The antiemetic effect of delta 9 -THC and related compounds has been confirmed clinically (Tramer et al., 2001). In animal studies, activation of CBR1 has dose-related antiemetic effects in experimental models of emesis (Darmani, 2001; Simoneau et al., 2001; Van Sickle et al., 2001; 2003; Darmani et al., 2003b; Parker et al., 2004). In non-humans, nausea is hard to measure, however, conditioned rejection reactions in rats may reflect a sensation of nausea (Parker & Kemp, 2001). Delta 9 -THC and CB1R agonists interfere with nausea elicited by lithium chloride and with conditioned nausea elicited by a flavor paired with lithium chloride (Parker et al., 2002; 2003). The same group also present evidence that CB1R activation may be effective to prevent an animal model of anticipatory nausea and vomiting. In Suncus murinus (musk shrew) the investigators paired a novel contextual cue with an emetogenic injection of lithium chloride. After training, the context alone could elicit retching in the absence of the toxin. This conditioned response was completely suppressed by pretreatment with delta 9 -THC, at a dose that did not suppress general activity (Parker & Kemp, 2001). A more detailed discussion of the site of action for the antiemetic effects of cannabinoids is discussed later, but multiple lines of evidence suggest that it is on CB1R vagal pathways both centrally and peripherally (see below).
Activity-dependent depolarization of a presynaptic neurone causes neurotransmitter release, which after binding to its receptor on the postsynaptic neurone, causes calcium influx. Increased calcium activates N-acyltransferase (NAT), which results in production of N-arachidonoyl phosphatidylethanolamine. Phospholipase D (PLD) liberates anandamide (AEA) from N-arachidonoyl phosphatidylethanolamine, which then could associate with a lipid binding protein (LBP), and be transported to the anandamide membrane transporter (illustrated as a pore in the plasma membrane of the postsynaptic neurone). AEA can then bind to CB1 receptors (CB1R) on the presynaptic neurone, resulting in decreased intracellular calcium and presynaptic inhibition. AEA signaling could be inactivated by reuptake through the anandamide membrane transporter, where it could bind a LBP and be transported to microsomal membranes (illustrated as parallel lines) for degradation by fatty acid amide hydrolase (FAAH) or esterification into phospholipids (PL) and/or acyglycerols (AG).
GI effects of cannabinoids
A growing body of literature indicates that substances which act on cannabinoid receptors (CBR) alter secretion and motility of the gastrointestinal (GI) tract (reviewed in Pinto et al., 2002a; Di Carlo & Izzo, 2003) and have antinociceptive or antihyperalgesic properties (reviewed in Rice et al., 2002). This makes them an attractive target for GI functional disorders, such as Irritable Bowel Syndrome (IBS). In the introduction, we will review the background on the cannabinoids and their receptors, and then we will focus on the GI effects of drugs that interact with the CBR.
GI effects of modulation of uptake, synthesis/degradation of EC
In contrast to AEA, 2-AG has more synthetic pathways, and these are dependent on the type of cell and tissue (Sugiura et al., 2002). Levels of 2-AG are elevated by increased calcium (Bisogno et al., 1997), activation of NMDA receptors (Stella & Piomelli, 2001), and in response to lipopolysaccharide (Di Marzo et al., 1999).
Taste and Gut Flora
While this study has yet to be performed in humans, rodent studies have confirmed that levels of the natural cannabinoid, 2-AG, spike during fasting. In fact, after 24 hours of fasting, mice have consistently higher levels of 2-AG than mice that have been allowed to continue normal feeding. These levels “rapidly returned to baseline […] by 15 minutes after refeeding”. That means 2-AG has a relationship to extreme lack of food. Potentially it means that 2-AG encourages the body to find food more attractive as necessary to prevent from starving. Rimonabant, which blocks CB1 receptors, has been shown to prevent the rise in 2-AG that occurs from fasting, meaning that this effect is also achieved through activation of the CB1 receptor. Interestingly enough, combined with the findings about 2-AG involving taste, we see that 2-AG spikes both during consumption of high fat food and also in extreme hunger, environmental stimuli that are seemingly at opposite ends of the spectrum.