Flashcards in Opioid receptors and their endogenous ligands Deck (39):
what is an opioid ?
it produces morphine like effects
what is an opiate ?
it has a morphine like structure
what are the 3 groups of endogenous opioid peptides ?
opioid peptides bind to opioid receptors, they are not opiates because they dont have the same chemical structure as morphine
what produces opioid peptides |?
produced by neuronal and non-neuronal cells
what are opioid peptides derived from ?
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
what are the preprohormones made up of ?
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
where is the preprohormone cleaved to produce active peptides ?
in the golgi and secretory vesicles
what are the different opioid receptors ?
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
what receptors does beta-endorphin act on ?
mu, delta and kappa- binds to the all equally
what receptors does leu-enkephalin act at ?
mu and delta, works better at delta
what receptors does met-enkephalin act on ?
mu and delta, works better at delta but works better at mu compared to leu-enkephalin
what receptors does dynorphin act on ?
mu, delta and kappa, works best at kappa, then mu and then delta
which receptors can bind all neuropeptides ?
mu and delta
what 2 systems are the effects of opioid most important ?
central nervous system and gastrointestinal tract
what effects does morphine have in the CNS ?
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
what are the cellular mechanisms of opioid actions ?
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
what effect do opioids have upon potassium channels ?
activates them t cause hyperpolarisation
- GIRK channels activated and this causes hyperpolarisation which increases the depolarisation threshold needed to generate an ap
what effect do opioids have on calcium channels ?
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
what effects are caused by the opioid receptors in the pre synaptic terminal ?
they will reduce the calcium activity and reduce neurotransmitter release
what effect do the opioid receptors in the post synaptic membrane cause ?
these activate the GIRK channels and induce hyperpolarisation to reduce activity
what is the gate control theory ?
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
what controls the gate control theory ?
descending inhibitory pathways
mechanoreceptors (A beta)
how does the descending inhibitory pathways affect the SG ?
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
how do mechanoreceptors affect the SG ?
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
what does the substantia gelatinosa contain and how does this help to reduce pain ?
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
what do opioids do to the descending control system ?
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
what are the several sites of action of opioids ?
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
what are the 6 main effects caused by opioids at opioid receptors ?
nausea and vomiting
effects on GIT
where is euphoria caused and what is it ?
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
how does respiratory depression occur ?
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
how does the cough reflex occur ?
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
how is nausea and vomiting induced ?
this is common affecting 40% of patients when they are given morphine
it is usually transient but it cannot be separated from analgesia
how does pupil constriction occur ?
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
what are the effects on the GIT ?
due to mu, kappa and delta receptors
increase in muscle tone
but decreases motility- constipation
these are major problems with opioid use
what is the link between opioids and tolerance ?
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
what effects are affected by tolerance and which ones are not as affected ?
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
what are the most likely reasons tolerance occurs ?
uncoupling of receptor from effector systems
changes to the effector system
what are the other reasons why tolerance occurs ?
increased metabolism of the drug
decreased receptor affinity
down regulation of receptors