Opioid receptors and naloxone
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Opioid receptors and naloxone
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[post_date] => 2024-12-23 18:10:54
[post_date_gmt] => 2024-12-23 23:10:54
[post_content] => Practice Passage (Question 1-6)
*This passage is the property of Khan Academy and has been reformatted into an AAMC-style interface in their entirety by MedLife Mastery. MedLife Mastery does not endorse and is not an affiliate of Khan Academy.
Opioids are a group of analgesic agents commonly used in pain management. There are three classical opioid receptors (DOR, KOR and MOR) – all of which are G-protein coupled receptors. Opioids can act on these receptors as agonists, antagonists or partial agonists. Opioid agonists cause cellular hyperpolarization upon binding to their receptors. Most clinically relevant opioid analgesics bind to MORs in the central and peripheral nervous system in an agonistic manner to elicit analgesia.
G-protein coupled receptors are composed of a transmembrane portion, which includes seven helices, and an intracellular portion, which consists of three subunits (α, β and γ). All of the opioid G-protein coupled receptors display similar cellular responses following receptor activation. The binding of an opioid agonist to the transmembrane portion of the receptor causes the α subunit of the G-protein to exchange its bound guanosine diphosphate (GDP) molecule with intracellular guanosine triphosphate (GTP). This then allows the α–GTP complex to dissociate from the βγ complex. The free complexes (α–GTP and βγ) interact with ion channels - usually inducing activation of potassium conductance and inhibition of calcium conductance - as well as intracellular proteins, inducing signaling outcomes as shown in Figure 1.
Figure 1 Cellular effects of opioid receptor activation, adapted from Pathan article cited below
When taken in large quantities, opioid medications, such as morphine, methadone, and fentanyl, can cause life-threatening symptoms, such as respiratory depression and reduced heart rate. Naloxone is an opioid antagonist that rapidly replaces drugs bound to opioid receptors, rapidly reversing symptoms of opioid toxicity. Figure 2 shows the relationship between dose and opioid receptor blockade 55 minutes after intravenous naloxone administration, and Figure 3 shows the relationship between opioid receptor blockade and time following administration of different doses of naloxone.
Figure 2 Percentage of opioid receptor blockade versus dose of IV naloxone (mg/kg) at t = 55 m post administration
Figure 3 Percentage of opioid receptor blockade versus time at different doses of naloxone
Sources: Pathan H, Williams J. Basic opioid pharmacology: an update. Br J Pain. 2012 Feb;6(1):11-6. doi: 10.1177/2049463712438493. PMID: 26516461; PMCID: PMC4590096. and Trøstheim, M., Eikemo, M., Haaker, J. et al. Opioid antagonism in humans: a primer on optimal dose and timing for central mu-opioid receptor blockade. Neuropsychopharmacol. 48, 299–307 (2023).
[post_title] => Opioid receptors and naloxone
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[question] => Which of the following would likely be a downstream effect of an opioid binding to its receptor?
I. Increase in concentration of cyclic adenosine monophosphate (cAMP)
II. Decrease in activity of protein kinase A
III. Increased protein phosphorylation and decrease in free phosphate
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[answer] => 1
[description] => Reason for Correct Answer:
G-protein coupled receptors are involved in two main intracellular signaling pathways: the cAMP (cyclic adenosine monophosphate) pathway and the phosphatidylinositol pathway. In the case of opioid receptors, Figure 1 shows the GPCR inhibiting adenylate cyclase, which would result in a reduction in cAMP levels. (So, point I is wrong.)
In eukaryotes, cyclic AMP works by activating protein kinase A (PKA), resulting in phosphorylation of PKA target proteins.
Therefore, the reduced cAMP levels would result in a decrease in the activity of PKA and a decrease in the phosphorylation of target proteins. (Point II is correct and point III is wrong.)
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[answers] => Array
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[0] => Array
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[each_answer] => A. II only
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[1] => Array
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[each_answer] => B. III only
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[2] => Array
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[each_answer] => C. I and III only
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[each_answer] => D. II and III only
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[quiz_unique_key] => 1403770772
[question] => Opioids’ effects on ion channels would have what effect on action potential generation?
[value] => Array
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[answer] => 2
[description] => Reason for Correct Answer:
Paragraph 2 states that opioid receptors cause “activation of potassium conductance and an inhibition of calcium conductance,” and Figure 1 also shows this happening.
The potassium concentration is higher on the inside of the nerve cell, so opening these channels results in more K+ exiting the cell. The calcium concentration is higher outside the nerve cell, so closing these channels results in less Ca2+ entering the cell.
More (+) charge exiting and less entering means the inside of the cell becomes more negative. Because the neuron is already negative, this makes the cell more polarized, or “hyperpolarized.”
Action potentials are triggered when membrane potentials become less negative, reaching a certain threshold, usually due to the opening of Na+ channels and flow of Na+ into the cell. Effects that make the cell more negative, like opioid binding, are inhibitory, because they make it harder for the cell to reach this threshold.
