Opioids Flashcards
endogenous opioids implications
- 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)
enkephalin localization and effect
midbrain: hedonia (profound high, analgesia, anti stress
dorsal horn of spine: analgesia
beta endorphin localization and effect
HPA axis: feeding/heomeostatis, CARE, LUST, analgesia, exercise-euphoria
dynorphin localization and effect
pons/medulla: autonomic functions
HPA: circadian-hunger, analgesia, anti stress
midbrain: tolerance
what brain area is KOR absent from?
- 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
which endogenous opioids activate which opioids receptors
MOR: beta-endorphin, enkephalin
KOR: dynorphin
DOR: enkephalin
MOR receptor activation effects
- Reward: inhibition of GABA interneurons in the VTA disinhibits DA neurons
- Reward is the association of pleasure with an object → gives a stimuli meaning - 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 - Associative reward learning: inhibition of GABA increases pyramidal cells in the hippocampus
- Hippocampus has a role in navigating the spatial environment - 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 - 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
KOR activation effects
- 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 - 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 - 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 - 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 - Global demotivation: inhibiting neurons that innervate the LC
- This can lead to panic - decreasing this can reduce someone’s tendency to panic
DOR activation effects
- Analgesia (chronic/slow brain): inhibition of pain due to nerve damage/inflammation in the periphery
- 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 - Enhances BNZ activity: positive anxiolytic effects
- Don’t have to use as high of a BNZ dose - Modulates MOR: forms oligomers
- Can turn each others activity on and off - Dose dependent regulation of respiration
- Low levels: enhances respiratory function
- High levels: risk of respiratory depression
Buprenorphine
a) use
b) activity on opioid receptors
- 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
Buprenorphine binding and activity length/strength
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
what are the features of opioid drugs we want?
- reduce the risk of death
- less likely to cause addiction
- wan to avoid dysphoria
