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Clin. Gastroenterol. Hepatol. · January 17, 2022
High-Definition Colonoscopy vs Cuff- and Cap-Assisted Colonoscopy
Gut · January 11, 2022
Cannabinoids could also act at the peripheral terminals of vagal afferents to alter visceral perception. CB1R is highly expressed in the nodose ganglion (the location of vagal sensory cell bodies (Partosoedarso et al., 2003b) and denervation of c-fiber afferents by perivagal capsaicin treatment abolished the increase in gastric volume evoked by i.v. delta 9 -THC (Ball et al., 2001). Consistent with this site of action, delta 9 -THC also inhibited the cisplatin-induced emesis (Van Sickle et al., 2003), and cisplatin induces an early emesis via serotonin release from gut enterochromaffin cells that acts on vagal afferents. Interestingly, CB1R and cholecystokinin1 receptors are co-expressed within vagal afferents that project to the stomach and duodenum, and the data suggest that these interact to modulate food intake and satiety (Burdyga et al., 2004). In this regard it is perplexing that, in a relatively small number of fibers tested, WIN 55,212-2 did not alter firing of gastric vagal mechanoreceptors in response to gastric distention (Lehmann et al., 2002).
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).
Probably all levels of the brain-gut axis can be modulated by exogenous and endogenous CBR agonists ( Figure 2 ), and so far, the evidence indicates that the ultimate effect on the organ is similar, no matter where the specific site of action(s) are. This makes the cannabinoid system quite attractive to target since a drug should have a similar effect whether it modulates the EC system locally in the gut or more remotely in the brain. The case can be made for beneficial effects of agonists (antiemetic and antimotility) and antagonists (anorexic and to prevent GI stasis/hypomotility) in this regard.
CBR sites of action mediating GI effects of cannabinoids
Little is known about the mechanism whereby ECs are released from the cell. In the section below, we will discuss uptake of EC’s through an anandamide membrane transporter. This transporter may be bidirectional ( Figure 3 ) and facilitate release of AEA (Hillard et al., 1997; Hillard & Jarrahian, 2003), however this mechanism is controversial. Once released, EC’s appear to remain localized at the site since there is synapse-specific inhibition of neurotransmitter release in cerebellar slices (Brown et al., 2003).
Characterization of the effects of CBR stimulation comes from administration of selective agonists, such as analogs of delta 9 -THC, and inverse agonists/antagonists. Since there have been several reviews on this subject in the last couple of years, we have focused on the most recent data and organized the known effects of cannabinoids on different regions of the upper to lower GI tract. In the subsequent section, we have reviewed the evidence for the potential sites of action of CBRs mediating these effects.
Delta 9 -THC inhibits adenylyl cyclase and reduces cellular cAMP levels, which identified its receptor as a G-protein coupled receptor (GPCR). Sequence similarity to known GPCRs lead to cloning of CB1R (Matsuda et al., 1990), and soon after the CB2R (Munro et al., 1993). The CB1R has been localized in neural tissue throughout the body and described most thoroughly in central (Tsou et al., 1998; Fride, 2002) and enteric (Kulkarni-Narla & Brown, 2000; Coutts et al., 2002; MacNaughton et al., 2004) neurons. The CB2R is primarily expressed in the immune system (reviewed in Parolaro et al., 2002). Both receptors are G protein coupled via Gi/o. CB1R is highly conserved in rodent and human (Gerard et al., 1991) and found in a wide variety of species. This conservation is somewhat unusual among GPCRs, and has enabled much progress in the understanding of the site and potential roles of CBR in physiological and pathophysiological systems relevant for human.
Upper GI transit is increased within 3 h after administration of croton oil. The GI transit effects of croton oil were assessed after intraperitoneal and intracerebroventricular administration of CB1R agonists, in an attempt to ascertain their most likely site of action (Izzo et al., 2000). In these mice, the ED50 values for WIN55,212-2 for inhibition of upper GI transit were lower for intracerebroventricular compared to intraperitoneal administration. In addition, the GI transit effects of WIN55,212-2 given centrally were reversed by hexamethonium (given i.p.). However, a 10-fold higher dose of the CB1R agonist, given intraperitoneally, resulted in reduced GI transit that was not altered by hexamethonium. This suggests that at higher doses there may be direct effects of CB1R activation on nonextrinsic nerves controlling the upper GI tract, that is, on the enteric nervous system. The overall data are consistent with the central site of action of cannabinoids being critical for regulation of upper GI transit, at least when the doses of exogenous agonist are low.
Of course, while supplying more external cannabinoids represents one method of stimulating a change in motility, disabling the body’s enzymes can also lead to greater activation of cannabinoid receptors. Specifically, inhibiting MGL, the enzyme that deconstructs the cannabinoid 2-AG, allows more 2-AG to stay bonded to CB1 receptors, allowing a prolonged change in intestinal motility. In response to a recent study involving enzyme inhibitors in which participants were hospitalized, we now know that disabling this inhibitor in humans may be dangerous and may not be a viable pathway for treating a gut condition where decreased motility is required. However, since effects were once again not observed in the presence of a CB1 receptor blocker, this represents a second confirmation that CB1 receptors control motility in the intestine.
IBS and Beyond
This list does not represent the entire spectrum of interaction between the endocannabinoid system and the gastrointestinal system. Moreover, in the same way that many of these relationships were unknown several decades ago, the next several decades will surely bring even more surprises. However, readers should now have an understanding of the multitude of interactions occurring between the two systems. The sheer number of connections makes this area of cannabinoid science one of the most exciting for us to follow, and we look forward to seeing what medicinal advancements develop from these findings.
To function, the intestine must absorb nutrients but also send food onward. The ability to move food onward is called “motility” and is driven by timed contraction of the intestinal muscle. The gut interacts with the brain to determine the pace of contraction and therefore, food motility. Unfortunately, sometimes the timing of contractions can go haywire. Cannabinoids, whether naturally occurring endocannabinoids or externally administered cannabinoids, have been shown to reduce motility in a dose-dependent matter. In other words, the more cannabinoids supplied, the slower the food moves through the gastrointestinal system (to a point). Scientists who initially observed this effect dug deeper by applying cannabinoid receptor antagonists to block effects from cannabinoid receptors. While the CB2 receptor blocker had no effect, the CB1 receptor blocker caused motility to resume as if cannabinoids had not been applied, indicating that these motility effects occur in response to activation of the CB1 receptor. Since the body’s two main endocannabinoids, anandamide (body’s version of THC) and 2-AG, both bind to the CB1 receptor, both are capable of influencing motility in the intestine.
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.