Opioids Flashcards
medical uses
pain → anti-nociceptive
blocks afferent transmission in the spinal cord/brainstem + PAG
safe and effective when used appropriately
PAG
periaqueductal gray
dorsal midbrain (tegmentum)
modulation of pain transmission - sets thresholds
opioid epidemic
skyrocketing opioid prescriptions preceded opioid-related death epidemic
opioids + sedatives
lethal mix
polypharmacy - depressant drugs
synergism of respiratory response
depression of critical brain functions (respiration) = low (or no) resp rate = no O2 flow
prevention of overdose
Naloxone
Methadone
First Responders
naloxone
opioid receptor antagonist
methadone
mu partial agonist → competes with other opioids for binding
delayed kinetics; reduces symptoms of withdrawal → used clinically to help recovery
NMDA receptor antagonist
sources of opioids
natural
semi-synthetic
synthetic
natural opioids
opium
contains morphine, codeine
semi-synthetic opioids
derived from opium
heroin
hydro-codone/-morphone, oxycodone
krokodil
buprenorphine, etorphine
synthetic opioids
methadone, meperidine
tramadol
fentanyl
composition of opium
narcotic (morphine [10%] + codeine [0.5%]) and non-narcotic alkaloids
kinetics of opium
morphine is 10x more potent than opium
CYP2D6 converts codeine to morphine in brain + liver
codeine
prodrug
requires metabolism to be active
pharmacogenomics of codeine
10% of caucasians have deficient CYP2D6 = codeine has no effect
2% of population has overactive CYP2D6 = morphine intoxication
heroin
semi-synthetic opioid = produced by modifying naturally-derived chemical
morphine + two acetyl groups = 10x more lipophilic
→ faster distribution to brain = rapid onset of euphoria
synthetic opioid sources
diphenylacetonitrile → methadone
cyclohexanone → tramadol
4-piperidone hydrochloride → fentanyl
discovery of opioid receptors
synthesis of naloxone → saw reversal of morphine effects
later, tracing of radiolabelled drugs to determine targets
Pert and Snyder
Pert and Snyder
discovery of opioid receptors in the brain by radio-labelling
→ radioligand binding
4 classes: mu, delta, kappa, ORL-1
presynaptic receptors
modulate neurotransmitter release
dopamine, norepinephrine, GABA
post synaptic receptors
alter membrane potential
endogenous opioids
18 different peptide ligands that bind to opioid receptors
endorphins are widest class → range of functions
all contain N-terminal tyrosine residue → morphine structure mimics tyrosine
functions of endorphins
pain, emotional responses, euphoria, eating, memory, stress, seizures, and alcohol dependence
mu opioid receptors
most opioids bind mu receptors
morpheus - sleep (tranquilizing effects)
expressed in VTA, NAc, PAG, hypothalamus, LC, brainstem, pupils, GI tract
involved in reward, addiction, analgesia, euphoria, anxiolysis, respiration, blood pressure, nausea, itch, vasoconstriction, constipation
delta opioid receptors
found in vas deferens tissue
expressed in neocortex, striatum, NAc, substantia nigra, olfactory bulb
enkephalins
endogenous opioids
bind delta receptors
kappa opioid receptors
ketocyclazocine → ligand specific to kappa receptor
expressed in pituitary, hypothalamus, PAG, spinal cord
bound by endorphins and dynorphins, + PCP and ketamine
kappa receptor → dysphoria
most aversive withdrawal symptoms → leads to relapse/binge
= target of potential treatments
ORL 1 opioid receptor
expressed in limbic system and spinal cord
bound by buprenorphine
contamination of drugs with fentanyl
fentanyl: similar appearance to rx pills (80mg oxycontin)
sold as heroin
fentanyl
use as surgical anaesthetic + analgesic
100x more potent than morphine
40-50x more potent than heroin
highly lipophilic
fentanyl derivatives
increased affinity for mu receptors + enhanced entry into the brain = higher potency
carfentanil
3-methylfentanyl
absorption
higher purity (rx) = safer administration → street opioids are often contaminated with adulterants (baking soda, talcum, fentanyl)
administration:
inhalation, injection, ingestion
distribution
most are not lipophilic (heroin and fentanyl are) → do not readily cross BBB
liver, lungs, spleen, GI, brain
metabolism
heroin → morphine in the brain
metabolized in the liver
pills → first pass metabolism = reduced bioavailability
alter route of administration (crush, heat, + inject) to get higher [ ]
excretion
kidneys
chasing the dragon
heat up on tin foil + inhale fumes
metal aerosolizes → metal toxicity, accumulation of metals in brain
linked to leukoencephalopathy
leukoencephalopathy
aversive effect of ‘chasing the dragon’ method of administration
destruction of white matter in CNS
brain tissue → spongiform (holes in brain)
progresses (over time) to ataxia, apathy, akathisia, to inability to move or speak
injecting heroin
mix drug with water, dissolve with acid/heat
