The cannabinoid system and its role in nociception

Massimiliano Beltramo, PhD

The plant: Cannabis

• Cannabis is a genus of flowering plants that includes three putative species:

– Cannabis sativa L.– Cannabis indica Lam.,– Cannabis ruderalis Janisch.

• These three taxa are indigenous to Central Asia, and South Asia.

• Importance of the classification from a legal point of view, only Cannabis sativa products were considered illegals.

Cannabis and Marijuana: Some historical information

• First used for cord and cloths (around 10.000 B.C.).

• Indian text Athera Veda (2000-1400 B.C.) refer to marijuana (bhang) for medical use.

• Chinese herbal, Pen-ts’ao (1-2 Century A.D.) first indication of its use mixed with wine for its pain relieving properties.

• O’Shaugnessey (1842) relieve of pain, anticonvulsant and muscle relaxant

Department of NeurobiologySCHERING-PLOUGHRESEARCH INSTITUTE

World map of cannabis use (2006-2007)

United Nation World Drug Report 2008

Annual prevalence of cannabinoid use

United Nation World Drug Report 2008

Evaluation of drug harm potentialDrugs effects

4-MTA Alcohol

Heroin

CocaineBarbiturates

KetamineMethadone

Cannabis

Amphetamine

Ectasy

Benzodiazepine

LSD

Khat

Tobacco

0

0.5

1

1.5

2

2.5

3

0 0.5 1 1.5 2 2.5 3 3.5

Dependence

Phy

sica

l har

m

(modified from Nutt et al Lancet 2007)

The use of cannabis in Western medicine(nineteenth century and early years twentieth century)

• Chlorodyne (Squibb Co)

• Corn collodium (Squibb Co)

• Dr. Brown’s sedative tablets (Eli Lilly)

• One Day Cough Cure (Eli Lilly)

• Etc, etc, etc.

• 28 different medicines contained cannabis as ingredient

Department of NeurobiologySCHERING-PLOUGHRESEARCH INSTITUTE

Cannabis active principles

• Cannabis sativa produces about 70 compounds which are chemically related to Δ9-THC

• These compounds are called cannabinoids• The psychotropic effects of cannabis product marijuana

and hashish are mostly attributed to Δ9-THC

Identification of cannabinoids’ binding site

(Herkenham et al 1990)

Localization of cannabinoids’ binding sites

(Herkenham et al 1990)

Autoradiographic study using [3H]CP55940

Discovery of the cannabinoid receptor 1(CB1)

• Cloning by receptor homology with bovine Substance K

Discovery of CB1

(Matsuda et al. 1990)

In situ hybridization

Discovery of CB1

Reduction of cAMP accumulation upon cannabinoid receptor stimulation

(Matsuda et al. 1990)

CB1 distribution

(Tsou et al 1998)

Immunolocalization of CB1

Basal ganglia

Hippocampus

Discovery of CB2Homology cloningPolimerase chain reaction with degenerated primers

Discovery of CB2

(Munro et al. 1993)

Binding studies