Opioids

Question 1

Opioids

Answer 1

opium: rare, untransformed material from poppies
opiates: any drug derived from opium
opioids: drugs that bind to opioid receptors

Question 2

Morphine

Answer 2

opiate and opioid
full agonist at Mu receptor

Question 3

Heroin

Answer 3

semi-synthetic opiate and opioid
full agonist at Mu receptor

Question 4

Fentanyl

Answer 4

opioid
full agonist at Mu receptor

Question 5

Pharmacodynamics

Answer 5

opioid receptors = Gi GPCRs
neuronal inactivation

Question 6

receptors

Answer 6

structurally similar but different effects
receptor distribution (different neurons)
ligand specificity (drugs are selective for different receptors)
brain, brainstem, spinal cord, peripheral neurons, intestine

Question 7

Mu

Answer 7

densely expressed in subcortical regions - emotion and behaviour
agonist: analgesia, reward, antitussive, respiratory depression, constipation
antagonist: aversive, prevent reward, block overdose

Question 8

Delta

Answer 8

densely expressed in cortex - decisions, processing information, executive function
agonist: not rewarding, analgesia only in chronic pain + migraine, seizure inducing (large distribution of receptors)
antagonist: no obvious effects

Question 9

Kappa

Answer 9

densely expressed in cortex - decisions, processing information, executive function
agonist: aversive, hallucinogenic, anxiogenic
antagonist: possible antidepressant

Question 10

ORL-1 (orphanin receptor ligand/nociceptin opioid peptide)

Answer 10

widely expressed in CNS
possibly fear processing

Question 11

Buprenorphine

Answer 11

partial mu agonist
mixed agonist-antagonist: partial mu agonist + kappa+delta antagonist
treatment for pain and opioid addiction

Question 12

beta-arrestins

Answer 12

intracellular proteins that regulate signal transfuction at GPCRs
receptor activation → phosphorylation of GPCR → signals beta-arrestin to bind
= blocks further G-protein signalling

Question 13

biased agonism

Answer 13

beta-arrestin activates own intracellular signalling that leads to side effects
ligand activates G-protein pathway instead of beta-arrestin

Question 14

tolerance

Answer 14

decreased response to drug effects = need higher dose for same effect
recruitment of beta-arresting to shut off signalling (desensitization) → receptor and agonist are pulled off the membrane
chronic use = less receptors on membrane for ligand to bind to

Question 15

pharmacokinetics

Question 16

absorption

Answer 16

well absorbed

Question 17

distribution

Answer 17

well distributed
greatest concentration in highly perfused tissues
crosses BBB and placental barrier

Question 18

metabolism

Answer 18

morphine → first pass metabolism (glucuronidation to M3G and M6G - phase II)
codeine: prodrug → morphine (CYP 2D6) = less first pass effect but more susceptible to pharmacogenomic diversity

Question 19

excretion

Answer 19

polar metabolites are excreted in urine
renal impairment - risk of sedation and respiratory depression

Question 20

Endogenous Opioid Peptides

Answer 20

widely distributed neurotransmitters
pain, reward, learning, memory, cognition
generated from protein precursor - modified at site they are used, cleaved into active form
common amino acid sequence: Tyr-Gly-Gly-Phe

Question 21

Enkephalin

Answer 21

pro-enkephalin
highest affinity at delta, high at mu, low at kappa

Question 22

Beta endorphin

Answer 22

pro-opioimelanocortin
highest at mu and delta, low at kappa

Question 23

Dynorphin

Answer 23

pro-dynorphin
high at kappa, low at mu and delta

Question 24

selectivity, not specificity

Answer 24

opioid peptides have different affinities for the three opioid receptor

Question 25

opioid effect on pain

Answer 25

opioids inhibit transmission from periphery to spinal cord mu and kappa receptors on primary and secondary afferents in skin and spinal cord

Question 26

pain experience

Answer 26

receptors in brainstem (rostroventral medulla) increase diffuse noxious inhibitory control circuit of descending excitatory and inhibitory neurons in medulla inhibit or activate pain synapses in spinal cord = gate amount of nociceptive information that reaches brain

Question 27

pain inhibition

Answer 27

activation of mu and delta receptors (Gi) on the ON cells in brainstem = inhibition of cells block descending amplification from rostroventral medulla = net reduction in nociceptive signals analgesia

Question 28

reward

Answer 28

Mu receptors in ventrotegmental area are located on GABAergic interneurons that synapse onto dopamine neurons (project to striatum) opioids inhibit inhibition = disinhibition = dopamine release

Question 29

nociception

Answer 29

relay of pain signal from periphery to brain

Question 30

pain

Answer 30

interpretation of pain signal with context (subjective)

Question 31

opioids inhibit pain

Answer 31

1. decreasing nociception 2. decreasing emotional and cognitive aspects of pain

Question 32

analgesics

Answer 32

most = mu agonists delta agonists: development for chronic migraines but beta-arrestin pathway causes seizures - TRV250 = biased agonism kappa agonists: target brain = dysphoria and hallucinations but target periphery = inhibit pain transmission in skin receptors (CR845)

Question 33

Chronic Use

Answer 33

tolerance dependence - withdrawal symptoms

Question 34

Opioid Use Disorder

Answer 34

addiction

Question 35

treatments

Answer 35

preventative - physical + chemical barriers, agonist/antagonist combination (buprenorphine + naloxone) agonist replacement therapy - use + therapy harm reduction - supervised consumption sites + injectable opioid therapy acute intoxication treatment - Narcan: Naloxone is a non-selective competitive opioid receptor antagonist