19 Opioids II Flashcards
Mu, delta, and kappa opioid receptors are localized on ______ and __________ in the skin and spinal cord
Mu, delta, and kappa opioid receptors are localized on primary and secondary afferents in the skin and spinal cord
What effect does agonist binding to opioid receptors have on pain transmission?
Agonist binding to opioid receptors inhibits pain transmission from skin to brain
____ and _____ opioid receptors are located on the ON cells in the ________
mu and delta opioid receptors are located on the ON cells in the medulla
Activation of opioid receptors leads to inhibition of _________.
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
______ is involved in motivated behaviour
dopamine is involved in motivated behaviour and reward
Dopamine neurons are mainly located in the ______
Dopamine neurons are mainly located in the ventral tegmental area (VTA)
Mu opioid receptors in the VTA are located on _________ interneurons
Mu opioid receptors in the VTA are located on inhibitory GABAergic interneurons
Because mu opioid receptors in the VTA are on inhibitory GABAergic interneurons (GABA is inhibitory), what effect do opioids have in this region?
Opioids inhibit inhibition (disinhibition) leading to dopamine release
Opioid receptors inhibit pain in two ways, what are they?
- By decreasing nociception at the level of the nociceptor, in the spinal cord and in the brainstem
- 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)
Most opioid agonists used for pain are ______
Most opioid agonists used for pain are mu agonists
How are opioids being developed for migraines?
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
Why have kappa agonists that penetrate the brain not been developed for pain?
Because they produce dysphoria/hallucinogenic effects
eg salvia
_________ kappa agonists do not cross the blood brain barrier
peripherally restricted kappa agonists do not cross the blood brain barrier
How do Peripherally restricted kappa agonists participate in pain relief?
Bind to kappa receptors in the skin and inhibit pain transmission, while avoiding CNS adverse events
Define tolerance
Decreased response to the effects of the drug, necessitating ever-larger doses to achieve the same effect
What aspects of opioid use can tolerance be developed for?
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)
How does Beta-arrestin recruitment lead to tolerance?
Following agonist binding and G-protein signaling, Beta-arrestin is recruited to shut off signaling (desensitization)
- Receptor+agonist is pulled off the membrane and recycled in an endosome
- either degraded or recycled back to the membrane
- Repeated opioid use leads to less receptors on the membrane = reduced agonist effect (tolerance)
- ie with continued stimulation, recycling can’t keep up
___________ develops following chronic opioid use and is revealed following abrupt discontinuance of drug as withdrawal
Physical dependence develops following chronic opioid use and is revealed following abrupt discontinuance of drug as withdrawal
What are 7 symptoms of acute opioid withdrawal?
- Rhinorrhea (runny nose)
- Lacrimation (tearing eyes)
- chills
- muscle aches
- diarrhea
- yawning
- anxiety
_______ is a brain disease driven by dysfunction in reward, motivation, memory circuitry
Addiction is a brain disease driven by dysfunction in reward, motivation, memory circuitry
What is an example of a physical barrier to preventing opioid use disorder?
Prevent chewing/crushing of oral tablets for IV/Intranasal drug use
-eg upon crushing, instead of becoming a powder, drug becomes a gel
What is a chemical barrier that prevents opioid use disorder?
Adding a chemical to resist extraction of the opioid by common solvents like water/alcohol
How do agonist/antagonist combinations prevent opioid use disorder?
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)
What is agonist replacement therapy?
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
What are 4 advantages to agonist replacement therapy?
- reduced drug cravings
- better participation in addiction tx (beh therapy) since withdrawal symptoms aren’t a distraction
- improved social fxn
- reduction in infectious diseases/death associated with illicit drug use
What is Methadone?
What is a disadvantage of methadone?
Long-acting full agonist at the mu-opioid receptor
- first replacement therapy approved for Opioid use disorder
- Full agonist = can still overdose
What is buprenorphine?
What is it marketed as?
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
What is naloxone (narcan)?
Non-selective competitive opioid receptor antagonist
