Opioid Analgesics

Question 1

Where are opioid receptors located?

Answer 1

In the membrane

Question 2

How many membrane spanning domains do opioid receptors have?

Answer 2

7

Question 3

What does activation of an opioid receptor cuse?

Answer 3

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

Question 4

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

Answer 4

Receptors can come together in heterodimers
Many possible combinations

Also alternative splicing occurs

Question 5

Outline alternative splicing

Answer 5

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

Question 6

Which polymorphism makes the mu receptor less sensitive to morphine?

Answer 6

A118G

Question 7

What does b-arr2 cause?

Answer 7

Increased activation of signalling pathways

Receptor endocytosis

Question 8

How is most of the analgesia from mu receptors caused?

Answer 8

Couple with VGCCs

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

Question 9

How do exogenous and endogenous opioids differ?

Answer 9

Exogenous - alkaloids

Endogenous - peptides

Question 10

Why are cannabinoids not as effective at analgesic as opioids?

Answer 10

Not as many receptors and less widely distributed

Question 11

What is the target of pregabalin?

Answer 11

Alpha2-delta subunit of Ca2+ channels

Question 12

What are the current types of VGCCs?

Answer 12

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

Question 13

Which current types of VGCCs are affected by opioid receptors?

Answer 13

N

P/Q

Question 14

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

Answer 14

L type

Question 15

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

Answer 15

T

Question 16

Where are T type VGCCs located?

Answer 16

Axon hillock

Question 17

Which type of VGCC influences gene expression?

Answer 17

L type

Question 18

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

Answer 18

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

Question 19

Which enzyme group metabolises opioids?

Answer 19

p450

Not morphine tho!

Question 20

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

Answer 20

CYP2D6

Question 21

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

Answer 21

CYP2D6 enzyme is very prone to polymorphism

Question 22

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

Answer 22

Not metabolised by p450

Question 23

What are the main issues surrounding opioid analgesia?

Answer 23

Tolerance

Addiction

Question 24

Why should opioids not be used in chronic pain?

Answer 24

Tolerance develops quickly

Question 25

How can morphine effects be seen without without mu nociceptor?

Answer 25

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

Question 26

What are the two types of tolerance?

Answer 26

Metabolic/pharmacokinetic | Functional/pharmacodynamic

Question 27

What occurs in opioid receptor tolerance?

Answer 27

Loss of coupling of MOPr to G proteins Reduction in receptor RNA and protein Christie 2008

Question 28

What occurs in cellular tolerance to opioid?

Answer 28

Adaptions to intracellular signalling cascades eg increased cAMP signalling (to small doses) Christie 2008

Question 29

What occurs at a systemic level in opioid tolerance?

Answer 29

Feedback circuits adapt

Question 30

How does opioid tolerance chance synaptic plasticity?

Answer 30

Altered presynaptic release probability | So synapses remodel to accomodate

Question 31

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

Answer 31

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

Question 32

Why does tolerance occur faster in heterozygous mu receptor models?

Answer 32

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

Question 33

Why other receptor is required for morphine tolerance?

Answer 33

Delta opioid receptor | Delta KO mice display less tolerance

Question 34

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

Answer 34

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

Question 35

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

Answer 35

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

Question 36

Outline the RAVE hypothesis

Answer 36

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

Question 37

Outline the barcode hypothesis

Answer 37

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

Question 38

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

Answer 38

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