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BMSC - Anaesthetics and Analgesia > Opioid Analgesics > Flashcards

Opioid Analgesics Flashcards

1
Q

Where are opioid receptors located?

A

In the membrane

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2
Q

How many membrane spanning domains do opioid receptors have?

A

7

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3
Q

What does activation of an opioid receptor cuse?

A

Activation of Gi/o - inhib of adenylyl cyclase, activation of K+ channels and inhibition of VGCC
B-arr-2 recruitment

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4
Q

How can several types of signalling be achieved by just the 3 opioid receptor genes?

A

Receptors can come together in heterodimers
Many possible combinations

Also alternative splicing occurs

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5
Q

Outline alternative splicing

A

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

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6
Q

Which polymorphism makes the mu receptor less sensitive to morphine?

A

A118G

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7
Q

What does b-arr2 cause?

A

Increased activation of signalling pathways

Receptor endocytosis

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8
Q

How is most of the analgesia from mu receptors caused?

A

Couple with VGCCs

Activation of mu leas to reduction of presynaptic Ca2+ entry into primary nociceptive neurons

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9
Q

How do exogenous and endogenous opioids differ?

A

Exogenous - alkaloids

Endogenous - peptides

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10
Q

Why are cannabinoids not as effective at analgesic as opioids?

A

Not as many receptors and less widely distributed

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11
Q

What is the target of pregabalin?

A

Alpha2-delta subunit of Ca2+ channels

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12
Q

What are the current types of VGCCs?

A 
L - long
PQ - purkinje
N - not L or T
R - resistant to all the drugs
T - transient
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13
Q

Which current types of VGCCs are affected by opioid receptors?

A

N

P/Q

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14
Q

Which current type of VGCC is at the cell body near the nucleus?

A

L type

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15
Q

Which type of VGCC current is more like a sodium receptor?

A

T

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16
Q

Where are T type VGCCs located?

A

Axon hillock

17
Q

Which type of VGCC influences gene expression?

A

L type

18
Q

What is the limiting factor in the duration of time which mu receptors can couple to Ca2+ channels ?

A

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

19
Q

Which enzyme group metabolises opioids?

A

p450

Not morphine tho!

20
Q

Which enzyme is required for the metabolism of codeine to morphine?

A

CYP2D6

21
Q

Why is there significant variation in peoples ability to metabolise codeine?

A

CYP2D6 enzyme is very prone to polymorphism

22
Q

Why is morphine less likely to cause drug-drug interactions?

A

Not metabolised by p450

23
Q

What are the main issues surrounding opioid analgesia?

A

Tolerance

Addiction

24
Q

Why should opioids not be used in chronic pain?

A

Tolerance develops quickly

25
Q

How can morphine effects be seen without without mu nociceptor?

A

Loss of mu opioid receptor in nociceptors gets rid of tolerance
If mu receptor kept active in microglia, analgesic effects stay

26
Q

What are the two types of tolerance?

A

Metabolic/pharmacokinetic

Functional/pharmacodynamic

27
Q

What occurs in opioid receptor tolerance?

A

Loss of coupling of MOPr to G proteins
Reduction in receptor RNA and protein

Christie 2008

28
Q

What occurs in cellular tolerance to opioid?

A

Adaptions to intracellular signalling cascades
eg increased cAMP signalling (to small doses)

Christie 2008

29
Q

What occurs at a systemic level in opioid tolerance?

A

Feedback circuits adapt

30
Q

How does opioid tolerance chance synaptic plasticity?

A

Altered presynaptic release probability

So synapses remodel to accomodate

31
Q

How do we know that morphine tolerance causes a decrease in anaesthesia?

A

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

32
Q

Why does tolerance occur faster in heterozygous mu receptor models?

A

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

33
Q

Why other receptor is required for morphine tolerance?

A

Delta opioid receptor

Delta KO mice display less tolerance

34
Q

Why is it probably that mu and delta receptors form dimers?

A

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

35
Q

Why is it through that endogenous opioid systems overcomes inflammatory hyperalgesia?

A

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

36
Q

Outline the RAVE hypothesis

A

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

37
Q

Outline the barcode hypothesis

A

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

38
Q

Why may opioids which are effective in hotplate analgesia still display tail flick reflexes?

A

Tail flick is a reflex which occurs in the spinal cord and doesn’t reach higher centres

BMSC - Anaesthetics and Analgesia (8 decks)

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