Endocannabinoid signaling and stress in CVSThangam Venkatesan, MD

Associate Professor of MedicineDivision of Gastroenterology and Hepatology

Medical College of WisconsinMilwaukee,WI

Disclosures

Significant relationships

Overview of the endocannabinoid system (ECS) elucidate the role of the ECS in vomiting and stress

Discuss use of marijuana in CVS Future direction

Cannabinoids as potential pharmacotherapy in CVS

Objectives

Pathogenesis of CVS

CVS

Stress

Endocannabinoids

Genetics

Marijuana

Personalized Medicine

“Your DNA test shows you’re predisposed to sue doctors.”

Breaking bad – Viewer discretion advised !

Cannabis and the Gut

Marijuana

Used for centuries as a herbal remedy in the East

Described as the “elixir of the Gods”

Legalized in many states in the US

40% of the CVS population uses marijuana for symptom relief (Choung et al. 2012)

White DG. University of Chicago Press. 1996. (Tara Tantra )

Is Cannabis the panacea of all ills?

Cannabis and the gut

What are cannabinoids ?

What are cannabinoids ?

The endocannabinoid system (ECS)

Phytocannabinoids (derived from the plant) THC , cannabidiol and

other compounds

Synthetic cannabinoids

Endocannabinoids Anandamide (AEA)

Derived from “ananda” or bliss in sanskrit

2- AG(2-arachidonylglycerol)

Receptors ( CB1 and CB2)

Enzymes involved in degradation of endocannabinoids

Devane et al. 1992), Mechoulamet al. 1995; Sugiura et al. 1995

CB1 & CB2 classical receptors for all types of CB agonists

endocannabinoids, phytocannabinoids synthetic CBs

Distributed in many areas in the CNS, enteric neurons, nerve fibers and terminals in the enteric nervous systemCB1 seen throughout the wall of the gutMacrophages & plasma cells are immunoreactive for both CB1 and CB2 receptors

Cannabinoid receptors

Pertwee, 2009

Fatty acid amide hydrolase (FAAH) degradation of AEA and some 2-AG

Monoacylglycerol lipase (MAG lipase) is responsible for the degradation of 2-AG

Causes degradation of 2-AG

Inactivation of AEA and 2-AG

Ahn et al., 2008Duncan et al., 2008

AEA or 2-AG

StressiRmR

FAAH

Precursor

T

↑Ca2

+

Et, AA

+

Postsynaptic neuron

↓Ca2+,K+

Presynaptic neuron

CB1

NT

Endocannabinoid signalling

Tetrahydrocannabinol (THC) , cannabidiolic acid (CBDA), cannabidiol (CBD) and other compounds CBDA and CBD are not psychoactive

Heating the plant cause changes in chemical composition

CBDA CBD THCA THC

Phytocannabinoids(plant derived)

THCA No psychoactive effects in rhesus monkeys up to 5

mg/kg Reduced LiCl induced vomiting in the musk shrew,effect

was reversed with rimonbant pretreatment Reduced conditioned gaping in rats ( a surrogate

marker for nausea) CBDA

Reduced LiCl, motion and cisplatin-induced vomiting in the shrew

Effects of phytocannabinoids

Role of endocannabinoids in health and disease

Food intake and feeding behavior Obesity Nausea and vomiting IBD Stress Cancer

Role of EC’s in the gut