19 Opioids II

Question 1

Mu, delta, and kappa opioid receptors are localized on ______ and __________ in the skin and spinal cord

Answer 1

Mu, delta, and kappa opioid receptors are localized on primary and secondary afferents in the skin and spinal cord

Question 2

What effect does agonist binding to opioid receptors have on pain transmission?

Answer 2

Agonist binding to opioid receptors inhibits pain transmission from skin to brain

Question 3

____ and _____ opioid receptors are located on the ON cells in the ________

Answer 3

mu and delta opioid receptors are located on the ON​ cells in the medulla

Question 4

Activation of opioid receptors leads to inhibition of _________.

Answer 4

Activation of opioid receptors leads to inhibition of medulla on cells

(in rostroventral medulla)

• This produces a net reduction in nociceptive signals reaching the brain

Question 5

______ is involved in motivated behaviour

Answer 5

dopamine is involved in motivated behaviour and reward

Question 6

Dopamine neurons are mainly located in the ______

Answer 6

Dopamine neurons are mainly located in the ventral tegmental area (VTA)

Question 7

Mu opioid receptors in the VTA are located on _________ interneurons

Answer 7

Mu opioid receptors in the VTA are located on inhibitory GABAergic interneurons

Question 8

Because mu opioid receptors in the VTA are on inhibitory GABAergic interneurons (GABA is inhibitory), what effect do opioids have in this region?

Answer 8

Opioids inhibit inhibition (disinhibition) leading to dopamine release

Question 9

Opioid receptors inhibit pain in two ways, what are they?

Answer 9

1. By decreasing nociception at the level of the nociceptor, in the spinal cord and in the brainstem
2. Decreasing the emotional and cognitive aspects of pain (makes it bother you less)

*** Drugs that target the sensory as well as cognitive and emotional circuits, will always be better analgesics ****

catch-22: opioids are effective analgesics because they are rewarding (addictive)

Question 10

Most opioid agonists used for pain are ______

Answer 10

Most opioid agonists used for pain are mu agonists

Question 11

How are opioids being developed for migraines?

Answer 11

Delta agonists are being developed

• initially halted because cause seizure
• can isolate the analgesic effects from seizures through biased agonism
• eg TRV250 - delta opioid receptor agonist under development

Question 12

Why have kappa agonists that penetrate the brain not been developed for pain?

Answer 12

Because they produce dysphoria/hallucinogenic effects

eg salvia

Question 13

_________ kappa agonists do not cross the blood brain barrier

Answer 13

peripherally restricted kappa agonists do not cross the blood brain barrier

Question 14

How do Peripherally restricted kappa agonists participate in pain relief?

Answer 14

Bind to kappa receptors in the skin and inhibit pain transmission, while avoiding CNS adverse events

Question 15

Define tolerance

Answer 15

Decreased response to the effects of the drug, necessitating ever-larger doses to achieve the same effect

Question 16

What aspects of opioid use can tolerance be developed for?

Answer 16

Analgesic, euphorigenic, sedative, and respiratory effects of the drug

• an opioid tolerant individual can take enormous doses (2g) (lethal dose for a drug naive individual is ~30mg)

Question 17

How does Beta-arrestin recruitment lead to tolerance?

Answer 17

Following agonist binding and G-protein signaling, Beta-arrestin is recruited to shut off signaling (desensitization)

1. Receptor+agonist is pulled off the membrane and recycled in an endosome
   
   • either degraded or recycled back to the membrane
2. Repeated opioid use leads to less receptors on the membrane = reduced agonist effect (tolerance)
   
   • ie with continued stimulation, recycling can’t keep up

Question 18

___________ develops following chronic opioid use and is revealed following abrupt discontinuance of drug as withdrawal

Answer 18

Physical dependence develops following chronic opioid use and is revealed following abrupt discontinuance of drug as withdrawal​

Question 19

What are 7 symptoms of acute opioid withdrawal?

Answer 19

1. Rhinorrhea (runny nose)
2. Lacrimation (tearing eyes)
3. chills
4. muscle aches
5. diarrhea
6. yawning
7. anxiety

Question 20

_______ is a brain disease driven by dysfunction in reward, motivation, memory circuitry

Answer 20

Addiction is a brain disease driven by dysfunction in reward, motivation, memory circuitry

Question 21

What is an example of a physical barrier to preventing opioid use disorder?

Answer 21

Prevent chewing/crushing of oral tablets for IV/Intranasal drug use

-eg upon crushing, instead of becoming a powder, drug becomes a gel

Question 22

What is a chemical barrier that prevents opioid use disorder?

Answer 22

Adding a chemical to resist extraction of the opioid by common solvents like water/alcohol

Question 23

How do agonist/antagonist combinations prevent opioid use disorder?

Answer 23

An antagonist can be added to an agonist to interfere with the euphoria associated with abuse; the antagonist is only released when oral tablet is tampered with (crushed, injected etc)

Question 24

What is agonist replacement therapy?

Answer 24

A comprehensive treatment approach including maintenance on opioid agonist and CBT (cog beh therapy)

• blunts the symptoms of opioid withdrawal
• replacement agonists have longer half-lives so avoid the repeated high/crash cycle

Question 25

What are 4 advantages to agonist replacement therapy?

Answer 25

1. reduced drug cravings
2. better participation in addiction tx (beh therapy) since withdrawal symptoms aren’t a distraction
3. improved social fxn
4. reduction in infectious diseases/death associated with illicit drug use

Question 26

What is Methadone?

What is a disadvantage of methadone?

Answer 26

Long-acting full agonist at the mu-opioid receptor

• first replacement therapy approved for Opioid use disorder
• Full agonist = can still overdose

Question 27

What is buprenorphine?

What is it marketed as?

Answer 27

Partial agonist at the mu-opioid receptors and an antagonist at the kappa and delta opioid receptor

• safer agonist profile
• antagonist activity at kappa may improve mood (treat depression/anxiety assoc with withdrawal)
• Marketed as Suboxone
  
  • Bupernorphine+naloxone

Question 28

What is naloxone (narcan)?

Answer 28

Non-selective competitive opioid receptor antagonist