Many researchers have claimed that the emotion of disgust functions to protect us from disease. Although there have been several discussions of this hypothesis, none have yet reviewed the evidence in its entirety. The authors derive 14 hypotheses from a disease-avoidance account and evaluate the evidence for each, drawing upon research on pathogen avoidance in animals and empirical research on disgust. In all but 1 case, the evidence favors a disease-avoidance account. It is suggested that disgust is evoked by objects/people that possess particular types of prepared features that connote disease. Such simple disgusts are directly disease related, are acquired during childhood, and are able to contaminate other objects/people. The complex disgusts, which emerge later in development, may be mediated by several emotions. In these cases, violations of societal norms that may subserve a disease-avoidance function, notably relating to food and sex, act as reminders of simple disgust elicitors and thus generate disgust and motivate compliance. The authors find strong support for a disease-avoidance account and suggest that it offers a way to bridge the divide between concrete and ideational accounts of disgust.

Disgust as a disease-avoidance mechanism.

http://cannabisinternational.org/info/Non-Psychoactive-Cannabinoids.pdf

Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb

This Resource Is a peer-reviewed article by Gobi et al. published in the 2005-12-13 issue of the Proceedings of the National Academy of Sciences. The authors show, quoting from the Abstract: '[how] URB597, a selective inhibitor of the enzyme fatty-acid amide hydrolase, which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide, exerts potent antidepressant-like effects in the mouse tail-suspension test and the rat forced-swim test... These actions are prevented by the CB1 antagonist rimonabant, are accompanied by increased brain anandamide levels... The findings support a role for anandamide in mood regulation and point to fatty-acid amide hydrolase as a previously uncharacterized target for antidepressant drugs.'

Antidepressant-Like Activity and Modulation of Brain Monoaminergic Transmission by Blockade of Anandamide Hydrolysis

Chemical signals, or neurotransmitters, represent the fundamental mode for intercellular communication in the nervous system. (1) The classical model for neurotransmitter action involves the uptake and storage of these small molecules into synaptic vesicles, release of vesicular contents into the synaptic cleft in response to depolarization of the presynaptic terminal by an action potential, binding of released neurotransmitters to cognate protein receptors on the postsynaptic (and presynaptic) terminal, and, finally, termination of signaling by protein-mediated uptake and degradation of neurotransmitters from the synaptic cleft. This model applies to a large number of well-studied neurotransmitters, including glutamate, γ-amino butyric acid (GABA), acetylcholine, and the monoamines, all of which represent aqueous solution-soluble molecules. More recently, lipids have emerged as an important class of chemical messengers in the nervous system that operate by a distinct mechanism.

The hydrophobic nature of lipids precludes their stable uptake and storage into synaptic vesicles. Instead, lipid messengers appear to be biosynthesized and released by neurons at the moment of their intended action, which is often referred to as “on-demand” production. Similarly, the capacity of lipids to freely cross cell membranes places the burden of signal termination largely on the action of degradative enzymes. Lipid signaling systems are thus embedded within an elaborate collection of metabolic pathways, the composition and regulation of which ultimately establish the magnitude and duration of transmitter action. Here, we will review these general concepts as they relate to a specific class of lipid transmitters, the endogenous cannabinoids (endocannabinoids), and highlight how delineation of their cognate metabolic enzymes has been translated into the development of chemical and genetic tools to test the role that the endocannabinoid system plays in nervous system signaling and behavior.

Endocannabinoids are defined as endogenous small molecules that activate the cannabinoid receptors CB1 and CB2, which are G-protein-coupled receptors that also recognize Δ9-tetrahydrocannabinol (THC), the psychoactive component of marijuana. (2, 3) The CB1 receptor is the major cannabinoid receptor in the nervous system and is responsible for mediating most of the neurobehavioral effects of THC. (4, 5) The CB2 receptor is predominantly expressed in immune cells, (6) where it appears to play a role in mediating the immunosuppressive effects of cannabinoids. Two principal endocannabinoids have been identified in mammals, N-arachidonoyl ethanolamine (anandamide) (7) and 2-arachidonoylglycerol (2-AG) (8, 9) (Figure 1). Each endocannabinoid also belongs to a much larger class of lipids, termed N-acyl ethanolamines (NAEs) and monoacylglycerols (MAGs), respectively, where individual members differ in the length and degree of unsaturation of their acyl chains (Figure 1). Several NAEs and MAGs have been ascribed potential biological activities in vivo; (10) however, most of these lipids do not serve as ligands for cannabinoid receptors, a property that appears to be restricted to polyunsaturated derivatives such as anandamide and 2-AG.



Figure 1

Two principle endocannabinoids, N-arachidonoyl ethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), which are members of theN-acyl ethanolamine (NAE) and monoacylglycerol (MAG) classes of lipids, respectively.



In the nervous system, endocannabinoids are hypothesized to act as retrograde messengers, being released by postsynaptic neurons and traversing the synaptic cleft to stimulate CB1 receptors on presynaptic termini (11, 12) (Figure 2). This model is supported by a large number of in vitro electrophysiological studies, (12) as well as by the restricted localization of the CB1 receptor to presynaptic structures in many regions of the nervous system. (13, 14) Once activated by endocannabinoids, CB1 receptors couple principally through the G i/G o class of G proteins to regulate calcium and potassium channels and reduce the probability of neurotransmitter release. (3) This suppression of neurotransmitter release can result in the inhibition or, paradoxically, disinhibition of neuronal circuits, depending on whether the CB1 receptor is expressed on glutamatergic or GABergic neurons.



Figure 2

General model for endocannabinoid-based retrograde signaling. Upon release of neurotransmitter (e.g., glutamate), postsynaptic receptors (e.g., α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl- d-aspartic acid (NMDA)) and ...



Despite sharing a common receptor and considerable structural similarity, anandamide and 2-AG can be distinguished by multiple factors. First, these endocannabinoids activate cannabinoid receptors to a differing degree in vitro, with anandamide displaying lower intrinsic efficacy than 2-AG, which results in the former lipid acting as a partial agonist (15) (it should be specified that the relevance of this distinction for signaling in vivo is unclear, especially when one considers that THC also acts as only a partial agonist for cannabinoid receptors in vitro (16)). Second, the endogenous quantities of anandamide and 2-AG differ dramatically, with the latter lipid being found at more than 100-fold higher concentrations in the nervous system. (16) Of course, these values are based on bulk tissue measurements of endocannabinoids, which almost certainly reflect a combination of metabolic and signaling pools of these lipids. Indeed, recent microdialysis studies have revealed that the extracellular concentrations of anandamide and 2-AG are nearly equivalent (within 2 5-fold), (17, 18) suggesting that, at least for the latter endocannabinoid, a large fraction of bulk tissue concentration may correspond to intracellular metabolic pools. Finally, and of greatest relevance for the subject of this review, anandamide and 2-AG are regulated by distinct biosynthetic and degradative pathways.

Over the past decade, several excellent reviews have appeared that discuss endocannabinoid metabolism and signaling. (10, 19-23) Here, we will focus on the most recent advances in our understanding of the composition and regulation of endocannabinoid metabolic pathways, especially as pertains to the nervous system. A pervasive theme throughout this review will be the importance of developing selective genetic and pharmacological tools to specifically perturb individual enzymatic pathways to test their contribution to endocannabinoid metabolism, nervous system function, and, ultimately, mammalian physiology and behavior.

https://www.scripps.edu/cravatt/pdf/Ahn2008ChemRevs.pdf

Enzymatic Pathways That Regulate Endocannabinoid Signaling in the Nervous System

https://link.springer.com/content/pdf/10.1007%2Fs13311-015-0387-1.pdf

Cannabidiol as a Potential Treatment for Anxiety Disorders

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

https://bpspubs.onlinelibrary.wiley.com/doi/epdf/10.1111/j.1476-5381.2010.01176.x

Regulation of nausea and vomiting by cannabinoids.