drawn up through cotton ball (filtration)
risks of injection
track marks
damage to blood vessels - needle, drug, injection rate, infection
uneven blood flow, thrombosis, clots
vessels collapse
heroin pharmacokinetics
faster distribution to the brain (lipophilic) = higher potency
can be snorted
metabolized to morphine in the brain → metabolites:
3-MAM and 6-MAM
6-MAM
6-monoacetylmorphine
metabolite of heroin - not naturally occurring, indicative of heroin use
binds mu receptor (3-MAM does not)
acute effects of opioids
brain
(medulla)
eyes
circulatory system
lungs
skin
GI
muscles
acute effects in brain
brainstem chemotrigger zones in area postrema of medulla → triggers nausea, vomiting (usually develop tolerance to effects)
euphoria
impaired judgement
reduced pain
acute effects in medulla
lowers blood pressure = hypotension
bronchoconstriction
itching
acute effects in eyes
mu and kappa receptors in oculomotor nucleus → constricted pupils
heroin = parasympathomimetic response
acute effects in skin and muscles
lowered body temp, flushed skin
muscle relaxation
acute effects in CV and lungs
vasodilation, lowered blood pressure
slowed respiration
physiological effects of opioids
reproduction
constipation
decreased urination
NAS
effect on reproduction
reduced levels of GnRH, LH, FSH = decreased libido, impotence, amenorrhea
constipation
isometric muscle contractions reduce bowel movements, secretions
decreased urination
constriction of ureter and sphincters of bladder, stimulation of anti-diuretic hormone release
neonatal abstinence syndrome
withdrawal
babies are irritable, vomit, diarrhea, seizures, respiratory distress
reinforcing mechanism of opioids in NAc
opioid binds to receptor on GABA interneuron = inhibition
→ less GABA release → no inhibition of dopamine neuron (= disinhibition)
→ increased dopamine release
opioid receptor origin
mu, delta, and kappa → separate Opr genes
expressed in multiple brain regions, spine, GI tract, etc.
ORL receptor shows structural homology
subtypes likely due to allelic variation → impacts function
receptor peptides
delta = enkephalin (met and leu)
kappa = dynorphin (A and B)
mu = endorphin (β, 1, 2)
opioid receptor signaling
ligand binds → triggers GPCR cascade (Gi = inhibition)
= inhibition of AC → reduced cAMP, inhibits PKA
alpha-GTP: activation of PLCβ and MAPK pathways
βy subunits - OR signaling
activate GIRK3 (K+ channel) = hyperpolarization
block Ca2+ channels = reduced intracellular Ca2+ → suppress NT release
ORs are GPCRs
Gi/o = inhibitory
chronic exposure to morphine
G-protein coupled receptor kinase-mediated phosphorylation of opioid receptors and binding of β arrestin → desensitization
two pathways connected to OR GPCR
G-protein → analgesia
β-arrestin → respiratory depression (shut off pathway)
biased agonism
differential activation of signaling pathways by OR ligand
selective operation of signaling cascades
selective activation of OR GPCR
- not all signaling is G-protein mediated → selective G-protein independent cascades depend on scaffold formation, direct physical contacts
- orthosteric stabilization of receptor conformations alter scaffolding
classic opioid signaling
biased G-protein effects:
morphine keeps receptor phosphorylation low
other opioids produce high receptor phosphorylation → receptor internalization, increased tolerance and dependence ex. fentanyl
non-synonymous mutations in mu opioid receptor
affect signaling and function
L85I and R181C are mutants that show altered patterns of internalization in presence of morphine
descending pain pathway
cortex → thalamus → PAG → RVM →dorsal horn of spine
*sometimes thalamus is bypassed
pain afferent threshold
set by tonic firing of GABA interneurons in RVM to dorsal horn
mechanism of opioid-mediated analgesia
activation of mu opioid receptor on GABA RVM interneurons
= reduced inhibition of RVM “off” projecting cells to spinal cord
→ elevated signaling from RVM to spinal cord = ↓ afferent pain transmission into the spine
activation of muOR on RVM ‘ON’ projecting cells to the spinal cord = decreased outputs to the dorsal horn
→ + analgesic effect
indirect role of amygdala
modifies pain transmission
state of mind; when in fight-or-flight, do not feel pain
in dorsal spine horns
pre-synaptic muOR activation on afferent pain neurons reduces neurotransmitter release and pain transmission
contextual memory → associative conditioning
hippocampal mu receptors
astrocyte mu receptors
hippocampal mu receptors
disinhibition of CA1 and dentate gyrus cells via GABA interneurons
astrocyte mu receptors
activation causes Glu release onto CA1 neurons
NAc medium spiny neurons
express D1-like receptors + D2-like receptors
→ functions are subdivided
D1 receptors
co-express dynorphin
