Opioid receptors and their endogenous ligands

Question 1

what is an opioid ?

Answer 1

it produces morphine like effects

Question 2

what is an opiate ?

Answer 2

it has a morphine like structure

Question 3

what are the 3 groups of endogenous opioid peptides ?

Answer 3

enkephalins
endorphins
dynorphins
opioid peptides bind to opioid receptors, they are not opiates because they dont have the same chemical structure as morphine

Question 4

what produces opioid peptides |?

Answer 4

produced by neuronal and non-neuronal cells

Question 5

what are opioid peptides derived from ?

Answer 5

derived from precursor polypeptides

• preproenkaphalins to proenkephalins to met-enkephalin and leu-enkephalin
• preproopiomelanocortin to proopiomelanocortin to betaendorphin
• preprodynorphin to prodynorphin to dynorphins

they are produced as bulky proteins which are then cleaved into smaller ones

Question 6

what are the preprohormones made up of ?

Answer 6

made up of several different prohormones

• preproopiomelanocortin is made up of gamma-MSH, AKTH, alpha-MSH and beta-lipoproteins
• preproenkephalin is made up of pep-e, M and L versions and Pep-F
• preprodynorphin is made up of alpha-neo, dyn and beta-neo

Question 7

where is the preprohormone cleaved to produce active peptides ?

Answer 7

in the golgi and secretory vesicles

Question 8

what are the different opioid receptors ?

Answer 8

they are GPCRs
mu- most analgesic opioid are mu receptor agonist, it is the most abundant in the CNS
delta- some contribution to analgesia, it is more important in the periphery- inflammation causes these receptors to become more efficacious in the PNS to try and reduce pain, they also cause fewer side effects in the CNS
kappa- analgesia at the spinal level

ORL- novel opioid like receptor, endogenous ligand is nociceptin

Question 9

what receptors does beta-endorphin act on ?

Answer 9

mu, delta and kappa- binds to the all equally

Question 10

what receptors does leu-enkephalin act at ?

Answer 10

mu and delta, works better at delta

Question 11

what receptors does met-enkephalin act on ?

Answer 11

mu and delta, works better at delta but works better at mu compared to leu-enkephalin

Question 12

what receptors does dynorphin act on ?

Answer 12

mu, delta and kappa, works best at kappa, then mu and then delta

Question 13

which receptors can bind all neuropeptides ?

Answer 13

mu and delta

Question 14

what 2 systems are the effects of opioid most important ?

Answer 14

central nervous system and gastrointestinal tract

Question 15

what effects does morphine have in the CNS ?

Answer 15

analgesia
effective against both acute a chronic pain- they are efficacious against neuropathic pain however the dose has to be increase as tolerance occurs
reduces pain- nociception
reduces distress(emotional pain)- affective component- effects of morphine can sometimes mean the patient still feels a bit of pain but they care much less about the pain

Question 16

what are the cellular mechanisms of opioid actions ?

Answer 16

activate Go/i coupled pathways- inhibit adenylate cyclase causing reduction in cAMP and this affects 2 types of ion channels

• causes activation of potassium channels
• causes inhibition of voltage gated calcium channels

Question 17

what effect do opioids have upon potassium channels ?

Answer 17

activates them t cause hyperpolarisation
- GIRK channels activated and this causes hyperpolarisation which increases the depolarisation threshold needed to generate an ap

Question 18

what effect do opioids have on calcium channels ?

Answer 18

inhibit N-type, Ltype, PQtype calcium channels

• • it is the beta-gamma subunit that affects the calcium channels
• it induces conformational changes causing the channel to be less sensitive to voltage - puts it into a relaxant state
• this reduces synaptic transmission

Question 19

what effects are caused by the opioid receptors in the pre synaptic terminal ?

Answer 19

they will reduce the calcium activity and reduce neurotransmitter release

Question 20

what effect do the opioid receptors in the post synaptic membrane cause ?

Answer 20

these activate the GIRK channels and induce hyperpolarisation to reduce activity

Question 21

what is the gate control theory ?

