## 4 Effects of Cannabinoids on Gastrointestinal Motility
### Endocannabinoids  
#### 4.1.1 Effects of AEA and 2-AG on Gastrointestinal Motility  
In ex vivo studies in mice, anandamide reduced spontaneous contractility of ileal longitudinal muscle strips via CB1 [53] and electrically evoked contractions in colon preparations via CB1 [54]. In guinea pig small intestine circular muscle preparations, anandamide reduced cholinergic and non-adrenergic-non-cholinergic (NANC) contractility (induced via electrical field stimulation) via CB1, without altering contractile response to exogenous substance P (SP) and acetylcholine (ACh). It also did not interact with L-NAME, naloxone, or phentolamine [55]. In human colonic longitudinal and circular muscle, anandamide and 2-AG inhibited the contractile response to ACh but did not inhibit the response to KCl, nor did they alter basal muscle tension. This effect on ACh response was not reversed by the CB1 receptor antagonist AM251 or the CB2 receptor antagonist JTE907, suggesting involvement of a non-CB1, non-CB2 pathway. Abolishing endocannabinoid breakdown via the FAA inhibitor aradichonoyl trifluoromethyl ketone reduced ACh response on its own but did not modify the suppressive effect of anandamide [56]. In rat ileal preparations, anandamide reduced the twitch response to ACh via CB1, by affecting neuro-neuronal and neuro-muscular neurotransmission as well as reducing excitatory junction potentials (EJPs) and inhibitory junction potentials (IJPs), while leaving intestinal slow waves unaffected [57]. An in vivo study demonstrated that anandamide reduced GIT motility and improved postprandial glycemia in mice [58]. Conversely, in guinea pigs, there are reports of anandamide stimulating intestinal contractions. Anandamide was found to increase basal ACh release and muscle tone in isolated guinea pig proximal small intestine myenteric plexus longitudinal muscle strips, an effect inhibited by the vanilloid receptor antagonist capsaicinpe and a combined blockade of NK1 and NK3 receptors. This was not, however, blocked by the CB1 or CB2 receptor antagonists [50]. This suggests that anandamide exerts its stimulatory effect on basal ACh release via TRPV1 receptor stimulation. In this study, anandamide also inhibited electrically evoked ACh release and contractions, whose effect was not blocked by capsaicinpe, combined NK1 and NK3 receptor blockade, or CB2 blockade, but was reduced by the CB1 receptor antagonist rimonabant. This inhibition by rimonabant of anandamide's effect on evoked ACh release was much less potent than rimonabant's inhibition of the CP55,940 effect on evoked ACh release. These results suggest that anandamide's inhibition of evoked ACh release is mediated via a receptor other than CB1 or CB2 [50]. In another study, anandamide and 2-AG were observed to contract guinea pig distal colon longitudinal muscle strips by stimulating myenteric cholinergic neurons independently of cannabinoid or vanilloid receptors. This was inhibited by the lipoxygenase inhibitor nordihydroquiaretic acid, suggesting that lipoxygenase metabolites may mediate these contractions [52]. This would seem to be supported by a later study, in which anandamide caused guinea pig ileal segments to contract, an effect that was strongly inhibited by indomethacin (a nonselective cyclooxygenase inhibitor), tetrodotoxin, or a combination of atropine and an NK1 receptor antagonist. The contractions were weakly reduced by atropine alone and partly diminished by the FAA inhibitor URB 597. Pre-treatment with capsaicin, a TRPV1 receptor antagonist, hexamethonium, and CB1 and CB2 receptor antagonists allfailed to influence the anandamide-induced contraction. Taken together, this suggests that anandamide's contractile properties are exerted via cyclooxygenase metasolites but do not involve TRPV1 receptors or capsaicin-sensitive neurons, and that the final mediators for the response are ACh and tachykinin peptides [59]. There have been several studies investigating the relationship between anandamide and pathological states of the intestine.