Regulation of nausea and vomiting by cannabinoids and the endocannabinoid system
Keith A. Sharkey, Nissar A. Darmani, and Linda A. Parker
European Journal of Pharmacology, 2014 January 5; 722.
doi : 10.1016/j.ejphar.2013.09.068.
Nausea and vomiting (emesis) are important elements in defensive or protective responses that animals use to avoid ingestion or digestion of potentially harmful substances. However, these neurally-mediated responses are at times manifested as symptoms of disease and they are frequently observed as side-effects of a variety of medications, notably those used to treat cancer. Cannabis has long been known to limit or prevent nausea and vomiting from a variety of causes.This has led to extensive investigations that have revealed an important role for cannabinoids and their receptors in the regulation of nausea and emesis. With the discovery of the endocannabinoid system, novel ways to regulate both nausea and vomiting have been discovered that involve the production of endogenous cannabinoids acting centrally. Here we review recent progress in understanding the regulation of nausea and vomiting by cannabinoids and the endocannabinoid system, and we discuss the potential to utilize the endocannabinoid system in the treatment of these frequently debilitating conditions.
Keywords : Cannabis; serotonin; emesis; brainstem; insular cortex; CB1 receptor; CB2 receptor
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.