Lectures 17-24 Flashcards
What are the 3 different types of cannabinoids and what are they?
o Phytocannabinoids- cannabinoids derived from plants
C21 terpenophenolic compounds
• e.g. THC, CBD, CBG, CBDV, THCV, CBC, CBN and THCVA
140 different phytocannabinoids
o Synthetic cannabinoids (from the lab)
Mostly CB1 agonists
• e.g. Nabilone, HU-210, AB-PINACA, JWH-018
Abused in society and potentially quite toxics
• Many synthetic cannabinoids are full agonists of cannabinoid receptors
o Endocannabinoids (in the brain and body)
Neuromodulatory lipids
• E.g. anandamide, 2-AG, noladin ether
How many cannabinoids are there in a plant? How many molecules in cannabis? How many cannabis strains?
• There are more than 100 cannabinoids in the plant- the vast majority are not intoxicating
o Each has its own therapeutic potential
o 500 molecules in cannabis, some of which are bioactive such as the terpenoids and flavonoids, which might also be considered in the actions of new cannabis based medicines
o Different cannabis strains (more than 2000) have different cannabinoid profiles
Describe the composition of street cannabis
o Street cannabis has high amounts of THC (14.9%) and low CBD (<0.1%)
What is the acid precursor to THC? How are they used?
o THC-A is the acid precursor to THC
In the biosynthesis of the plant, you have enzymes like THC-acid synthase and CBD-acid synthase that create acid precursors-> those are then decarboxylated with exposure to light and heat into the neutral forms (THC and CBD)
Why is CBD better than THC?
• CBD might make cannabis more healthy
o Cannatonic- more balanced strain of cannabis (1:1 THC:CBD)
o Industrial hemp: high CBD: low THC
o CBD is not psychoactive
o CBD could be a good anxyolitic compound
What percentage of cannabis is used for pain in Australia?
• Cannabis and its uses in Australia- o Pain (34%)
What percentage of cannabis is used for anxiety disorders in Australia?
o Anxiety disorder (15%)
What percentage of cannabis is used for depression in Australia?
o Depression (11%)
What percentage of cannabis is used for sleep disorders in Australia?
o Sleep disorder (7%)
What percentage of cannabis is used for PTSD in Australia?
o PTSD (6%)
What percentage of cannabis is used for epilepsy/seizure disorders in Australia?
o Epilepsy/seizure disorder (5%)
What percentage of cannnabis is used for cancer in Australia?
o Cancer (4%)
What percentage of cannabis is used for gastro-intestinal disorders in Australia?
o Gastro-intestinal disorder (4%)
What percentage of cannabis is used for attention deficit disorders in Australia?
o Attention deficit disorder (3%)
What percentage of cannabis is used for spinal cord injury in Australia?
o Spinal cord injury (2%)
What is the role of endocannabinoid in homeostasis and how does it do so?
• Endocannabinoid (endCBs) system maintains homeostasis
o EndoCBs comprise a homeostatic regulatory system and subserves normal physiological functions
o EndoCBs synthesised on demand to maintain balance
o EndoCBs activate receptors in a lock and key fashion which regulate cell function in different organs of the body
o Levels of endoCBs are tightly regulated by synthetic and catabolic enzymes
o The optimal function of the endoCB system maintains health
What does THC mimic and activate?
o Δ9-THC mimics endocannabinoids and activates CB1 cannabinoid receptors
Where are CB1 cannabinoid receptors mainly expressed? What are these areas responsible for/ why are they expressed in those areas?
o CB1 cannabinoid receptors are highly expressed in the cortex, amygdala, the hippocampus, throughout the striatum, ventral midbrain and cerebellum, but lowly expressed in the brainstem Motor related regions of the brain • THC can shut down motor functions Memory related (hippocampus) Planning (prefrontal cortex) Anxiety (amygdala) Low expression of brainstem • Hard to overdose on cannabis- has no ability to shut down respiratory/cardiovascular system
Where are CB2 receptors found in the brain?
o CB2 found in the brain and microglia- neuronal expression is controversial
Might help reduce neuroinflammation
What fat molecules activate cannabinoid receptors and what do cannabinoid receptors tend to be coupled with?
o 2-AG (fat molecules) activate cannabinoids receptors
Cannabinoids receptors- tend to be coupled to inhibitory Gi proteins (G-protein coupled)
What are the functions of endocannabinoid signalling in cells?
o Functions:
Activates inwardly rectifying potassium channels: leaks potassium out of cell
• Causes cell hyperpolarisation-less likely that the cell will fire
Inhibit calcium channels
• Inhibits neurotransmitter release and have neuromodulatory function
Affect different enzymatic cascades in cells
• Inhibit adenylate cyclase-> inhibits protein kinase A cascade and changes cellular function
Are endocannabinoids retrograde or anterograde messengers?
o Endocannabinoids are retrograde messengers
CB1 receptors are largely presynaptic
Endocannabinoids are synthesised on-demand from lipids
Travel backwards from post-synaptic to presynaptic
What is the process of endocannabinoid messaging and when does it occur?
Process-
• Calcium influx into excitatory pyramidal neurons causes neurotransmitters (e.g. glutamate) to traverse across the synapse to activate post-synaptic receptors
o Feedforward
• Dysfunction of glutamate release (too much)
o Can lead to epilepsy, brain hyperexcitability and neuronal death
• Dysfunction triggers mechanism to synthesise 2-AG, liberate it from the post-synaptic membrane and then travel backwards to activate pre-synaptically located CB1 receptors
o CB1 blocks calcium channels, stops calcium influx which impedes ability of further neurotransmitter release
What does the endocannabinoid system act on to perform its function?
Endocannabinoid system is involved to act on presynapse and block the release of glutamate
• Has neuroprotective applications