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



EXPERIMENTAL APPROACH The potential of systemic and intra-DRN administration of 5-HT1A 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-HT1A receptors and to modify the ability of the 5-HT1A agonist, 8-OH-DPAT, to stimulate [35S]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 [35S]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-HT1A 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://dxdoiorg/101111/bph2012165issue-8 To view Part I of Cannabinoids in Biology and Medicine visit http://dxdoiorg/101111/bph2011163issue-7

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 ability of cannabidiolic acid (CBDA) to reduce nausea and vomiting and enhance 5-HT1A 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-HT1A receptor activation by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and mouse whole brain CB1 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-HT1A 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 Emax 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-HT1A 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.

/pdf/cannabidiolic-acid-prevents-vomiting-in-suncus-murinus-and-tg4ef1lcgj.pdf

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

Cannabidiol (CBD), a non-intoxicating component of cannabis, or the psychoactive Δ9-tetrahydrocannabiol (THC), shows anti-hyperalgesia and anti-inflammatory properties 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, ip) or orally before and/or after carrageenan In addition, we assess the effects of oral administration of THC or CBDA, their mechanism of action, and the efficacy of combined ineffective doses of THC and CBDA in this model Finally, we compare the efficacy of CBD and CBDA CBDA given ip 60 min prior to carrageenan (but not 60 min after carrageenan) produced dose-dependent anti-hyperalgesia and anti-inflammatory effects In addition, THC or CBDA given by oral gavage 60 min prior to carrageenan produced anti-hyperalgesia effects, and THC reduced inflammation The anti-hyperalgesia effects of THC were blocked by SR141716 (a cannabinoid 1 receptor antagonist), while CBDA’s effects were blocked by AMG9810 (a transient receptor potential cation channel subfamily V member 1 antagonist) In comparison to CBDA, an equivalent low dose of CBD did not reduce hyperalgesia, suggesting that CBDA is more potent than CBD for this indication Interestingly, when ineffective doses of CBDA or THC alone were combined, this combination produced an anti-hyperalgesia effect and reduced inflammation CBDA or THC alone, as well as very low doses of combined CBDA and THC, has anti-inflammatory and anti-hyperalgesia effects in this animal model of acute inflammation

Effect of cannabidiolic acid and ∆ 9-tetrahydrocannabinol on carrageenan-induced hyperalgesia and edema in a rodent model of inflammatory pain

Anticipatory nausea (AN) experienced by chemotherapy patients is resistant to current anti-nausea treatments. In this study, the effect of manipulation of the endocannabinoid (EC) system on a rat model of nausea (conditioned gaping) was determined. The potential of cannabidiol (CBD) and the fatty acid amide hydrolase (FAAH) inhibitor, URB597 (URB) to reduce conditioned gaping in rats were evaluated. In each experiment, rats received four conditioning trials in which they were injected with lithium chloride immediately before placement in a distinctive odor-laced context. During testing, in experiment 1, rats were injected with vehicle (VEH), 1, 5 or 10 mg/kg CBD 30 min before placement in the context previously paired with nausea and in experiment 2, rats were injected with VEH, 0.1 or 0.3 mg/kg URB 2 h before placement in the context. Additional groups evaluated the ability of the CB1 antagonist/inverse agonist, SR141716A, to reverse the suppressive effects of URB. Experiment 3 measured the potential of URB to interfere with the establishment of conditioned gaping. When administered before testing, CBD (1 and 5, but not 10 mg/kg) and URB (0.3, but not 0.1 mg/kg) suppressed conditioned gaping. The effect of URB was reversed by pre-treatment with the CB1 antagonist/inverse agonist, SR141716A. When administered before conditioning, URB also interfered with the establishment of conditioned gaping. Manipulations of the EC system may have therapeutic potential in the treatment of AN.

/pdf/the-effect-of-cannabidiol-and-urb597-on-conditioned-gaping-a-2rctqrrgc8.pdf

Erin M. Rock

Papers

Regulation of nausea and vomiting by cannabinoids.

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

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

Effect of cannabidiolic acid and ∆ 9-tetrahydrocannabinol on carrageenan-induced hyperalgesia and edema in a rodent model of inflammatory pain

The effect of cannabidiol and URB597 on conditioned gaping (a model of nausea) elicited by a lithium-paired context in the rat