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[each_answer] => A. Inhibitory, because they make the cell less polarized
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[each_answer] => B. Inhibitory, because they make the cell more polarized
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[each_answer] => C. Excitatory, because they make the cell less polarized
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[each_answer] => D. Excitatory, because they make the cell more polarized
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[2] => Array
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[quiz_unique_key] => 1403770772
[question] => The inhibition of voltage-gated calcium channels by opioid medications would have what effect on the cell?
[value] => Array
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[answer] => 2
[description] => Reason for Correct Answer:
When an action potential reaches the presynaptic terminal, it triggers the opening of voltage-gated calcium channels, allowing calcium ions to enter the cell.
The influx of calcium ions plays a crucial role in the release of neurotransmitters into the synapse.
https://pittmedneuro.com/synaptic.html
By inhibiting voltage-gated calcium channels, the entry of calcium ions is reduced, leading to a decrease in the release of neurotransmitters from the presynaptic neuron. This decrease in neurotransmitter release from the presynaptic neuron helps with reduced transmission of pain signals.
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[answers] => Array
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[each_answer] => A. Decreased response to neurotransmitter binding to the postsynaptic membrane
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[each_answer] => B. Decreased neurotransmitter release from the presynaptic neuron
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[each_answer] => C. Increased reuptake of neurotransmitters into the presynaptic membrane
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[each_answer] => D. Increased degradation of neurotransmitters in the nerve terminal
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[quiz_unique_key] => 1403770772
[question] => The median effective dose (ED50) is the dose of a medication that produces 50% of the maximal response. It is a convenient way to compare drug potencies. According to the data shown, what is the approximate ED50 of naloxone for KOR blockade?
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[answer] => 2
[description] => Reason for Correct Answer:
To answer this question, you need to look at the data in Figure 2, which shows percent blockade vs. naloxone dose at the different receptors.
For the ED50, you need to look for the dose that results in 50% blockade, since this is “50% of the maximal response,” with the maximal response being 100% blockade.
Blockade of KOR receptors is indicated by the middle line on this graph.
As shown, the dosage corresponding to 50% blockade is between 0.01 and 0.1, but closer to 0.01 so 0.018 must be correct. Note that this is a log scale, so the distribution of values between 0.01 and 0.1 is not even.
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[each_answer] => A. 0.0023
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[each_answer] => B. 0.018
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[each_answer] => C. 0.050
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[each_answer] => D. 0.094
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[question] => In neonates and pediatric patients, naloxone is initially administered in doses of only 0.01 mg/kg and is often effective at reversing the symptoms of opioid toxicity at this dosage. This information, combined with the data shown in the passage, suggests that most of the therapeutic effects of naloxone administration are caused by its blockade of which opioid receptors?
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[answer] => 1
[description] => Reason for Correct Answer:
Figure 3 shows the effects of different doses on blockade of each of the receptors, so this is the data you want to look at to answer this question.
The 0.01 mg/kg dose data is shown in the upper right corner of the figure.
This graph shows this dosage resulting in a nearly full blockade of MORs but only a partial (<50%) blockade of the other receptors.
This suggests that, if 0.01 kg/mg is an effective/therapeutic dosage, then most of the therapeutic effects of naloxone could be the result of blocking MORs.
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[answers] => Array
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[each_answer] => A. MORs
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[each_answer] => B. DORs
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[each_answer] => C. KORs
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[each_answer] => D. MORs and DORs
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[quiz_unique_key] => 1325138223
[question] => Administration of which of the following compounds would be LEAST likely to exacerbate the side effects of opioids on nerve cells?
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[answer] => 4
[description] => Reason for Correct Answer:
The passage indicates that opioids have an inhibitory effect on nerve cells because they allow K+ to flow out of the cell and block Ca2+ from flowing in – this hyperpolarizes the cell and makes it harder to stimulate an action potential. So, drugs that exacerbate the effects of opioids would also have an inhibitory effect on neurons.
In regards to Choices A and B, remember that GABA and glycine are inhibitory neurotransmitters, whereas glutamate and aspartate are excitatory neurotransmitters.
Therefore, the effect of opioids would be exacerbated by drugs that enhance the function of GABA and glycine or inhibit the effects of glutamate and aspartate – as these will both have an overall inhibitory effect.
In regards to Choices C and D, remember that both Cl- and Na+ are more concentrated outside of nerve cells.
Opening Cl- channels will cause Cl- to enter the cell, making the cell more negative and therefore also having an inhibitory effect. This could exacerbate the inhibitory effects of opioids.
Opening of Na+ channels will cause Na+ to enter the cell, making the cell less negative; this effect is excitatory, not inhibitory, as it makes it easier for an action potential to occur. Therefore, this would not exacerbate the inhibitory effects of opioids.
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[each_answer] => A. Drugs that enhance the function of neurotransmitters GABA and glycine
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[each_answer] => B. Drugs that inhibit the function of neurotransmitters glutamate and aspartate
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[each_answer] => C. Drugs that cause the opening of chloride channels in the neuronal membrane
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[each_answer] => D. Drugs that cause the opening of sodium channels in the neuronal membrane
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Figure 1
Figure 2
Figure 3
