Role of EC ’ s in the gut

1. Role of EC’s in the gut Food intake and feeding behaviour Obesity Nausea and vomiting IBD Stress Cancer

2. Food intake Bellocchio et al., 2008 ,Kunos, 2007 Matias and Di Marzo, 2007 • CB1 receptor agonists including Δ9-THC • “munchies” or craving for high fat diets • promote body weight gain

3. Role in obesity • CB1 receptors located on vagal afferent neurons • may be involved in CB-induced modulation of appetite • anandamide might act as a “hunger signal” in the intestine • OEA -related compound, stimulates appetite Storr & Sharkey, 2007

4. Role in obesity Lo Verme et al. ,2009 • peripherally restricted CB1 receptor antagonist (URB447) • effective at suppressing food intake • reducing body weight in genetically obese ob/ob mice.

5. Role of EC’s in the gut Food intake and feeding behavior Obesity Stress Nausea and vomiting IBD Cancer

6. Effects of endocannabinoids • Anandamide (AEA) and 2- AG • ↓ anadamide in motion sickness • ↓ CB1 receptor activity • ↓2-AG in major depression

7. Nausea and vomiting Van Sickle et al., 2001, 2003, 2005; Darmani et al., 2007 Ray et al., 2009 • CBs inhibit emesis in animal models • acute cisplatin and delayed emesis • morphine • radiation-induced emesis • anticipatory nausea and vomiting • FAAH inhibitor URB597 • suppressed cisplatin • nicotine-induced vomiting (in the house musk shrew through CB1 receptors)

8. Rimonabant : A new Pill To Combat Obesity Van Gaal et al., 2005 Pi-Sunyer et al., 2006 Van Gaal et al.,2008 • CB1 receptor antagonist • effective weight loss agent • withdrawn from the market in 2008 • increased risk of depression and vomiting

9. Role of the ECS in stress What is stress?

11. “People are disturbed not by a thing, but by their perception of a thing.”Epictetus • Difficult to define • Hence difficult to measure • Highly subjective • First coined in the 1930’s by “Hans Selye”

12. Stress… Uncontrollable Unpredictable

13. Role of the ECS in stress Psychological stress induces endocrine, sympathetic, and behavioral responses that allow the individual to cope with stress The endocannabinoid/CB1 receptor signaling system (ECS) serves to oppose these stress-induced changes

14. Role in stress • Stress produces an increase in circulating endocannabinoids • inversely related to stress-induced physiological effects, including sympathetic activation and circulating glucocorticoid concentrations • Enables the host to adapt to stress and terminates ongoing sympathetic and hypothalamic-pituitary-adrenal (HPA) axis activation

15. Role in stress Studies with CB1 receptor antagonists, such as rimonabant used in Europe for obesity support the role of the ECS in stress-related disorders Rimonabant was associated with significant depression and nausea as a side effect

16. And so …. EC’s make you happy , fat and dumb ! Laurel and Hardy

17. And so does weed ! BUT

18. Problems with marijuana

19. http://www.policyalmanac.org/crime/archive/marijuana.shtml