Cannabinoid receptors

Cannabinoids are a group of chemicals which activate the bodys cannabinoid

receptors.

There are three general types of cannabinoids:

Endogenous cannabinoids

produced in the bodies of humans and other animals

Herbal cannabinoids

present in the Cannabis plant

Synthetic cannabinoids

similar compounds produced in a laboratory CANNABINOIDS ;;

Receptors
Cannabinoid receptors are part of the endocannabinoid system, which
consists of -cannabinoid receptor,
o -endogenous cannabinoids (endocannabinoids),
o -and the enzymes that synthesis and degrade
endocannabinoids.
The cannabinoid receptors are a class of cell membrane receptors under
the G protein-coupled receptor superfamily.
Cannabinoid receptors are activated by three major group of ligands,
endocannabinoids;;; plant cannabinoids;; synthetic cannabinoids .
All of the endocannabinoids and plant cannabinoids are lipophilic, i.e. fat
soluble, compounds. Cannabinoid receptors ;;

TYPES OF CANNABINOID RECEPTORS

two cannabinoid receptors have been identified, the CB1 and the CB2
receptor
they differ in signaling mechanisms, tissue distribution, and sensitivity to
certain agonists and antagonists that show marked selectivity for one or the
other receptor type .
 Activation of cannabinoid receptors causes inhibition of adenylate cyclase,
thus, inhibiting the conversion of ATP to cyclic AMP (cAMP).
Both CB1 and CB2 receptors belong to the superfamily of G protein-coupled
receptors, coupling to inhibitory G proteins (Gi/o).

CB1 receptor:

The CB1 receptor was first cloned as orphan receptor from a rat cDNA
Mainly expressed in ;;;;; BRAIN (CNS),, LIVER,, LUNGS,, KIDNEY;; ON
MALE FEMALE REPRODUTIVE SYSTEM;;
BRAIN region- basal ganglia;; limbic system;; hippocampus;; cerebellum {
involved with thinking & memory,attention , movement control}
In addition, CB1 receptors inhibits presynaptic N- and P/Q- type calcium
channels and activate inwardly rectifying potassium channels.

CB2 receptors:

CB2 receptors are mainly expressed in ;;; T CELSS of immune system;; on

B CELLS;; on MACROPHAGES;;on HEMATOPOIETIC CELLS . ALSO
expressed on peripheral nerve terminal .
IN BRAIN;;expressed by microglial cells .
HAVE function as;; KERATINOCYTES;&;play a role in NOCICEPTION
(percepion of pain )

Signal transduction mechanisms of cannabinoid receptors

Both CB1 and CB2 cannabinoid receptors are members of the superfamily
of G-protein-coupled receptors, so the signal transduction properties of
these receptors are mediated by the process of G-protein activation.

CB1 and CB2 are members of the p-glycoprotein family of receptors. Signal
transduction pathways include inhibition of cyclic adenosine
monophosphate (cAMP) production, modulation of ion channels, and
promotion of mitogen-activated protein kinase (MAPK) activation.
 Main signaling pathways activated by cannabinoid receptors. The
canonical signaling pathway initiated by the binding of a cannabinoid to
CBRs involves the coupling of the receptor to G i/0 proteins.

i subunits can inhibit the activity of adenylyl cyclase (AC) and the
synthesis of cAMP.

This results in a decreased activation of PKA and an increased activation

of potassium channels type A, which leads to membrane
hyperpolarization.

0 subunits can in turn inhibit voltage dependent Ca 2+ channels

contributing to the inhibition of membrane depolarization.

subunits interact with other intracellular pathways related to PI3K or

PKB/Akt. CBRs are also coupled to neutral sphingomyelinase (EMN), an
enzyme that mediates the generation of ceramide from sphingomyelin
(EM) in the plasma membrane. Ceramide acts as an intracellular signaling
molecule than can activate several transcription factors including ERK,
JNK and p38, and is involved, among other functions, on the control of
cell fate and survival. AC: adenylyl cyclase; FAN: factor associated with
neutral sphingomyelinase activation; N, P/Q: voltage-dependent calcium
channels type N, P/Q; PKA: protein kinase A; PKB/Akt: protein kinase B;
ERK: extracellular signal-regulated kinase; JNK: c-Jun N-terminal kinase;
FAK: focal adhesion kinase; PI3K: phosphoinositide-3 kinase.
Pharmacology of agonist and antagonists:

Agonists:

Kinetics:

Tetrahydrocannabinol and other cannabinoids are rapidly absorbed after

inhalation

orally, THC seems to undergo variable absorption from the gastrointestinal

tract

THC is degraded by metabolism in the liver before reaching the circulation

(first-pass metabolism), although the metabolite 11- hydroxy d-9THC is also
psychoactive

Cannabinoids are metabolised in the liver, and a major metabolite is 11-

hydroxy-d9THC, which is more potent than d-9THC and may be responsible for
some of the psychological and physiological effects of cannabis
Acute effects:

Cannabis produces euphoria and relaxation, perceptual alteration, time

distortion and the intensification of normal sensory experiences such as eating.