mu receptors are usually co-expressed on D1 receptor expressing cells
D2 receptors
co-express enkephalin
metabolic tolerance
changes in distribution → faster breakdown = more tolerant of effects
cellular tolerance
opioid receptors are down-regulated→ need higher dose for same effects
molecular uncoupling may disrupt OR signals (internalization of receptor → desensitization)
behavioural tolerance
behaving sober when intoxicated
tolerance reduces some effects
tolerant to: analgesia, vomiting, euphoria, respiratory depression
no tolerance to: constipation + pupil constriction
lower tolerance in different locations
tolerant rats given high doses in same or different environments
higher (nearly double) mortality in different environment
rat park experiment
morphine administration is influenced by psychosocial environment
isolated rats administered much more morphine
behavioural sensitization
gauge psychological addiction → escalation of behavioural responses to a stimulus (drug of abuse) after drug-free period
factors: receptor density, NT levels, cell signaling deregulation
behavioural sensitization driven by NAc inputs
dopamine-ergic projections from VTA and glutamatergic from PFC to the NAc
blocking D1 (antagonist) in NAc impairs sensitization
morphine sensitization
elevated D1 expression in NAc shell + elevated transcription factor (ERK1/2 MAPK) activity
AMPA/NMDA receptor antagonists
block the induction of sensitization
do not block expression of sensitization → if it has already been learned, the pathways are already established and it can’t be blocked
desensitization
cellular tolerance
rapid; direct consequence of drug-receptor activation
depends on Ca2+ and K+ activities
sustained desensitization reduces acute effects (analgesia) but enhances intracellular signaling
GRK phosphorylation of muOR
causes B-arrestin binding and reduced euphoria/analgesia
causes addicts to use higher doses for same effect = tolerance
hyperalgesia
caused by desensitization
heroin tolerance: decreased latency in pain sensing
used barbadin: B-arrestin inhibitor = stops hyperalgesia
short term opioid exposure
internalization of receptor; once B-arrestin is shut off, receptor is recycled and returns to membrane surface
long term opioid exposure
internalization of receptor; eventual receptor degradation = permanent removal
increased levels of AC, PKC, PKA, and NMDA → hyperalgesia
withdrawal
stages:
1. 6 hrs after last dose → emotional response = craving, anxiety
2. 12-14 hrs → physical symptoms = yawning, sweating, watery eyes, runny nose
3. 14-16 hrs → opposite of acute effects = dilated pupils, goose bumps, hot/cold flashes, fever, diarrhea, aching, no appetite
4. 2-5 days → weakness, depression, insomnia, elevated BP/heart rate/breathing, restlesness, hyperglycemia
affective signs of withdrawal
cognitive symptoms
dysphoria, anxiety, irritability, cravings
mesolimbic system
targets for therapy, prevention of relapses
mesolimbic system - withdrawal affective signs
NAc
LC
NAc - affective withdrawal signs
naloxone injection = conditioned place aversion
D2-like receptor agonist injection attentuates somatic withdrawal signs
DA in NAc is decreased
LC - affective withdrawal signs
LC expresses mu and kappa opioid receptors
chronic use suppresses LC activity = ↓ NE released
tolerance → up regulation of activity to normal
= removal of opioids → overactivity = NE surge:
sweating, chills, stomach cramps, emesis, diarrhea, muscle pain, runny nose/eyes
LPGi
lateral paragigantocellularis in rostroventral medulla
stimulates LC via glutamatergic inputs
modulates withdrawal symptoms
withdrawal treatment
anti-adrenergics: clonidine/lofexidine
synthetic opioids: buprenorphine, methadone
clonidine or lofexidine
alpha2 adrenoceptor agonist
prevents NE release via pre-synaptic alpha2 autoreceptors
targets LC projections
buprenorphine
for maintenance
semi synthetic partial agonist
out competes morphine, blocks heroin
suboxone
4:1 buprenorphine:naloxone sublingual
[naloxone can not cross mucosal membranes]
→ if injected, effects are blocked (naloxone = antagonist)
methadone
for maintenance
long half-life
NMDA receptor antagonist
methadone kinetics
stable plasma concentration = does not reach ‘high’ level but doesn’t dip below into withdrawal symptoms
opioid overdoses
triad:
coma = unresponsive
depressed respiration
pinpoint pupils
naloxone
prevents opioid overdose
targets mu, kappa, and delta ORs
competitive antagonist
short-acting ~20-40 min
main brainstem network
Pre-Botzinger complex + retro-trapezoid nucleus/parafacial respiratory group = coupled oscillator that influences motoneurons → produce breathing
depressed respiration
reduced pre-Botzinger complex output
unresponsiveness
upperairway obstruction due to reduced upper airway muscle tone (genioglossus)
