ReviewRegulation of nausea and vomiting by cannabinoids and the endocannabinoid system
Introduction
Reflex mechanisms that serve to protect a host from injury and disability represent important and frequently well-conserved adaptations to a hostile external environment. Rarely do these adaptations, such as blinking or sneezing, become “hijacked” by physiological or pathophysiological processes in the body, not involving the organ they evolved to protect. Unfortunately, that is not the case for nausea and vomiting. Nausea is an aversive experience that often precedes emesis (vomiting), but is distinct from it (Borison and Wang, 1953, Carpenter, 1990, Horn, 2008, Andrews and Horn, 2006, Stern et al., 2011). Retching and vomiting lead to the forceful expulsion of gastric and/or upper intestinal contents, the primary function of which is to remove ingested materials or food that may be contaminated or potentially harmful. Nausea associated with emesis serves as an unconditioned stimulus for learning and memory; food that becomes associated with nausea and vomiting will be avoided in future encounters (Borison and Wang, 1953, Carpenter, 1990, Horn, 2008, Andrews and Horn, 2006, Stern et al., 2011).
In the natural environment, as a protective reflex, nausea and vomiting are very important adaptations found in most vertebrate species (Borison et al., 1981). However, possibly because of its importance, the sensitivity of this reflex is very low, making it easily activated. In various disease states, e.g. diabetes and labyrinthitis (Koch, 1999, Schmäl, 2013), the inappropriate activation of this reflex leads to severe and debilitating symptoms. Many central nervous system conditions, including elevated intracranial pressure, migraine headache and concussion also cause nausea and vomiting (Edvinsson et al., 2012, Mott et al., 2012, Stern et al., 2011). Nausea and vomiting are frequent, unwanted, side-effects of a range of medications used to treat a variety of conditions, notably cancer chemotherapeutic agents (Hesketh, 2005, Rojas and Slusher, 2012). Pregnancy-induced nausea and vomiting are reportedly adaptive mechanisms, but hyperemesis gravidarum can severely compromise both the health of the mother and the developing fetus (Patil et al., 2012, Sanu and Lamont, 2011, Sherman and Flaxman, 2002). Finally, motion sickness, which results from a sensory conflict between visual and vestibular stimuli, can be of immense discomfort, and severely limit certain activities (Schmäl, 2013, Yates et al., 1998). Nausea and vomiting are significant in our society and understanding them represents both an important goal and a major challenge; the former because of the substantial health implications, but the latter because it is hard to judge if an experimental animal is nauseated and commonly used laboratory animals are some of the few species that do not vomit! Nevertheless, significant progress has been made in our understanding of the processes of nausea and vomiting, which has led to new and improved pharmacological treatments for these disorders in the last 20–30 years, as described in many of the accompanying articles in this volume and previous reviews (Rojas and Slusher, 2012, Sanger and Andrews, 2006, Schmäl, 2013).
One of the oldest pharmacological remedies for nausea and vomiting is the plant cannabis (Kalant, 2001). In clinical trials, cannabis-based medicines have been found to be effective anti-emetics and even surpass some modern treatments in their potential to alleviate nausea (Cotter, 2009, Tramèr et al., 2001). However, it was not until the early 1990s that the mechanism of action of cannabis was established following the cloning of the “cannabinoid” (CB) receptors (Howlett et al., 2002, Pertwee et al., 2010). The significance of this discovery was enhanced when it was realized that these receptors were part of an endogenous cannabinoid (endocannabinoid) system in the brain and elsewhere in the body (Di Marzo and De Petrocellis, 2012, Izzo and Sharkey, 2010, Mechoulam and Parker, 2013, Piomelli, 2003). The endocannabinoid system serves to modulate the expression of nausea and vomiting when activated by central or peripheral emetic stimuli (Darmani and Chebolu, 2013, Parker et al., 2011).
In this article we will outline the endocannabinoid system and then describe what is known about this system in relation to the neural circuits of nausea and vomiting. We will describe recent findings on the anti-emetic effects of cannabinoids and show how manipulation of elements of the endocannabinoid system can modify the expression of emesis. We will discuss at some length the evidence that cannabinoids and the endocannabinoid system can regulate nausea, because this is an area that has been not been considered so fully in the past. We will then briefly describe the paradoxical effect of chronic exposure to high doses of cannabis that in some people causes a cyclic vomiting syndrome. Finally, we will conclude with some future directions for this research by identifying gaps in our knowledge of the regulation of nausea and vomiting by cannabinoids and the endocannabinoid system.
