Opioids

Question 1

endogenous opioids implications

Answer 1

• three major peptide neurotransmitters: enkephalin, beta endorphin, dynorphin
• all implicated in analgesia and modulation of stress
• have different affinity for Op receptors
• primary inhibitory and modulatory effect is via GABA (disinhibits what GABA is inhibiting) and glutamate (inhibits activities that are excitatory like dampening aggression)

Question 2

enkephalin localization and effect

Answer 2

midbrain: hedonia (profound high, analgesia, anti stress
dorsal horn of spine: analgesia

Question 3

beta endorphin localization and effect

Answer 3

HPA axis: feeding/heomeostatis, CARE, LUST, analgesia, exercise-euphoria

Question 4

dynorphin localization and effect

Answer 4

pons/medulla: autonomic functions
HPA: circadian-hunger, analgesia, anti stress
midbrain: tolerance

Question 5

what brain area is KOR absent from?

Answer 5

• PFC
• medulla: safeguard action because the medulla has a role in autonomic function –> respiration –> a KOR agonist might not affect respiration negatively but a MOR and DOR agonist may induce respiratory depression

Question 6

which endogenous opioids activate which opioids receptors

Answer 6

MOR: beta-endorphin, enkephalin
KOR: dynorphin
DOR: enkephalin

Question 7

MOR receptor activation effects

Answer 7

1. Reward: inhibition of GABA interneurons in the VTA disinhibits DA neurons
   - Reward is the association of pleasure with an object → gives a stimuli meaning
2. Analgesia (acute/fast pain): inhibition of GABA and Glu in PAG and raphe (where the cell bodies of major serotonin pathways are)
   - Glu promotes pain which is inhibited
3. Associative reward learning: inhibition of GABA increases pyramidal cells in the hippocampus
   - Hippocampus has a role in navigating the spatial environment
4. Stress dampening: inhibition of locus coeruleus NE neurons (Nucleus in the midbrain where the cell bodies of NE neurons are)
   - When there is arousal it activates this pathway which causes stress
   - Inhibiting this pathway decreases the tendency to flee and arousal goes down
   - May have opposite effects in withdrawal → extreme stress when the drug is taken away and there is physical dependence
5. Respiratory depression: inhibition of the medulla (regulates autonomic function) and pons
   - Suppresses autonomic functions of breathing
   - But at very low doses morphine can be used to relieve stress associated with breathing in palliative care patients

Question 8

KOR activation effects

Answer 8

1. Diffuse inhibitory effects: on neurotransmission by blocking presynaptic release
   - Works in a dose dependent way - we can tone activity down which can be useful for modulatory effects
2. Aversion/avoidance: inhibition of DA in nucleus accumbens and PFC
   - Nucleus accumbens is a critical region for reward, motivation and seeking goals when the outcome is something you want to
3. Decreased cue reactivity: inhibition of Glu in the NAcc
   - The look and smell of a drug can be a powerful trigger so if we can stop this then we might help prevent relapse
4. Decreased arousal to important stimuli: inhibition of Glu and corticopin releasing factors (CRF) in the locus coeruleus (LC)
   - Glutamate activates stress through the HPA axis and feeds into LC by dampening activity and reducing the tendency to flee
5. Global demotivation: inhibiting neurons that innervate the LC
   - This can lead to panic - decreasing this can reduce someone’s tendency to panic

Question 9

DOR activation effects

Answer 9

1. Analgesia (chronic/slow brain): inhibition of pain due to nerve damage/inflammation in the periphery
2. Enhances neuroplasticity: increases BDNF which leads to positive antidepressant effects
   - Implicated in effects of antidepressants → its downstream effects on 5Ht manifests as the capacity to learn
   - Enhancing this capacity with a DOR agonist would increase the effects of antidepressants
3. Enhances BNZ activity: positive anxiolytic effects
   - Don’t have to use as high of a BNZ dose
4. Modulates MOR: forms oligomers
   - Can turn each others activity on and off
5. Dose dependent regulation of respiration
   - Low levels: enhances respiratory function
   - High levels: risk of respiratory depression

Question 10

Buprenorphine
a) use
b) activity on opioid receptors

Answer 10

• long term opioid substitution therapy (newer than methadone)
• Actions on the opioid receptors
• Partial MOR agonist → addresses cravings without causing a high, allows us to control the level of activity more than an antagonist
• Full KOR antagonist → implicated in antidepressant effects
• Full DOR antagonist

Question 11

Buprenorphine binding and activity length/strength

Answer 11

Higher binding affinity than full MOR agonists → extremely low Ki value
- It is extremely difficult to displace the drug

Long but low levels of activity
- Long activity prevents withdrawal symptoms that would promote further drug use
- Activity is very low so that craving is addressed but it does not cause a high

Question 12

what are the features of opioid drugs we want?

Answer 12

• reduce the risk of death
• less likely to cause addiction
• wan to avoid dysphoria