Regulation of nausea and vomiting by cannabinoids

Abstract

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 (D 9 -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 ARTICLESThis 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 Abbreviations 2-AG, 2-arachidonolylglycerol; 5-HT, 5-hydroxytryptamine; 5-HT3, 5-hydroxytryptamine receptor 3; 5-HT1A, 5-hydroxytryptamine receptor 1A; 5-HTP, 5-hydroxytryptophan; 5,7-DHT, 5,7-dihydroxytryptamine; 8-OH-DPAT, 8-hydroxy-N,N-dipropyl-2-aminotetralin; D 9-THC, D 9 -tetrahydrocannabinol; AN, anticipatory nausea; AP, area postrema; CB1,cannabinoid receptor 1; CB2, cannabinoid receptor 2; CBD, cannabidiol; DMNX, doral motor nucleus of the vagus; DRN, dorsal raphe nucleus; DVC, dorsal vagal complex; FAAH, fatty acid amide hydrolase; Gi, inhibitory G protein subunit; LiCl, lithium chloride; MAGL, monoacylglycerol-lipase; M6G, morphine-6-glucuronide; MRN, medial raphe nucleus; NADA, n-arachidonoyl-dopamine; NTS, nucleus of the solitary tract; S. murinus, Suncus murinus; TRPV1, transient receptor potential vanilloid 1 IntroductionA major advance in the control of acute emesis in chemotherapy treatment was the finding that blockade of one subtype of the 5-hydroxytryptamine (5-HT) receptor, the 5-HT3 receptor, could suppress the ...

Variants in the CNR1 gene predispose to headache with nausea in the presence of life stress

“…Accumulating evidence supports cannabis and endocannabinoids supressing emesis and nausea through the CB1 receptor (Parker et al 2011; Sharkey et al 2014). In animal models, cannabinoid derivatives have a distinctive effect compared to other available antiemetic drugs in being able to suppress not only vomiting but also anticipatory and delayed nausea, probably via the inhibitory effect of CB1 receptors on serotonin release in the insular cortex (Parker et al 2015); this is a possible mechanism in humans as well.…”

“…The neural regulator of emesis is integrated at the dorsal vagal complex, which receives peripheral (gut), vestibular, and cerebral inputs and initiates motor response characteristic for vomiting (Parker et al 2011; Sharkey et al 2014). Nevertheless, the neuronal control of nausea is poorly understood but is clearly distinctive from the emesis control.…”

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…These antinausea/antiemetic effects are mediated by activation of somatodendritic 5-HT 1A receptors in the dorsal raphe nucleus (662,732).…”

Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse

“…However, both agonists and antagonists at this receptor tend to have side effects that limit their usefulness as medications. For example, direct-acting CB 1 agonists such as Δ 9 -tetrahydrocannabinol (THC) exert antiemetic (Parker et al, 2011) and antispasmodic effects (Oreja-Guevara, 2012), but are also liable to produce dependence (Hall and Degenhardt, 2009) and amnesia (Ranganathan and D'Souza, 2006). On the other hand, CB 1 antagonists are effective in the treatment of obesity and tobacco addiction (Cahill and Ussher, 2011), but can also induce depressive states (Johansson et al, 2009).…”