Section snippets
The endocannabinoid system
The isolation of Δ9-tetrahydrocannabinol (Δ9-THC) as the major psychoactive ingredient in cannabis was an important milestone in neuropharmacology (Howlett et al., 2002, Pertwee et al., 2010). This discovery provided the impetus for extensive investigations that led to an understanding of many of the central and peripheral sites of action of cannabis and ultimately to the cloning of the two G-protein coupled cannabinoid receptors; CB1 and CB2. CB1 receptors are distributed throughout the
The endocannabinoid system at sites in the brain and gastrointestinal tract involved in nausea and vomiting
The key components of the brain-gut circuitry mediating emesis have been well described (Andrews and Horn, 2006, Hornby, 2001). As outlined above, emesis can be initiated peripherally or centrally. However, most commonly, emesis is evoked from the gastrointestinal tract by ingestion of toxins, including bacteria or bacterial products, or food that is not tolerated. It may also be caused by drugs such as the cancer chemotherapeutic agent cisplatin and radiation. In most of these examples, the
Anti-emetic effects of cannabinoids and endocannabinoids
Cannabis is a well-known anti-emetic whose actions have been extensively reviewed (Cotter, 2009, Darmani and Chebolu, 2013, Izzo and Sharkey, 2010, Parker et al., 2011, Tramèr et al., 2001). Following the isolation of Δ9-THC, the mechanism and site of action of cannabinoids were established. In humans and animal models, plant-derived cannabinoids, synthetic cannabinoids and endocannabinoids inhibit emesis evoked peripherally or centrally with drugs or natural stimuli. Cannabinoids block both
Cannabinoids and endocannabinoids in the control of nausea in humans
There is clearly a need of treatments for acute, delayed and anticipatory nausea in chemotherapy treatment (e.g., Poli-Bigelli et al., 2003). One of the first recognized medicinal benefits of cannabis was for the treatment of nausea (Iversen, 2008). The most investigated compound has been Δ9-THC (see Cotter, 2009, Tramèr et al., 2001 for reviews); however, other nonpsychoactive compounds in the cannabis plant have recently been reported to also have benefits in preclinical models of nausea and
Cannabinoid and endocannabinoid regulation of nausea in animal models
Animal models of vomiting have been valuable in elucidating the neural mechanisms of the emetic reflex (Hornby, 2001); however, the central mechanisms regulating nausea are still not well understood (Andrews and Horn, 2006). Considerably greater progress has been made toward the control of vomiting than the control of nausea. One reason is that nausea is much more difficult to quantify than is vomiting, and therefore, preclinical model development has been challenging. Although vomiting is a
Contextually-elicited conditioned gaping reactions: a model of anticipatory nausea
Rats not only display conditioned gaping reactions when re-exposed to a flavor previously paired with a nausea-inducing drug, but they also display conditioned gaping reactions when re-exposed to a context previously paired with a nausea-inducing drug (Chan et al., 2009, Limebeer et al., 2008, Rock et al., 2008;). As well, the house musk shrew also displays conditioned retching when re-exposed to a context previously paired with toxin-induced vomiting (Parker and Kemp, 2001, Parker et al., 2006
Cannabis and hyperemesis: the paradoxical effect of chronic exposure to cannabis
Heavy chronic cannabis use in some people, frequently young ones, leads to a constellation of symptoms that include abdominal pain, recurrent nausea and intractable cyclic vomiting (Galli et al., 2011, Nicolson et al., 2012, Simonetto et al., 2012). This syndrome was first reported about 10 years ago (Allen et al., 2004). These symptoms are, of course, exactly the opposite of what has been outlined above and hence represent a paradoxical effect of cannabis. Relief from these symptoms can be
Future directions in using the endocannabinoid system in the treatment of nausea and vomiting
As can be appreciated from the discussion in the previous sections, we believe that the endocannabinoid system has the potential to be used for the treatment of nausea and likely as an adjunct therapy for the treatment of emesis, particularly delayed emesis, where current therapies are limited in their degree of efficacy. There are, however, many gaps in our knowledge, most of which were highlighted above. One of the biggest limitations is the very widespread nature of the CB1 receptor and the
Acknowledgements
Original work in the authors' laboratories is supported by the Canadian Institutes of Health Research (KAS), the Natural Sciences and Engineering Research Council of Canada (LAP) and NIH grants-NIDA 12605 and CA115331 (ND). KAS is the recipient of a Killam Annual Professorship and holds the Crohn's & Colitis Foundation of Canada Chair in Inflammatory Bowel Disease Research at the University of Calgary. LAP is the recipient of a Tier 1 Canada Research Chair in behavioural neuroscience at
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