## 4 Effects of Cannabinoids on Gastrointestinal Motility
### Endocannabinoids
#### 4.1.1 Effects of AEA and 2-AG on Gastrointestinal Motility
Anandamide levels in the whole small intestine were found not to differ between mice with inflammation induced by croton oil and control animals. There was, however, increased activity of FAAH, the enzyme responsible for anandamide breakdown, as well as increased CB1 receptor expression [60]. A later study by the same author, using the same model, analyzed anandamide concentrations in the individual portions of the small intestine, finding that anandamide levels were significantly lowered in the jejunum, but not the duodenum or ileum, of croton oil-treated mice, as compared to the control group. The study also found upregulation of CB1 receptors in the jejunum, and upregulation of TRPA1 receptors and downregulation of CB2 receptors in the entire small intestine [61]. Another study demonstrated an increase in murine whole small intestine anandamide (but not 2-AG or PEA) levels in a model of acetic acid-induced paralytic ileus. Additionally, overexpression of CB1 receptors was observed. Paralytic ileus was alleviated by the CB1 receptor antagonist SR141716A and exacerbated by the anandamide uptake inhibitor VDM11. No significant changes in FAAH activity were observed, as compared to controls, implying that the rise in anandamide concentration was not due to a reduction in inactivation. Taken together, this suggests a causative role for anandamide in paralytic ileus [62]. One study, investigating changes in GIT motility and tissue endocannabinoid levels due to obesity, used both rat and mice models. In mice with high-fat diet-induced obesity, baseline intestinal transit was increased, whereas small intestinal anandamide levels were decreased and 2-AG was increased. In addition, overnight fasting increased endocannabinoid levels in the duodenum of both Zucker and lean rat strains. Endocannabinoid dysregulation, in the form of reduced anandamide levels, may be responsible for increased intestinal transit in mice with diet-induced obesity [63]. In guinea pig myenteric plexus longitudinal muscle preparations, anandamide at lower concentrations was shown to have an inhibitory effect on ethylenediamine-induced GABA release, decreasing the inhibition of contractions by ethylenediamine. At higher concentration, however, anandamide increased contractile inhibition by ethylenediamine, an effect that was eliminated by the TRPV1 antagonist capsaicinepine in combination with the GABA(B) antagonist CGP54626A. This suggests that anandamide has an inhibitory effect on electrically induced contractions independently of GABA and CB receptors, via TRPV1. Anandamide also inhibited electrically induced contractions on its own via CB1 [64]. Similarly, anandamide was observed to inhibit electrically induced adenosine release in the myenteric plexus longitudinal muscle of the guinea pig ileum [65]. In another study, anandamide inhibited the contractile response to brushstroke stimulation in three-compartment rat colon preparations (orad motor, central sensory, and caudal motor compartments). Anandamide decreased SP release and ascending contraction in the oral motor compartment, VIP release and descending relaxation in the caudal motor compartment, and release of the sensory transmitter CGRP in the central sensory compartment. The reverse was true for the CB1 antagonist AM-251. This would suggest that the inhibition of peristalsis by cannabinoids is caused by inhibition of both excitatory cholinergic and inhibitory VIPergic motor neurons, as well as sensory neurons initiating the peristaltic reflex [66].