Lecture 17 - Opioids I Flashcards
dried latex obtained from a poppy
opium
any drug derived from opium
opiates
any drug that binds to an opioid receptor (includes opiates, as well as synthetic opioid agonists)
opioid
used by law enforcement to refer to illegal use of opioids for non-medical purposes
narcotics
opioid receptors are:
inhibitory GPCRs (Gi)
activation of opioid receptors leads to:
neuronal inactivation and reduced neurotransmitter release
what are the four types of opioid receptors?
- mu
- kappa
- delta
- ORL1
why do the different opioid receptors produce different effects when activated?
differences due to receptor distribution (different neurons, different brain circuits), and ligand specificity (drugs are selective for different opioid receptors)
where is ORL1 expressed?
widely expressed in the CNS
the last opioid receptor discovered (based on sequence homology), poorly studied, and may be involved in fear processing
ORL1
what are the effects of mu opioid agonists?
- analgesia
- reward
- antitussive
- respiratory depression
- constipation
morphine, codeine, and heroin are all:
full mu opioid agonists
what are the effects of mu opioid antagonists?
- aversive
- prevent reward
- block overdose
naloxone is a:
mu opioid antagonist
what are the effects of delta opioid agonists?
- not rewarding
- no analgesia except in chronic pain and migraines
- some are seizure inducing
what are the effects of delta opioid antagonists?
no obvious effects
what are the effects of kappa opioid agonists?
- hallucinogenic
- anxiogenic
- analgesic and antipuretic
salvia is a(n):
kappa opioid agonist
what are the effects of kappa opioid antagonists?
potential antidepressant/anxiolytic
a partial agonist at the mu opioid receptor; has mild to moderate analgesic efficacy, but a safe therapeutic index
buprenorphine
which is a more potent opioid agonist: fentanyl or morphine?
fentanyl
true or false: opioid ligands can have multiple effects on more than one opioid receptor
true
drug which acts as a partial agonist at the mu opioid receptor and an antagonist at the delta/kappa opioid receptor
buprenorphine
buprenorphine is a common treatment for:
pain and opioid addiction (opioid agonist therapy)
delta agonists are being developed to treat:
chronic migraine
at first, the development of delta agonists was restricted due to the risk of triggering seizures, but later on it was found that you can isolate the analgesic effects of delta agonists from seizures through:
biased agonism
what is TRV250?
a delta opioid receptor biased agonist
what are the two major pathways that can be triggered by activity at the delta opioid receptor?
G protein pathway and beta-arrestin pathway
arrests G protein signalling that leads to tolerance following chronic opioid use, and activates its own intracellular signalling pathways that contributes to some of the drug effects
beta-arrestin
what are beta-arrestins?
a family of intracellular proteins important for regulating signal transduction at GPCRs
following receptor activation and G-protein cleavage, the GPCR is ______, which signals ______
phosphorylated, beta-arrestin to bind
beta-arresting binding blocks ______, redirects ______, and targets ______
further G-protein signalling, signalling to alternative pathways, receptors for internalization
selectivity for different receptor subtypes
receptor selectivity
selectivity for different signalling pathways coupled to the same receptor
functional selectivity
do all opioids lead to beta-arrestin recruitment?
no
for the delta opioid receptor, which pathways blocks migraines and which pathways drives seizures?
G-protein signalling pathway blocks migraines, and the beta-arrestin signalling pathway drives seizures
kappa agonists that penetrate the brain have not been developed for pain because of:
dysphoria/hallucinogenic effects
peripherally restricted kappa agonists do not cross the:
blood brain barrier
these drugs bind kappa receptors in the skin and inhibit pain transmission, while avoiding adverse events in the CNS
kappa opioid agonists
a kappa opioid agonist which acts as a potent analgesic, anti-inflammatory, and has anti-itch properties with little CNS effects
nalfurafine
where are kappa opioid receptors located?
on the terminals of dopamine neurons in the striatum
kappa receptors are upregulated in disorders associated with:
dysphoria (depression, chronic pain, and addiction)
a kappa antagonist which has completed phase 2 clinical trials with promising results for major depressive disorder
aticaprant
most mu agonist opioids are ______ when taken orally
well absorbed
when ingested, morphine undergoes:
extensive first-pass metabolism
is codeine more or less impacted by first-pass metabolism than morphine?
less, since it is a prodrug that is metabolized into morphine by liver enzymes
opioid agonists are widely distributed through body tissues, with highest concentrations in:
highly perfused body tissues (brain, lungs, liver, kidney, spleen)
distribution of opioid agonists depends on:
route of administration
true or false: opioid agonists can cross placental barriers, and exert effects on fetus that can result in both respiratory depression and physical dependence in neonates
true
morphine is metabolized by:
phase II glucuronidation
morphine is metabolized into:
morphine-3-glucuronide and morphine-6-glucuronide
the most important glucuronidation enzyme is:
UGT2B7
morphine-6-glucuronide is an:
active metabolite (can prolong morphine effects)
codeine is metabolized into morphine by:
CYP2D6
genetic polymorphisms of CYP2D6 are linked to:
variation in analgesic and adverse responses among patients (particularly for codeine)
polar metabolites, including glucuronide conjugates of opioid analgesics, are excreted mainly in the:
urine
