Chapter 20 — Quiz

Endorphins, Enkephalins, and the Opioid Peptides

22 items. Multiple choice, true/false with justification, and short answer. The answer key is at the bottom, collapsed. Work the whole quiz before opening it.

1. Multiple choice

Opioid receptors were characterized before their endogenous ligands were identified. The best interpretation of that historical sequence is:

  • (a) Morphine created the receptors through repeated exposure over centuries of poppy use
  • (b) The receptors exist for endogenous peptides, and morphine is a coincidental structural fit
  • (c) The receptors are vestigial and morphine reactivates them
  • (d) The endogenous ligands were discovered first but not recognized as such

2. Multiple choice

Which precursor yields β-endorphin?

  • (a) Proenkephalin
  • (b) Prodynorphin
  • (c) Proopiomelanocortin
  • (d) Prepronociceptin

3. Multiple choice

Met-enkephalin, leu-enkephalin, β-endorphin, and dynorphin A all begin with the same four residues. Those residues are:

  • (a) Tyr-Gly-Gly-Phe
  • (b) Phe-Gly-Gly-Tyr
  • (c) Gly-Gly-Phe-Met
  • (d) Tyr-Pro-Trp-Phe

4. Short answer

Nociceptin has the sequence Phe-Gly-Gly-Phe at its N-terminus. State the single chemical difference from the classical opioid motif, and give one experimental consequence.

5. Multiple choice

Which receptor is primarily responsible for the dysphoria produced by some opioid compounds?

  • (a) Mu
  • (b) Delta
  • (c) Kappa
  • (d) NOP

6. True or false, with justification

All three classical opioid receptors are excitatory, which is why they increase signaling in pain pathways.

7. Multiple choice

Proopiomelanocortin also yields α-MSH, covered in Chapter 13 as part of appetite regulation. What does that fact best illustrate?

  • (a) That appetite and pain are the same physiological system
  • (b) That the products of one precursor form a functional team
  • (c) That tissue-specific processing lets one gene serve unrelated physiologies
  • (d) That β-endorphin regulates appetite

8. Short answer

Name the two brain regions and the spinal target that make up the descending inhibitory pathway, in order.

9. Multiple choice

Endogenous opioid peptides suppress pain transmission in the dorsal horn by:

  • (a) Destroying the incoming nociceptive fiber
  • (b) Reducing neurotransmitter release presynaptically and hyperpolarizing the projection neuron
  • (c) Increasing calcium influx into the presynaptic terminal
  • (d) Blocking the peripheral nociceptor directly

10. True or false, with justification

The amount of pain a person experiences is a direct readout of the amount of tissue damage present.

11. Short answer

Electrical stimulation of the periaqueductal gray produces analgesia, and naloxone reduces that analgesia. State precisely what the naloxone result adds that the stimulation result alone does not.

12. Multiple choice

The principal weakness of "exercise raises plasma β-endorphin" as evidence for the runner's high is:

  • (a) The measurement is unreliable
  • (b) β-endorphin is not an opioid peptide
  • (c) Plasma β-endorphin does not freely reach the brain, so it is the wrong compartment
  • (d) The effect has never been replicated

13. Short answer

Name the competing (or complementary) system that has been implicated in exercise-induced mood change, and state the physical property that makes it a more parsimonious candidate for a central effect.

14. Multiple choice

In the classic 1978 experiment, naloxone was given to patients who had responded to placebo with pain relief. The result — reduced placebo analgesia — is important because:

  • (a) It proved that placebo can replace analgesic medication
  • (b) A receptor antagonist should have no effect on a purely reported phenomenon, so the effect must be receptor-mediated
  • (c) It showed that placebo responders were not really in pain
  • (d) It established that all placebo effects run through opioid receptors

15. True or false, with justification

Because naloxone blocks placebo analgesia, all placebo effects are mediated by endogenous opioids.

16. Short answer

Later work found that placebo analgesia induced by verbal expectation was naloxone-reversible, while placebo analgesia conditioned with a non-opioid analgesic largely was not. What does that dissociation establish?

17. Multiple choice

Which of the following is not one of the three joints in the "boost your own peptide" test?

  • (a) Magnitude
  • (b) Duration
  • (c) The existence proof
  • (d) Cost of goods

18. Short answer

State the "existence proof" argument against endorphin supplements in two sentences.

19. Multiple choice

The claim "our capsule provides the amino acid building blocks your body needs to make endorphins" fails principally because:

  • (a) Amino acids are toxic in supplement form
  • (b) β-endorphin is cut from a ribosomally synthesized precursor protein, and output is not limited by free amino acid supply in a nourished person
  • (c) Endorphins are made from fatty acids, not amino acids
  • (d) Phenylalanine does not appear in any opioid peptide

20. Multiple choice

Ziconotide is best described as:

  • (a) A mu receptor agonist derived from a cone snail
  • (b) A kappa receptor agonist that does not cross the blood-brain barrier
  • (c) A synthetic peptide that blocks N-type voltage-gated calcium channels and is not an opioid
  • (d) An enkephalinase inhibitor given orally

21. Short answer

Ziconotide must be administered intrathecally. Explain why that requirement is itself evidence, and about what.

22. Short answer

Difelikefalin is a kappa agonist deliberately designed not to cross the blood-brain barrier. Explain how a delivery limitation was converted into a therapeutic advantage, and name the indication it is approved for.