Short-term memory and attention, motor skills, reaction time and skilled
activities are impaired while a person is intoxicated

Effects on the cardiovascular system include tachycardia, with heart rate

increasing by 2050% within few minutes; this effect lasts for up to 3 h.

Blood pressure decreases when standing but not in the sitting position

Adverse effects of cannabinoids:

Sedation

Drowsiness, dizziness and lethargy are common

Psychological effects

Euphoria, dysphoria, anxiety, feeling of loss of control, mental clouding,

impaired memory, depersonalisation, fear of dying, paranoia, hallucinations,
depression and altered time perception.

Physical symptoms and signs

Dry mouth, ataxia, blurred vision, incoordination, muscle weakness, tremor,

slurred speech, palpitations, tachycardia and hypotension.
Therapeutic uses of cannabinoids:

cannabinoids are reported to be of therapeutic value in neurological

disorders associated with spasticity, ataxia and muscle weakness
the most promising use of cannabinoids in the management of pain.

Anti-emetic use

Cannabinoids have been used in the prevention of nausea and vomiting

caused by anticancer drugs. Nabilone and dronabinol (THC in sesame oil) have
been shown to be as effective or more effective

Appetite stimulation

Cannabinoids stimulate appetite and may have a use in palliative care for
anorexia caused by opioids, antiviral drugs, AIDS-related illnesses or terminal
cancer [67]. Nabilone given in small doses may be effective in stimulating
appetite
Epilepsy

Cannabinoids have complex actions on seizure activity and exert both

anticonvulsant and proconvulsant effects

Glaucoma

Several studies have shown that smoked or orally administered cannabis and
intravenous infusions of THC can decrease intraocular pressure (IOP)

Bronchial asthma

Acute administration of cannabis and THC exert a definite bronchodilator

effect on the small airways of the lungs

Mood disorders, psychiatric conditions

Cannabis and cannabinoids have been advocated as antidepressants,

anxiolytics, sedatives, hypnotics and as treatment for alcohol and opiate
withdrawal syndromes

Other uses

In addition, cannabinoid receptor agonists have potential as neuroprotective

agents through CB1 receptor-mediated inhibition of glutamate release [18] in
the treatment of dyskinesia that is produced by l-DOPA in patients with
Parkinson's disease [72].

Potential therapeutic applications have also been suggested for CB1 receptor
antagonists/ inverse agonists. These include the management of acute
schizophrenia [73] and the amelioration of cognitive and memory dysfunctions
associated with disorders such as Alzheimer's disease

Adverse effects of cannabinoids:

Sedation

Drowsiness, dizziness and lethargy are common

Psychological effects

Euphoria, dysphoria, anxiety, feeling of loss of control, mental clouding,

impaired memory, depersonalisation, fear of dying, paranoia, hallucinations,
depression and altered time perception.

Physical symptoms and signs

Dry mouth, ataxia, blurred vision, incoordination, muscle weakness, tremor,

slurred speech, palpitations, tachycardia and hypotension.

Antagonists:

Endogenous cannabinoids

Two families of endogenous cannabinoids are known Endocannabinoids

are eicosanoids acting as agonists for cannabinoid receptors and they
occur naturally in the body.
The first identified was anandamide (arachidonoyl ethanolamide) and
the second was 2-AG (2-arachidonoyl glycerol).
 Additional endocannabinoids include virodhamine (O-arachidonoyl
ethanolamine), noladin ether (2-arachidonoyl glyceryl ether) and NADA
(N-arachidonoyl dopamine).

Applications

CB2 selective agonists are effective in the treatment of pain,

inflammatory diseases (in animal
models)osteoporosis[31] and atherosclerosis.[37]
CB1 selective antagonists have previously been used for weight
reduction and smoking cessation (see Rimonabant).
Activation of CB1 provides neuroprotection after brain injury.[38]