Opioid Analgesics and Antagonists Flashcards
opium
- effects known for over 5000 years
- chewed or smoked usually
- greeks and romans used opium to produce sleep
- heroin was banned in 1924 given its abuse potential
poppy plant opium comes from
papaver somniferum
- sap from flower pod contains drug
opioids vs opiates
opioids - all naturally occurring and synthetic substances which bind to opioid receptors in brain and periphery. so, anything that binds to opioid receptors.
opiates - drugs derived from opium
analgesia
absence of sense of pain without loss of consciousness
spinal analgesia
suppression of pain by analgesic drugs into the the space around the spinal cord
- at the level of the spinal cord, opiates interfere with the transmission of the pain messages between neurons and therefore prevent them from reaching the brain
supraspinal analgesia
suppression of pain by drugs in the brain itself
- allows a person to know he or she is experiencing a given stimuli/sensation that would be otherwise painful
- reduces pain perception
Opioid receptor subtypes? What class of receptor are they?
µ, ∂, and kappa
- all GPCRs
µ (mu) opioid receptor
(function and endogenous peptide affinities)
function
- supraspinal and spinal analgesia
- sedation
- inhibition of respiration
- slowed gastrointestinal transit
- modulation of hormone and NT release
endorphins> enkephalins>dynorphins
∂ (delta) opioid receptor
(function and endogenous peptide affinities)
supraspinal and spinal analgesia, modulation of hormone and NT release
enkephalins> endorphins>dynorphins
kappa opioid receptor
(function and endogenous peptide affinities)
modest suprapsinal and spinal analgesia, psychotomimetic effects (producing an effect on the mind similar to that of a psychotic state) like dysphoria and depersonalization, slowed GI transit, disorientation, miosis (pupil constriction), and mild resp depression
dynorphins»> endorphins and enkephalins
(dynorphins have a MUCH higher potency)
Number of genes for each of the mu, delta, and kappa receptors
one gene only - thought that differential splicing produces variants within each subcategory (ex. multiple µs)
Established cellular actions of opioids
Opioids have two G protein-coupled actions on neurons
1. close voltage-gated calcium channels on presynaptic nerve terminals which reduces release of glutamate, Ach, NE, 5HT, substance P
(this is how it blocks pain)
2. open K+ channels which inhibits and hyperpolarizes postsynaptic neurons
µ (mu) opioid receptor
(location)
located in:
all pain-control areas of the brain and spinal cord
- periaqueductal gray in midbrain
- spinal trigeminal nucleus
- caudate nucleus
- thalamic nucleus
in respiratory control centres and nucleus accumbens
exogenous ligands of µ OR
morphine and fentanyl
kappa opioid receptor
(location)
- basal ganglia
- nucleus accumbens
- ventral tegmentum
- cortex
- hypothalamus
- PAG
- spinal cord
exogenous ligands of kappa OR
responds to mixed agonist-antagonists like pentazocine and endogenous dynorphin
a mixed agonist-antagonist has affinity for two or more types of opioid receptors and _____
blocks opioid effects on one receptor type while producing opioid effects on a second receptor type
Salvinorin A
pure kappa OR agonist
(compared binding of LSD to salvinorin, LSD binds to a bajiillion things and salvinorin only to kappa OR)
delta opioid receptor
(location)
also found in pain areas of the brain
- PAG
- spinal trigeminal nucleus
- caudate nucleus
- thalamic nucleus
and the nucleus accumbens and libmic system
exact same areas as µ ORs except: present in limbic system and not in respiratory centres
exogenous ligands of delta OR
etorphine
nociceptors
(and two specific types)
general term to describe neurons that carry pain info from skin, muscle to neurons in the spinal cord (detect noxious stimuli)
- mechanoreceptors: respond to pressure
- capsaicin receptors: respond to extremes of heat, to acids, to capsaicin, and to inflammation caused by tissue damage
are inhibited by inhibitory interneurons releasing endorphins
How does that brain interpret pain and send pain-moderating signals
- inhibitory interneurons synapse onto substance-P-releasing-nociceptors and release endorphins to modify pain signal
- the endorphins or other endogenous opioids inhibit release of substance P (or any other NT carrying pain info) onto another neuron that would normally carry the pain signal back to the brain
How do opioids block pain?
block calcium channels (calcium influx is needed for NT release) which prevents the pain NT from being released (substance P)
ALSO
hyperpolarize the post-synaptic cell by enhancing potassium efflux which makes it more difficult for the neuron to fire an AP and signal ‘pain’ to the brain
ALSO
moderate the central perception of pain to make if less aversive when perceived
opioid agonists
Endogenous: enkephalins, endorphins, endomorphins, dynorphin
exogenous: morphine/codeine, heroin
Endorphins (4, including biological derivation)
- short for ENDogenous mORPHINE
- endogenous opioid peptide
- beta endorphin - pain
- derived from POMC pro-opiomelanocortin which is produced by the pituitary gland and the hypothalamus and released into blood stream from pituitary and into spinal cord from hypothalamus
- highest affinity for µOR
Difference between morphine and codeine
have same chemical structure except one carbon and 2 Hs removed to make codeine from morphine
- codeine is much less potent than morphine and a lot of its analgesic-properties come from its metabolism to morphine
why does heroin have a higher abuse potential than morphine?
much more fat soluble
- crosses BBB easily and is fast acting
Methadone
- just as potent as morphine but less sedation; sub for heroin and other narcotic street drugs.