Answer 21

it has never been completely proven
suggests a gate at the level of the spinal cord- it opens to enable nociceptive signals from the PNS to enter into the CNS but when it is closed the pain isnt felt
therefore if the gate is closed reduced pain is felt

Question 22

what controls the gate control theory ?

Answer 22

descending inhibitory pathways

mechanoreceptors (A beta)

Question 23

how does the descending inhibitory pathways affect the SG ?

Answer 23

it provides positive inputs to the SG to close the gate

it can be affected by severe stress- helping to close the gate and reduce pain

Question 24

how do mechanoreceptors affect the SG ?

Answer 24

many projections enter into the SG and this provides it with exictatory inputs to try and reduce the inhibitory inputs from nociceptive fibres
e,g rubbing your skin increases mechanosensntive activity and reduces feeling of pain

Question 25

what does the substantia gelatinosa contain and how does this help to reduce pain ?

Answer 25

it contains interneurons which can inhibit the excitation of 2nd order neurons going to the thalamus which reduces the feelings of pain
the interneurons release GABA and this makes the 2nd order neurons less responsive to info from the periphery

Question 26

what do opioids do to the descending control system ?

Answer 26

causes excitatory effects at the PAG and NRPG - this is in the CNS where they activate to inactivate the pain felt at the level of the spinal cord
causes inhibition of the pain sensations from the nociceptive neurons in the dorsal horn

Question 27

what are the several sites of action of opioids ?

Answer 27

1- increase the descending inhibitions
2- act directly on the spinal cord to reduce transmission of nociceptive impulses by inhibiting the release of glutamate and substance P
3- reduce affective component (distress) due to action on limbic system

Question 28

what are the 6 main effects caused by opioids at opioid receptors ?

Answer 28

euphoria
respiratory depression 
cough reflex
nausea and vomiting 
pupil constriction 
effects on GIT

Question 29

where is euphoria caused and what is it ?

Answer 29

occurs at mu receptors
sense of well being
if a drug is given by iv you get a sudden rush
can be balanced by dysphoria at kappa receptors
more modern drugs have reduce euphoria but they cant completely eliminate it
it is the most problematic side effect with addication

Question 30

how does respiratory depression occur ?

Answer 30

by mu receptors
occurs at normal doses for analgesia
it is the most common cause of death in acute opioid poisoning
caused by a decrease in sensitivity of the respiratory centre to the partial pressure of carbon dioxide

Question 31

how does the cough reflex occur ?

Answer 31

correlates poorly with analgesia and respiratory depression
coedine suppresses the cough reflex at subanalgesic doses which is why it is present in cough syrups
- it may be an off target response- acting at other receptors to mu

Question 32

how is nausea and vomiting induced ?

Answer 32

this is common affecting 40% of patients when they are given morphine
it is usually transient but it cannot be separated from analgesia

Question 33

how does pupil constriction occur ?

Answer 33

due to binding at mu and kappa receptors - it is an indicator of drug overdose
centrally-mediated effect - oculomotor nucleus
can get pupil dilation via theta receptors

Question 34

what are the effects on the GIT ?

Answer 34

due to mu, kappa and delta receptors
increase in muscle tone
but decreases motility- constipation
these are major problems with opioid use

Question 35

what is the link between opioids and tolerance ?

Answer 35

the dose of opioid has to be increased to produce the same effect because tolerance occurs- can increase by 10x in very short period
with morphine tolerance can occur within 12-24 hours
e.g hot plate test= in mice after 3 days dose of morphine required for analgesia was increased by 5 fold
this is important in drug addication because it may need to be inreased by 50 fold

Question 36

what effects are affected by tolerance and which ones are not as affected ?

Answer 36

tolerance extendds to analgesia, euphoria, and respiratory depressionn
it affects pupil constriction and constipation to a much lesser extent - this is why constipation can be such a big problem with opioids

Question 37

what are the most likely reasons tolerance occurs ?

Answer 37

uncoupling of receptor from effector systems

changes to the effector system

Question 38

what are the other reasons why tolerance occurs ?

Answer 38

increased metabolism of the drug
decreased receptor affinity
down regulation of receptors

Question 39

what is the gold standard treatment for analgesia?

Answer 39

opioids - very effective at suppressing pain