Lecture 13 Flashcards
What are the central effects of THC?
- impaired short-term memory and motor coordination
- altered sense of time
- changes in mood (euphoria/dysphoria)
- catalepsy (trance-like state)
- hypothermia (read out of THC action)
- analgesia
- antiemetic
- increase in appetite
What are the peripheral effects of THC?
- tachycardia (risk of myocardial infarction)
- vasodilation (bloodshot eyes)
- fall in intraocular eye pressure
- bronchodilation
What are the pharmacokinetics of THC?
- smoked or taken orally
- smoking > oral (due to quicker onset)
- metabolised by conjugation and enterohepatic circulation (prolongs duration)
- lipophilic (sequestered in body fat, detectable after several weeks of admin)
How was the CB1 cannabinoid receptor discovered?
- ligand-binding assay
- tritiated form of a cannabinoid
- specific binding occurred and analogue was displaced by delta 9 THC and was saturable
- if binding was non-specific= no saturation
- decreased binding of a non-hydrolysable GTP analog suggests it is a GPCR which acts through allosteric regulation
How was the CB2 cannabinoid receptor discovered?
- identified among cDNAs based on similarity in sequence to CB1 receptor
- molecular explanation of cannabinoid effects on the immune system
- inhibits adenylyl cyclase activity
What is the distribution of the cannabinoid receptors?
- CB1= widespread brain distribution e.g. cortex. hypothalamus, amygdala
- CB2= more defined pattern in cells and tissues of the immune system e.g. glial cells
What are the mechanisms of cannabinoid GPCR activation?
- couples with G protein
- inhibits Ca2+ channels
- activates K+ channels
- inhibits cAMP and PKA
- inhibition of synaptic transmission
What are the effects of knocked out CB1 receptors (in mice)?
- increased mortality
- leanness, resistance to diet induced obesity, enhanced leptin sensitivity
- loss of THC-induced hypothermia
- less pain sensitive in tests of supraspinal pain responses
What were the first identified endogenous ligands for CB receptors?
- anandamide
- 2-arachidonoyl glycerol (2-AG)
- all are lipids
- both activate CB1 + CB2
What are the properties of the endogenous ligands?
- produced on demand and not stored in vesicle
- produced following elevation of intracellular Ca2+ by Ca2+ sensitive enzymes
How is anandamide synthesised?
- enzymatic hydrolysis of a family of membrane phospholipids (NArPE)
- NAPE-PLD is Ca2+ sensitive and catalyses the hydrolysis of NArPE to anandamide
How is 2-AG synthesised?
DAGs converted into 2-AG via two Ca2+-sensitive DAG lipases (DAG-α and DAGL-β)
How are cannabinoids synthesised and released?
- produced from phospholipids present in the cell membrane
- released in a regular and retrograde direction
- CB receptors present on both the pre and post synapse
- also receptors present on glial cells
What enzymes terminate cannabinoid activation?
- MAGL (monoacylglycerol lipase)
- FAAH (fatty acid amide hydrolase)
What is the function of FAAH?
Main metabolising enzyme for the fatty acid amides (e.g. anandamide)
What would be the effects of FAAH KO?
- analgesic phenotype (reduced pain sensation)
- hypersensitivity to exogenous anandamide (cannot be broken down)
What is the role of the endocannabinoid membrane transporter (EMT)?
- releases cannabinoids from cells
- inhibition abolishes phasic and tonic endogenous cannabinoid-mediated control of excitatory synaptic transmission
- fatty acid binding protein 5 shown to be transporter
What is the function of cannabinoid retrograde signalling?
- usually GABA activates GABARs
- postsynaptic depolarisation synthesises cannabinoids
- cannabinoids released back onto presynaptic neuron
- inhibits DSI (depolarisation suppression of inhibition)
How are cannabinoids associated with glial cells?
- glia can release cannabinoids (contain enzymes which make and break them)
- Ca2+ rises occur if cannabinoids are applied
How do synthetic derivatives of cannabinoids differ from naturally-occurring ligands?
- higher affinity and efficacy
- increased potency
K2/Spice as a synthetic cannabinoid
- not easily detectable in urine/blood samples
- strict structure-activity relationship
- hypertension, tachycardia, hallucinations, seizures and panic attacks
What are examples of cannabinoid derivatives?
- nabilone synthetic THC analogue
- dronabinol (THC tradename)
- levonantradol THC analogue
- cannabidiol (CBD)
What are desirable effects of cannabinoid derivatives?
- anti-emetic effects e.g. nabilone for chemotherapy
- analgesia e.g. CB1 agonists
- appetite stimulation e.g. anorexics, cachexia (weight loss associated w/ cancer)
- multiple sclerosis e.g. agonists reduce spasms and pain
- anti-cancer e.g. THC inhibits tumour growth
What are the reported benefits of CBD (cannabidiol)?
- relieve pain
- treat depression and anxiety
- reduce acne
- neuroprotective properties
- increase cardiac health
- antipsychotic effects
- substance abuse treatment
