endo-cannabinoids in pain and inflammation

1. Endo-cannabinoids system:
Therapeutic target for pain and
inflammation
Dr Akhil Agrawal
PG Resident
SKNMC,Pune

2. OUTLINE
• Introduction
• Receptors
• Signalling
• Therapeutic targets for pain and inflammation
• Recent advances

5. History
• Marijuana, or cannabis, is the most widely used illicit drug in
Western societies
• Chinese texts described its usefulness in the relief of pain and
cramps
• In ancient India, the anxiety relieving effect of bhang had been
recorded more than 3000 years ago.
• cannabis extracts had gained widespread use for medicinal
purposes until 1937, when concern about the dangers of
abuse led to the banning of marijuana for further medicinal
use in the United States

6. Plant derived Cannabinoids
Cannabis sativa, the hemp plant- used for its psychoactive
properties
Tetrahydrocannabinol- main psychoactive component.(THC)
Initially thought non-selective(lipophilic nature)
Pharmacological effects:
o Sensation of relaxation and well being
o Fellings of sharpened awareness

7. Central effects measured:
o Impairment of short term memory
o Impairment of motor coordination
o Catalepsy
o Analgesia
Peripheral effects:
o Tachycardia
o Vasodilatation
o Reduction of IOT
o Bronchodilatation

8. PK
• Effects develop in 1 hr(smoking mode) & lasts for 2-3 hrs.
• Small fraction converted- 11-hydroxy THC(more active)
• Highly lipophilic
• Identification and quantification imp for medico-legal reasons

9. Adverse effects
• THC is relatively safe(not life threatening)
• Euphoria accompanied by hallucinations precluded
widespread medical use
• Produces teratogenic and mutagenic effects(rodents)
• Tolerance and physical dependence only in heavy users.

10. Cannabinoid receptors
2 types of receptors:
• CB1 (brain) (share only 44%
• CB2 (peripheral-immune,hematopoietic) homology)
Act primarily through the Gi/o subtypes of G protein
Coupling to adenylate cyclase through Gi/o usually results in
inhibition of cyclase activity
Inhibit different types of Ca channels and activate certain K+
channels
Activate mitogen-activated protein kinases including p44/42
MAP kinase, p38 kinase , and JUN-terminal kinase and activate
the phosphatidylinositol-3-kinase pathway

11. CB1 Receptors
Abudant in brain
Located in:
• Hippocampus(memory)
• Cerebellum(coordination)
• Hypothalamus(appetite & body temperature)
• Substantia nigra & mesolimbic pathway(reward)
• Absent in brain stem(lack of serious side-effects)
At cellular level-located pre-synaptically,inhibit neuro-
transmitter release
modulation of dopamine D2 and adenosine A2A transmission

13. CB2 Receptors
• Located mainly in lymphoid tissues (spleen,tonsils and
thymus)
• Also present in microglia-immune cells
• Similar mechanism to CB1 receptor except( no Ca++ channels)
• Present in athero-sclerotic lesions

14. Endocannabinoids
• Endogenous mediators for cannabinoids
o (Anandamide)
o 2-arachidonoylglycerol (2-AG)
• Agonist ligand for TRPV1 channel( other than typical receptor)
• perhaps the most important physiologic system involved in
establishing and maintaining human health.
• In each tissue, the cannabinoid system performs different
tasks, but the goal is always the same: homeostasis, the
maintenance of a stable internal environment despite
fluctuations in the external environment.
• autophagy, a process in which a cell sequesters part of its
contents to be self-digested and recycled, is mediated by the
cannabinoid system.

16. Termination
 Rapidly taken up by endocannabinoid me,brane transporter
 Key enzyme-FAAH(fatty acid amide hydrolase)
 Research is going on to develop FAAH inhibitors.
Physiology
 Depolarisation induced suppresion of inhibition.
 Occurs in hippocamal pyramidal cells.
 Steps :
Depolarised by an excitatory input
Suppress GABA-mediated inhibitory input
Depolarised pyramidal cell to inhibitory axons
(reverse flow of info from post to pre-synaptic cell)

20. Pain
Present in pain circuits from the peripheral sensory nerve
endings up to the brain
CB1-Modulate nociceptive thresholds by regulating neuronal
activity
CB2- contribute to antinociception by inhibiting the release of
proinflammatory factors by non-neuronal cells located near
nociceptive neuron terminals
CB2-attenuation of NGF-induced mast cell degranulation and
of neutrophil accumulation
CB2-indirect stimulation of opioid receptors located in primary
afferent pathways

21. Inflammation
• Multiple lines of evidence support the important role of the
cannabinoid signaling system in the modulation of immune
function and inflammation
• First, cannabinoid receptors are present on immune cells,
where their expression is modulated by microbial antigens or
other stimuli that induce immune activation.
• Second, stimulation of immune cells by bacterial toxins such
as lipopolysaccharide (LPS) increases the cellular levels of
endocannabinoids and their degrading enzyme(s).
• Third, cannabinoid agonists modulate immune function both
in vitro and in vivo via cannabinoid receptor-dependent and -
independent mechanisms.

22. The anti-inflammatory effects of cannabinoids are complex and may involve-
 modulation of cytokine (e.g., TNF-α, IL-12, IL-1, IL-6, and IL-10) and
chemokine production (e.g., CCL2, CCL5, CXCL8, and CXCL10)
 modulation of adenosine signaling (Carrier et al., 2006),
expression of adhesion molecules (e.g., ICAM-1, P- intercellular adhesion
molecule-1 and Pselectin)
 the migration, proliferation, and apoptosis of inflammatory cells (reviewed
in Klein et al., 1998, 2003; Walter and Stella, 2004; Klein, 2005).

23. References