Opioid Analgesics Flashcards
Where are opioid receptors located?
In the membrane
How many membrane spanning domains do opioid receptors have?
7
What does activation of an opioid receptor cuse?
Activation of Gi/o - inhib of adenylyl cyclase, activation of K+ channels and inhibition of VGCC
B-arr-2 recruitment
How can several types of signalling be achieved by just the 3 opioid receptor genes?
Receptors can come together in heterodimers
Many possible combinations
Also alternative splicing occurs
Outline alternative splicing
mRNA coded and transcribed to pre-mRNA
Taken to the splicer zone of the nucleus to remove introns and also specific exons based on goal
More than one type of exon leads to many proteins from one gene
Which polymorphism makes the mu receptor less sensitive to morphine?
A118G
What does b-arr2 cause?
Increased activation of signalling pathways
Receptor endocytosis
How is most of the analgesia from mu receptors caused?
Couple with VGCCs
Activation of mu leas to reduction of presynaptic Ca2+ entry into primary nociceptive neurons
How do exogenous and endogenous opioids differ?
Exogenous - alkaloids
Endogenous - peptides
Why are cannabinoids not as effective at analgesic as opioids?
Not as many receptors and less widely distributed
What is the target of pregabalin?
Alpha2-delta subunit of Ca2+ channels
What are the current types of VGCCs?
L - long PQ - purkinje N - not L or T R - resistant to all the drugs T - transient
Which current types of VGCCs are affected by opioid receptors?
N
P/Q
Which current type of VGCC is at the cell body near the nucleus?
L type
Which type of VGCC current is more like a sodium receptor?
T
Where are T type VGCCs located?
Axon hillock
Which type of VGCC influences gene expression?
L type
What is the limiting factor in the duration of time which mu receptors can couple to Ca2+ channels ?
The alpha subunit “releases” the betagamma unit which then goes to bind to the calcium channel to produce incomplete inhibition
The alpha subunit then breaks down GTP to GDP. At this point its high affinity for betagamma is returned and they form a single unit again
Which enzyme group metabolises opioids?
p450
Not morphine tho!
Which enzyme is required for the metabolism of codeine to morphine?
CYP2D6
Why is there significant variation in peoples ability to metabolise codeine?
CYP2D6 enzyme is very prone to polymorphism
Why is morphine less likely to cause drug-drug interactions?
Not metabolised by p450
What are the main issues surrounding opioid analgesia?
Tolerance
Addiction
Why should opioids not be used in chronic pain?
Tolerance develops quickly
How can morphine effects be seen without without mu nociceptor?
Loss of mu opioid receptor in nociceptors gets rid of tolerance
If mu receptor kept active in microglia, analgesic effects stay
What are the two types of tolerance?
Metabolic/pharmacokinetic
Functional/pharmacodynamic
What occurs in opioid receptor tolerance?
Loss of coupling of MOPr to G proteins
Reduction in receptor RNA and protein
Christie 2008
What occurs in cellular tolerance to opioid?
Adaptions to intracellular signalling cascades
eg increased cAMP signalling (to small doses)
Christie 2008
What occurs at a systemic level in opioid tolerance?
Feedback circuits adapt
How does opioid tolerance chance synaptic plasticity?
Altered presynaptic release probability
So synapses remodel to accomodate
How do we know that morphine tolerance causes a decrease in anaesthesia?
Tail withdrawal tests compared between a morphine naïve mouse and a mouse given morphine for 4 days
Both given same does of morphine
Noted that naïve mouse in less pain
Why does tolerance occur faster in heterozygous mu receptor models?
With homozygous/WT - there are already more than needed, so if a few get endocytosed to start with its not a massive deal
But in het there are just enough receptors, so you get rid of a couple and you see a big diff right away
Why other receptor is required for morphine tolerance?
Delta opioid receptor
Delta KO mice display less tolerance
Why is it probably that mu and delta receptors form dimers?
Delta KO caused reduced tolerance
Thought that mu and delta dimerise via C-terminals
Delta with no c-terminals still show less tolerance
Manglik et al 2012
Why is it through that endogenous opioid systems overcomes inflammatory hyperalgesia?
Paw withdrawal tests with von frey filaments
After 14 days, inflammation remains but withdrawal/pain response decreases
Naltexone reverse this decrease
Suggests that opioids are relevant
Corder et al 2013
Outline the RAVE hypothesis
Agonists activate receptors without inducing endocytosis
These can cause more tolerance
Because endocytosis enables the re-sensitisation of desensitised receptors
The receptors stay in the cell surface, but are not functional
Outline the barcode hypothesis
Peptides/endogenous opioids activate receptors different than alkaloids/exogenous opioids to cause two different cascades
Peptides cause internalisation of the receptor
Alkaloids cause beta arrestin signalling to activate c-Src, ERK and Raf pathways
Why may opioids which are effective in hotplate analgesia still display tail flick reflexes?
Tail flick is a reflex which occurs in the spinal cord and doesn’t reach higher centres
