Lecture 15: Opioids (Part 1)

Question 1

What is opium?

Answer 1

dried latex obtained from the poppy

Question 2

What are opiates?

Answer 2

any drug derived from opium

Question 3

What is an opioid?

Answer 3

any drug that binds to an opioid receptor

includes opiates, as well as synthetic opioid agonists (fentanyl, heroin, oxycontin)

Question 4

What is a narcotic?

Answer 4

from Greek “narco” = “to make numb”

originally referred to any drug with sleep inducing properties, but now usually used by law enforcement to refer to illegal use of opioids for non-medical purposes

Question 5

What are the characteristics of opioid receptors?

Answer 5

inhibitory G-protein coupled receptors

activation of opioid receptors inhibits adenylate cyclase, inhibits calcium release, and activates K+ channels –> neuronal inactivation and reduced neurotransmitter release

Question 6

What are the four types of opioid receptors?

Answer 6

opioid receptors come in four types: mu, delta, kappa, ORL-1 (orphanin receptor ligand)

all are Gi GPCRs, but produce very different effects when activated

Question 7

Why do the different types of opioid receptors produce different effects when activated?

Answer 7

differences are due to receptor distribution (different neurons, different brain circuits)

ligand specificity: drugs are selective for different opioid receptors

Question 8

What is the opioid receptor distribution in the brain?

Answer 8

Mu: midbrain, amygdala

Delta: cortex

Kappa: cortex

Question 9

What are ORL-1 receptors?

Answer 9

widely expressed in the central nervous system

it was the last opioid receptor to be identified based on sequence homology (not function)

poorly studied, but does not share functional similarities with the other opioid receptors

may be involved in fear processing

Question 10

What are the functions of Mu opioid receptor agonists?

Answer 10

analgesia
reward
antitussive (cough suppression)
respiratory depression
constipation
(i.e., morphine, codeine, heroine)

Question 11

What are the functions of Mu opioid receptor antagonists?

Answer 11

aversive
prevent reward
block overdose
(i.e. naloxone)

Question 12

What are the functions of Delta opioid receptor agonists?

Answer 12

not rewarding
no analgesia (except in chronic pain, migraine)
some are seizure-inducing (not commercially available, under investigation)

Question 13

What are the functions of Delta opioid receptor antagonists?

Answer 13

no obvious effects

Question 14

What are the functions of Kappa opioid receptor agonists?

Answer 14

aversive
hallucinogenic
anxiogenic
(i.e. Salvia)

Question 15

What are the functions of Kappa opioid receptor antagonists?

Answer 15

potential antidepressant/anxiolytic

Question 16

What are examples of full mu opioid receptor agonists?

Answer 16

morphine, methadone, fentanyl, and heroin

Question 17

What are examples of partial mu opioid receptor agonists?

Answer 17

buprenorphine

mild to moderate analgesic efficacy, but safer therapeutic index

Question 18

What are high versus low potency of opioid ligands?

Answer 18

full agonists can have different potencies (fentanyl versus morphine)

like efficacy, potency applies to all aspects of the drug (analgesia, euphoria, respiratory depression)

Question 19

In what way are opioid ligands mixed agonist-antagonists?

Answer 19

opioid ligands can have multiple effect on more than one opioid receptor

buprenorphine is a partial agonist at the mu opioid receptor and antagonist at the delta and kappa opioid receptor

common treatment for pain and opioid addiction (opioid agonist therapy)

Question 20

In what way are opioid ligands biased agonists?

Answer 20

beta-arrestins are a family of intracellular proteins important for regulating signal transduction at GPCRs

following receptor activation and G-protein cleavage, GPCR is phosphorylated, which signals beta-arrestin to bind

beta-arrestin binding blocks further G-protein signaling redirects signaling to alternative pathways, and targets receptors for internalization

beta arrestin arrests G protein signaling that leads to tolerance following chronic opioid use

beta arrestin also activates its own intracellular signaling pathways that contribute to some of drug effects

Question 21

What is receptor selectivity?

Answer 21

selectivity for different receptor subtypes

Question 22

What is functional selectivity?

Answer 22

selectivity for different signaling pathways coupled to the same receptor

Question 23

Why do not all opioid ligands lead to beta-arrestin recuitment?

Answer 23

different opioid ligands can differently activate G-protein versus beta-arrestin signaling pathways

these signaling pathways drive different aspects of the drug

Question 24

What is the absorption of opioids?

Answer 24

most mu agonist opioids are well absorbed when taken orally

but, morphine undergoes extensive first pass metabolism

codeine is a prodrug that is metabolized into morphine by liver enzymes, therefore, less impacted by first-pass metabolism (but more susceptible to pharmacogenomic diversity)

Question 25

What is the distribution of opioids?

Answer 25

opioid agonists are widely distributed through body tissues, with highest concentrations in highly perfused tissues such as the brain, lungs, liver, and kidney and spleen

depends on route of administration

cross placental barrier, and exert effects on fetus that can result in both respiratory depression and physical dependence on neonates

Question 26

What is the metabolization of opioids?

Answer 26

morphine is metabolized by phase II glucuronidation 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 metabolized into morphine by CYP2D6 (i.e. codeine is a prodrug)

genetic polymorphisms of YP2D6 (fast or slow metabolizers) linked to variatuin in analgesic and adverse responses among patients, particularly for codeine

Question 27

What is the excretion of opioids?

Answer 27

polar metabolites, including glucuronide conjugates (M3G and M6G) of opioid analgesics, are excreted mainly in the urine

small amounts of unchanged drug may also be found in the urine

in patients with renal impairment the effects of active polar metabolites (Morphine-6-Glucuronide) should be considered before the administration of potent opioids such as morphine due to the risk of sedation and respiratory depression