Atypical Transmitters: ENDOCANNABINOIDS (RW)
Cannabis
Cannabis sativa is a plant native to Central Asia that has spread all
over the world and is probably the most widely used recreational
drug
Has been used in hemp, oil, medicine and narcotics
Medicinally, cannabis has been used over the centuries for its
sedative, intoxicant, analgesic and narcotic properties
2700 BC: first documented use of cannabis in the oldest known text
on medical drug use
1842: previously banned, cannabis use is re-favoured in Victorian
times as a treatment for menstrual cramps (by Queen Victoria
herself)
2000: UK allows cannabis to be prescribed for medical use
Plant cannabinoids
The therapeutic value of cannabis was assessed scientifically in the
1830s by Sir W.B O’Shaughnessy
The first active components of cannabis (termed cannabinoids) to
be isolated & characterised were cannabinol and Δ9
tetrahydrocannabinol (THC), in 1964 (Gaoni and Mechoulam –
latter the founding father of cannabis research)
Cannabinol is the non-psychoactive component of cannabis (current
therapeutic interest), whereas THC is the psychoactive component
Δ9 tetrahydrocannabinol (THC)
THC is the prototypical cannabinoid and is responsible
for the psychotropic activity of cannabis (psychoactive
component)
Lipid-like molecule with a hydrophobic tail
THC induces altered perception, euphoria, hallucination, analgesia
and enhanced appetite, reduced motor activity and impaired short-
term memory in experimental animals – cannabis clearly has a
profound effect on neurotransmission
THC also exerts profound effects on several biological systems other
than the nervous system such as suppression of immune responses
(by acting on immune cells)
Therapeutic interest in cannabis
Outside of the nervous system, cannabis has therapeutic
implications in appetite disorders, anti-nausea treatment
(chemotherapy) and glaucoma
Within the nervous system, cannabis has been used in:
Pain relief (spinal injury, arthritis, rheumatics): modulation of ion
, channels to alleviate chronic pain
Muscle spasm in multiple sclerosis: licensed drug Sativex
alleviates MS motor symptoms (extensive campaigning to licence
treatment)
Epilepsy (treatment-resistant paediatric form): current campaigns
to legalise various forms of cannabis to treat paediatric epilepsy
Cannabinoid receptors
Took a long time to identify binding sites of cannabinoids in
mammalian systems
The first ∆9-THC binding site was identified by Devane et al. in 1988
and cloned by Matsuda et al. in 1990, termed cannabinoid receptor
1 (CB1)
A second CB receptor subtype, CB2, was cloned by Munro et al. in
1993
Both CB1 and CB2 are 7-TM spanning GPCRs
CB1 is the most abundant GPCR in the mammalian brain, and
mediates most of the NS effects of cannabinoids
CB2 mediates most of the immune system effects of cannabinoids
Evidence for additional cannabinoid receptors – many orphan GPCRs
with no known ligands are activated by lipid-like molecules so are
likely to be additional CB receptors (e.g. GPR55 – potential CB3
receptor)
Emerging evidence for heterodimerisation of CB1/CB2 with other
GPCRs, resulting in complex signalling responses e.g. Dopamine
receptor
CB1/2 receptor structure
Same conserved GPCR structure but CB2
receptor is slightly shorter (shorter N- and C-
termini)
Again, CB1 mainly expressed in brain, CB2 in
immune system (spleen, tonsil)
CB1 distribution & signal transduction
PET imaging reveals the widespread
distribution of CB1 receptors in the brain:
CB1 functions in cortex, basal ganglia,
cerebellum, medulla, hypothalamus,
hippocampus and spinal cord.
Two downstream signalling pathways
regulating neurotransmission and
metabolism:
Cannabis
Cannabis sativa is a plant native to Central Asia that has spread all
over the world and is probably the most widely used recreational
drug
Has been used in hemp, oil, medicine and narcotics
Medicinally, cannabis has been used over the centuries for its
sedative, intoxicant, analgesic and narcotic properties
2700 BC: first documented use of cannabis in the oldest known text
on medical drug use
1842: previously banned, cannabis use is re-favoured in Victorian
times as a treatment for menstrual cramps (by Queen Victoria
herself)
2000: UK allows cannabis to be prescribed for medical use
Plant cannabinoids
The therapeutic value of cannabis was assessed scientifically in the
1830s by Sir W.B O’Shaughnessy
The first active components of cannabis (termed cannabinoids) to
be isolated & characterised were cannabinol and Δ9
tetrahydrocannabinol (THC), in 1964 (Gaoni and Mechoulam –
latter the founding father of cannabis research)
Cannabinol is the non-psychoactive component of cannabis (current
therapeutic interest), whereas THC is the psychoactive component
Δ9 tetrahydrocannabinol (THC)
THC is the prototypical cannabinoid and is responsible
for the psychotropic activity of cannabis (psychoactive
component)
Lipid-like molecule with a hydrophobic tail
THC induces altered perception, euphoria, hallucination, analgesia
and enhanced appetite, reduced motor activity and impaired short-
term memory in experimental animals – cannabis clearly has a
profound effect on neurotransmission
THC also exerts profound effects on several biological systems other
than the nervous system such as suppression of immune responses
(by acting on immune cells)
Therapeutic interest in cannabis
Outside of the nervous system, cannabis has therapeutic
implications in appetite disorders, anti-nausea treatment
(chemotherapy) and glaucoma
Within the nervous system, cannabis has been used in:
Pain relief (spinal injury, arthritis, rheumatics): modulation of ion
, channels to alleviate chronic pain
Muscle spasm in multiple sclerosis: licensed drug Sativex
alleviates MS motor symptoms (extensive campaigning to licence
treatment)
Epilepsy (treatment-resistant paediatric form): current campaigns
to legalise various forms of cannabis to treat paediatric epilepsy
Cannabinoid receptors
Took a long time to identify binding sites of cannabinoids in
mammalian systems
The first ∆9-THC binding site was identified by Devane et al. in 1988
and cloned by Matsuda et al. in 1990, termed cannabinoid receptor
1 (CB1)
A second CB receptor subtype, CB2, was cloned by Munro et al. in
1993
Both CB1 and CB2 are 7-TM spanning GPCRs
CB1 is the most abundant GPCR in the mammalian brain, and
mediates most of the NS effects of cannabinoids
CB2 mediates most of the immune system effects of cannabinoids
Evidence for additional cannabinoid receptors – many orphan GPCRs
with no known ligands are activated by lipid-like molecules so are
likely to be additional CB receptors (e.g. GPR55 – potential CB3
receptor)
Emerging evidence for heterodimerisation of CB1/CB2 with other
GPCRs, resulting in complex signalling responses e.g. Dopamine
receptor
CB1/2 receptor structure
Same conserved GPCR structure but CB2
receptor is slightly shorter (shorter N- and C-
termini)
Again, CB1 mainly expressed in brain, CB2 in
immune system (spleen, tonsil)
CB1 distribution & signal transduction
PET imaging reveals the widespread
distribution of CB1 receptors in the brain:
CB1 functions in cortex, basal ganglia,
cerebellum, medulla, hypothalamus,
hippocampus and spinal cord.
Two downstream signalling pathways
regulating neurotransmission and
metabolism:
