Cannabinoids for Pain Flashcards
what is the relationship between THC and CBD?
- they differ in physiology and pharmacology
- can be considered as separate compounds
- there are drug interactions between them
THC Pharmacological actions
wide range of actions in brain and body
CB1
- anxiolytic/euphoria/CNS depressant
- analgesic
- anti emetic
- appetite stimulation
- anti convulsant
- antispastic
CB2
- anti-inflammatory/immune suppresant
THC receptors
CB1: neurons in the CNS and PNS (g linked)
- most numerous G linked receptor in the brain
CB2: in immune system and microglia (g linked)
What are the THC endogenous ligands and where do they bind? Where and how are they formed? How are they broken down? How does THC counterfeit their actions?
- anandamide (AEA) and 2-arachidonylglycerol (2AG)
- they bind to CB1 in the brain and CB2 in the body
- they are eicosanoids –> derived from the membrane
- formed by the action of phospholipases on plasma membrane phospholipids
- broken down by FAAH and other enzymes
- blocking FAAH extends their half-life
- THC counterfeits their actions as a partial agonist
CB1 MOA
CB1 receptors are located pre-synaptically
- provide negative feedback for NTs: GABA, Glutamate, NE, DA, 5HT
- release of glutamate in presynaptic neuron occurs due to an AP and influx of Ca
- glutamate binds to mGlu receptors on post synaptic cell which releases Ca inside the neuron and activates phospholipase
- AEA and 2AG are synthesized by phospholipase in the post synaptic neuron and released
- AEA and 2AG diffuse backwards to the pre-synaptic cell and bind to CB1 receptors
- this inhibits further NT release by closing Ca++ channels and opening K+ channels which prevents the efflux of K+
- this hyper polarizes the membrane which decreases NT release
- this is retrograde inhibition
retrograde inhibition
feedback inhibition controlled by post synaptic mechanisms
CB2 MOA
- provide negative feedback
- inhibit release of cytokines in inflammatory factors
- this mediates the anti-inflammatory effect of THC
CB1 agonists
endogenous
- AEA
- 2AG
plant derived
- THC (partial agonist)
synthetic
- nabilone
- dronabilon
- WIN 55, 212-2
nabilone and dronabilon use
- anti-emetic for cancer patients experienced chemotherapy induced nausea
- they analgesic purposes but have high effects on the brain –> these side effects are accepted for their use
CB1 antagonists and inverse agonists
antagonist
- cannabidiol (CBD) ?? (but no proof in lab)
inverse agonist
- rimonabat - discontinued due to side effect of weightloss
role of CB1 and CB2 agonists in analgesia
- CB1 and CB2 agonists are thought to antagonize pain - especially neuropathic pain and chronic inflammatory pain
- anti pain effects of CB1 are mediated in the thalamus (slow burning pain), PAG and RVM (pain override system), dorsal horn and periphery
- anti pain/inflammatory effect of CB2 are due to inhibition of cytokines that causes inflammation
THC as an analgesic support
- smoking or ingesting THC OTC decreases pain
- THC related drugs have been developed
- nabilone (casamet) and dronabinol (marinol) are THC analogs
- sativex is a combination of 50/50 THC and CBD –> thus CBD must not be blocking THC if it is sold for pain
- works in the tail immersion test
behavioural tetrad for THC in rodents
- hypolocomotion
- catalepsy
- hypothermia
- analgesia
CBD pharmacological actions
well documented:
- does not make you high (important when looking at analgesics)
- antiseizure effects
claimed
- analgesic
- antidepressant, anxiolytic
- anti cancer
- anti inflammatory (prof also believes it is)
CBD receptors
does not act on:
- CB1 and CB2 (very low affinity)
probably acts on
- 5HT 1A - partial agonist (antidepressant? anxiolytic?)
- TRPV1 - weak agonist, desensitization (exists in the brain and not skin - analgesia?)
- Mu and Delta opioid receptors - allosteric modulators (analgesic?)
- PPAR - antagonist (cell growth??)
- GPR55 - antagonist
