (LH), a cognitive/motivational state relevant to MDD, and BDNF mRNA in various limbic regions, was investigated.

Methods: In Sprague-Dawley male rats, LH was induced by escape training, using a triadic design of stressor controllability involving exposure to no shocks (NS), escapable shocks (ES) or yoked inescapable shocks (IES).

The ventral pallidum as a critical region for fatty acid amide hydrolase inhibition of nausea-induced conditioned gaping in male Sprague-Dawley rats.

Here we investigate the involvement of the ventral pallidum (VP) in the anti-nausea effect of fatty acid amide hydrolase (FAAH) inhibition with PF-3845, and examine the pharmacological mechanism of such an effect. We explored the potential of intra-VP PF-3845 to reduce the establishment of lithium chloride (LiCl)-induced conditioned gaping (a model of acute nausea) in male Sprague-Dawley rats. As well, the role of the cannabinoid 1 (CB) receptors and the peroxisome proliferator-activated receptors-α (PPARα) in the anti-nausea effect of PF-3845 was examined.

Oleoyl glycine: interference with the aversive effects of acute naloxone-precipitated MWD, but not morphine reward, in male Sprague-Dawley rats.

Rationale: Oleoyl glycine (OlGly), a recently discovered fatty acid amide that is structurally similar to N- acylethanolamines, which include the endocannabinoid, anandamide (AEA), as well as endogenous peroxisome proliferator-activated receptor alpha (PPARα) agonists oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), has been shown to interfere with nicotine reward and dependence in mice.

Objectives And Methods: Behavioral and molecular techniques were used to investigate the ability of OlGly to interfere with the affective properties of morphine and morphine withdrawal (MWD) in male Sprague-Dawley rats.

Results: Synthetic OlGly (1-30 mg/kg, intraperitoneal [ip]) produced neither a place preference nor aversion on its own; however, at doses of 1 and 5 mg/kg, ip, it blocked the aversive effects of MWD in a place aversion paradigm.

Conditioned aversive responses produced by delayed, but not immediate, exposure to cocaine and morphine in male Sprague-Dawley rats.

Rationale: To determine the conditions under which tastes paired with delayed access to experimenter-delivered cocaine and morphine elicit a conditionally aversive affective state.

Objectives And Methods: The potential of saccharin paired with immediate access to cocaine (5, 10, 20 mg/kg, sc and ip) and delayed (30 and 10 min) access to cocaine (20 mg/kg, sc and ip) and morphine (10 mg/kg, sc) to elicit a pattern of aversive responding in the taste reactivity test (Grill and Norgren 1978a) was evaluated. Cocaine-induced aversions were compared with those produced by a moderate dose of LiCl (50 mg/kg).

Effect of cannabidiolic acid and ∆-tetrahydrocannabinol on carrageenan-induced hyperalgesia and edema in a rodent model of inflammatory pain.

Rationale: Cannabidiol (CBD), a non-intoxicating component of cannabis, or the psychoactive Δ-tetrahydrocannabiol (THC), shows anti-hyperalgesia and anti-inflammatory properties.

Objectives: The present study evaluates the anti-inflammatory and anti-hyperalgesia effects of CBD's potent acidic precursor, cannabidiolic acid (CBDA), in a rodent model of carrageenan-induced acute inflammation in the rat hind paw, when administered systemically (intraperitoneal, i.p.

Conditioned gaping produced by high dose Δ-tetrahydracannabinol: Dysregulation of the hypothalamic endocannabinoid system.

Δ-tetrahydracannabinol (THC) is recognized as an effective treatment for nausea and vomiting via its action on the cannabinoid 1 (CB) receptor. Paradoxically, there is evidence that THC can also produce nausea and vomiting. Using the conditioned gaping model of nausea in rats, we evaluated the ability of several doses of THC (0.

Nausea-Induced 5-HT Release in the Interoceptive Insular Cortex and Regulation by Monoacylglycerol Lipase (MAGL) Inhibition and Cannabidiol.

Using the rat conditioned gaping model of nausea, the interoceptive insular cortex (IIC) has been identified as a critical site for the regulation of lithium chloride (LiCl)-induced nausea. Indirect evidence supports a model where serotonin (5-HT) acts on postsynaptic 5-HT receptors and its release is suppressed by elevating 2-arachidonylglycerol (2-AG) by monoacylglycerol lipase (MAGL) inhibition to suppress nausea. Here, we directly test the hypothesis that systemic LiCl elevates 5-HT in the IIC, and this is prevented by pretreatments that reduce 5-HT release.

Cannabidiolic acid methyl ester, a stable synthetic analogue of cannabidiolic acid, can produce 5-HT receptor-mediated suppression of nausea and anxiety in rats.

Background And Purpose: The aim of this study was to compare the abilities of cannabidiolic acid methyl ester (HU-580) and cannabidiolic acid (CBDA) to enhance 5-HT receptor activation in vitro and produce 5-HT -mediated reductions in nausea and anxiety in vivo.

Experimental Approach: We investigated the effects of HU-580 and CBDA on (i) activation by 8-hydroxy-2-(di-n-propylamino)tetralin of human 5-HT receptors in CHO cell membranes, using [ S]-GTPγS binding assays, (ii) gaping by rats in acute and anticipatory nausea models, and (iii) stress-induced anxiety-like behaviour, as indicated by exit time from the light compartment of a light-dark box of rats subjected 24 h earlier to six tone-paired foot shocks.

Key Results: HU-580 and CBDA increased the E of 8-hydroxy-2-(di-n-propylamino) tetralin in vitro at 0.

Suppression of acute and anticipatory nausea by peripherally restricted fatty acid amide hydrolase inhibitor in animal models: role of PPARα and CB receptors.

Background And Purpose: Effective treatments of nausea are limited. In this study we evaluated the ability of the peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor, URB937, to suppress acute and anticipatory nausea in rats and examined the pharmacological mechanism of this effect.

Experimental Approach: We investigated the potential of URB937 (administered i.