Answer key **1. (b).** Evolution does not construct stereochemically selective receptor systems for a plant alkaloid. A high-affinity binding site implies an endogenous ligand, which is exactly what was found within a few years. (§20.1) **2. (c) Proopiomelanocortin.** Proenkephalin yields the enkephalins; prodynorphin yields the dynorphins; prepronociceptin yields nociceptin/orphanin FQ, which is related but conventionally kept outside the classical opioid family. (§20.2) **3. (a) Tyr-Gly-Gly-Phe.** This is the shared "message" motif. Option (d), Tyr-Pro-Trp-Phe, is the reported N-terminus of a different putative peptide and is not the shared motif. (§20.2) **4.** The N-terminal tyrosine is replaced by phenylalanine — the difference is a single hydroxyl group on the aromatic ring, which is a required element of the opioid pharmacophore. Consequence: nociceptin does not activate the classical mu, delta, or kappa receptors and is not blocked by naloxone; it acts at its own receptor, NOP. (§20.1, §20.2) **5. (c) Kappa.** Mu activation produces euphoria; kappa produces dysphoria and aversion. This is the central reason kappa agonists have low abuse liability and poor tolerability at the same time. (§20.3) **6. False.** All three couple to inhibitory G proteins. They inhibit adenylyl cyclase, open potassium channels (hyperpolarizing the neuron), and close voltage-gated calcium channels (reducing transmitter release). Opioid signaling is a braking system; every effect in the chapter follows from applying that brake somewhere specific. (§20.3) **7. (c).** Tissue-specific prohormone convertase expression determines which products a given cell makes from POMC. One gene, several cell types, several unrelated physiological outputs. The products are not a team — (b) is precisely the error the chapter warns against. (§20.2) **8.** Periaqueductal gray → rostral ventromedial medulla → spinal dorsal horn. Credit also for noting that the PAG receives input from hypothalamus, amygdala, and prefrontal cortex — the anatomical route by which context and expectation enter the system. (§20.4) **9. (b).** Both mechanisms operate: presynaptic reduction of transmitter release from the incoming fiber, and postsynaptic hyperpolarization of the projection neuron. Both are the inhibitory GPCR consequences of §20.3 applied at a specific address. (§20.4) **10. False.** Pain signaling is actively modulated at its first synapse by descending circuitry, and that circuitry is driven partly by context, threat appraisal, and expectation. A patient whose pain exceeds their imaging findings may have a differently set modulatory system — a physiological statement, not a psychological accusation. (§20.4) **11.** The stimulation result alone shows only that activating that region produces analgesia — which could in principle be non-specific electrical disruption. The naloxone result shows the analgesia is *mediated by opioid receptor activation*, meaning the stimulation causes release of endogenous opioid peptides. It converts an anatomical finding into a mechanistic one. (§20.4) **12. (c).** β-endorphin is a 31-residue peptide; peptides of that size do not freely cross the blood-brain barrier. Plasma β-endorphin is largely pituitary in origin and released alongside ACTH. Two pools, one name, no established quantitative relationship. (§20.5, Ch 22) **13.** The endocannabinoid system. Endocannabinoids such as anandamide are small lipid molecules that cross the blood-brain barrier far more readily than a 31-residue peptide, so a peripheral rise is a more plausible route to a central effect. Rodent work found the effects survived opioid blockade but were abolished by cannabinoid CB1 blockade. (§20.5) **14. (b).** That is the entire logical force of the experiment: it converts a psychological question into a pharmacological one and answers it. Note that (a) and (d) are both overreaches the chapter explicitly refuses. (§20.7) **15. False.** Several placebo effects are demonstrably not opioid-mediated — placebo analgesia conditioned with a non-opioid drug, placebo responses in Parkinson's disease (dopamine), and nocebo hyperalgesia (linked to a different signaling system). "The placebo effect" is a family of responses, not one thing. (§20.7) **16.** That expectation and conditioning are dissociable mechanisms recruiting different neurochemical systems. It is also the cleanest internal evidence that not all placebo analgesia is opioid-mediated — which is why the ✅ rating in this chapter is scoped to a population and an endpoint rather than issued to "placebo" in general. (§20.7) **17. (d) Cost of goods.** The three joints are magnitude, duration, and the existence proof — with the delivery argument from Chapter 4 running underneath all three. (§20.8, Ch 13) **18.** Every human being already has a fully functional endogenous opioid system, and having it does not produce pharmacological analgesia — if it did, nobody would ever have needed morphine. The system is not idle waiting to be switched on; it is running continuously, and its output is the baseline you experience as ordinary. (§20.8) **19. (b).** β-endorphin is excised from POMC, a protein made by ribosomes from a gene transcript; enkephalins come from proenkephalin the same way. In an adequately nourished person, peptide hormone output is limited by transcription, processing, and release signals — not by dietary phenylalanine. "Provides the building blocks" is a category error about how peptide hormones are made. Note that (d) is factually wrong: phenylalanine is the fourth residue of the shared opioid motif. (§20.8) **20. (c).** Ziconotide is a synthetic equivalent of a cone snail venom peptide, 25 residues, held by three disulfide bonds. It is **not** an opioid and does not bind mu, delta, or kappa. It blocks N-type voltage-gated calcium channels presynaptically in the dorsal horn — reaching the same endpoint an opioid reaches indirectly, since mu receptor activation inhibits that same channel class. (§20.9) **21.** Ziconotide is a 25-residue peptide and cannot cross the blood-brain barrier, so the only way to get it to its site of action is to place it in cerebrospinal fluid directly. That is evidence about how absolute the barrier is: an approved drug with every commercial incentive to find an easier route has not found one. The route of administration is a measurement of the obstacle. (§20.9, Ch 22) **22.** Because difelikefalin cannot enter the brain, it engages peripheral kappa receptors without producing the central dysphoria that has blocked every previous kappa program — the barrier becomes a selectivity filter rather than an obstacle. It is approved for pruritus (severe itch) associated with chronic kidney disease in patients on hemodialysis. Note carefully: **not** for pain. (§20.9)