- slow metabolism and very high lipid solubility
- half-life is 24-36 hours so need once a day admin
- cannot be injected
Synthetic analgesics
- dihydrocodeine
- fentanyl (used in anesthesia)
- hydromorphone
- meperidine
fentanyl
- 80-times more potent. than morphine
- fentanyl family of compounds can be active in the sub-100 ug range. which makes it one of the most potent medications known to exist
safer version of fentanyl
Remifentanil is ultra short acting (safer because it is faster clearing and does not linger around long enough to cause resp depression)
Hydromorphone and hydrocodone
Dilaudid (drug name) = hydromorphone
Hycodan (drug name) = hydrocodone
- most commonly used opioid
- analgesic and antitussive (anti-coughing) effects
- µOR agonist
Meperidine
Demerol (drug name)
- short acting, weak-agonist
- muscarinic and µOR effects
oxycodone
oxycontin long-acting form, every 12 hours
pentazocine
mixed agonist antagonist
- agonist of Kappa and antagonist of µ
- less addiction potential (since it’s blocking µ)
buprenorphine
mixed agonist antagonist
- weak µ agonist, antagonizes kappa and delta
- has equal affinity but less intrinsic activity than endogenous opiates
- less addiction potential
Opiate antagonists
- nalaxone (narcan) (displaces agonist)
- nalmefene
- naltrexone (for alcoholism)
Mu OR
Mu 1
- analgesia
Mu 2
- sedation, vomiting, resp depression, euphoria, anorexia, urinary retention, physical dependence
Opiates act on the…
brainstem, limbic system, and pain system
Effects of opiate admin (10)
- hypothermia
- hypotension (decrease in BP)
- peripheral vasodilation, skin flushed and warm
- miosis (pupil constriction)
- drying of secretions
- constipation
- rep depression (usually the cause of death by overdose)
- dangerous if another depressant co-present
- decreased sex drive
- sedation and anxiolytic effect
Opiates and reward
opiates increase release of DA in Nacc
- inhibits inhibitory effect of GABA on DAergic neurons in VTA (VTA to NAcc is part of reward system)
- increase in activity of reward system
Tolerance vs Dependence
tolerance - CNS adaptation to a drug (higher doses needed for same effect)
dependence
physical - a physiological state of adaptation, leads to withdrawal in absence of drug
psychological - sense of need or craving for its positive effects or avoidance of its negative withdrawal effects
Tolerance and dependence are less of an issue if the opiate is taken for ___ rather than for ___
pain control
recreational use
Reasons for opiate withdrawal
- upregulated receptors in response to reduced NT release, in absence of drug there is hyperactivity (normal NTs and still more receptors)
OR
- opiates may block an enzyme acutely - system may compensate by upregulating and there is an overabundance of enzyme without drug
Symptoms of opiate withdrawal
- serious drug craving
- dysphoria
- yawning and panting
- perspiration, runny nose, teary eyes
- pupil dilation
- piloerection, fever, chills
- tremors, muscle twitches
- severe aching and painful sensations
- loss of appetite
- diarrhea
Behavioural Pharm: How do we assess analgesia
- tail flick off hot plate
- hot plate (they’ll lick their paws after. being removed to cool them down)
(will take longer to move tail and lick paws on morphine)
Molecular pathways that opioids act through
G-proteins and ß-arrestin
- g proteins lead to 2nd messengers and cell response
- beta arrestin leads to signalling via kinases, transcriptional transactivation and trafficking (internalization and translocation)
Which pathway is implicated if you see that receptors are trafficked differentially depending on the ligand?
Beta arrestin pathway is responsible for trafficking so you know that with greater or less recovery the receptors are interacting more or less with beta-arrestin (depending on the ligand)
SNC-80 vs DPDPE
What happens when you knock out beta-arrestin 2 portion of opioid signalling?
(according to that one study***)
enhanced morphine analgesia (degree of analgesia and length)
- constant G protein stimulation
- no desensitization
but continued physical dependence
- morphine becomes more rewarding without beta arrestin
less constipation and respiratory depression
NOW THOUGHT TO NOT BE TRUE
Conditioned place preference
animals injected with drug of abuse only on one side of compartment and the test involves letting the animals roam freely after and seeing where they spend the most time
biased signalling of GPCRs
GPCRs signal in two ways: g-protein dependent and g-protein independent (beta arrestin dependent)
biased agonists activate the pathways differentially
Biased signalling and developing new opioid analgesic
if the G-protein is responsible for analgesic and beta arrestin is responsible for constipation, resp depression, and developing tolerance then maybe you can make a drug that preferentially activated G-protein and not BA.
HOWEVER,
newer studies have shown that effects are not different between KOs
summary of lab findings about biased signalling compound that supposedly activates g-protein and not BA
one lab had all these findings but other labs could not replicate the studies
Accusan locomotor box
tests motor activity (both horizontal and vertical)
- some drugs induce vertical activity in rodents (they’ll walk to walls and stand on hind-legs)
Tail suspension and forced swim test
animals struggle more and swim more when given antidepressant drugs
Morris water maze
tests learning and memory
- hidden platform in water, see how fast they go back to platform (did they learn cues?)
Zero and Plus maze
test anxiety behaviours
- maze has open and covered portions
- animals go to covered compartment more than open one when they are more anxious
