Chapter 22 — Exercises

Neuropeptide Y, Substance P, and the Peptides That Regulate Stress, Pain, and Appetite in the Brain

These exercises are graded from recall to synthesis. Items marked † are harder — they require you to combine material from more than one section, or from an earlier chapter, or to defend a judgment rather than report a fact. There are no answers here; several items have no single right answer, and the ones that do are worth the effort of finding.

Nothing in this set asks you to design a protocol, calculate a dose, or evaluate a product for purchase. If an exercise seems to be heading that way, you have misread it.

Part A — Co-transmission and the neuromodulator idea (§22.1)

A. In one sentence each, state where classical fast transmitters and neuropeptides are stored, and what firing condition releases each.

B. Explain why a neuron firing at a low rate and the same neuron firing in a sustained burst are sending chemically different messages, not the same message at two volumes.

C. Neuropeptides have no reuptake transporters. Name two consequences of that fact — one for how long the signal lasts, and one for how quickly the neuron can send the signal again.

D. † An SSRI works by blocking a reuptake transporter. Explain why no drug can work on a neuropeptide system by the same mechanism, and name what a drug would have to do instead.

E. Define neuromodulator in your own words, without using the words "modulate" or "modulator."

F. † §22.1 argues that neuropeptide drugs are harder to demonstrate in clinical trials than fast transmitter drugs. Reconstruct that argument in three steps, then say which of the four programs in this chapter it best explains.

Part B — Neuropeptide Y (§22.2–22.3)

G. How many amino acids are in NPY, and what does the letter "Y" in its name refer to?

H. NPY, PYY, and pancreatic polypeptide belong to the same structural family, yet NPY drives feeding and PYY suppresses it. Explain how that is possible without either molecule being mischaracterized.

I. Which arcuate neuron population co-releases NPY and AgRP, and what does leptin do to that population?

J. † Chapter 13 described the persistent hunger many people experience after substantial weight loss. Using §22.2, describe the peptide-level account of that experience — and state clearly what that account does not license you to conclude about any individual's behavior.

K. Antagonists at feeding-associated Y receptors were taken into human obesity trials. What happened, and what are the three explanations §22.2 offers?

L. † Someone argues: "The NPY antagonists failed, so NPY must not really drive appetite." Identify the error in that inference and write a two-sentence correction.

M. State the finding from high-stress human populations that underlies most consumer NPY claims, and identify the study design.

N. List the four causal interpretations §22.3 says are equally consistent with that finding.

O. † Apply Chapter 13's three-joint test to the claim "this supplement supports healthy NPY levels for stress resilience." Write one paragraph per joint, and state which joint fails hardest.

P. † §22.3 distinguishes circulating NPY from central NPY. Explain why that distinction is not a technicality, and name the section of this chapter that supplies the underlying physical reason.

Part C — Substance P and the NK1 story (§22.4–22.5)

Q. Write out the tachykinin C-terminal signature motif and name the three peptides that share it.

R. Where are the cell bodies and central terminals of the neurons that contain most of the spinal cord's substance P, and what kind of sensory information do those neurons carry?

S. Give three independent lines of preclinical evidence that supported the substance P hypothesis of pain transmission.

T. † Rewrite the NK1 analgesic hypothesis as it would have been stated in a grant application in 1995 — one paragraph, in the confident voice of someone who believes it. Then annotate the paragraph, marking each sentence as mechanism, animal evidence, or inference.

U. In which indications were NK1 antagonists tested as analgesics, and what was the result?

V. Describe what happened to the NK1 antidepressant program: the initial finding, the confirmatory program, and the outcome.

W. † Human PET studies confirmed that NK1 antagonists occupied their receptor in the brain at the doses used in the failed trials. Explain, in precise terms, which candidate explanations for the failure this eliminates and which it leaves open.

X. What indication did NK1 antagonists ultimately succeed in, and what type of emesis do they handle particularly well?

Y. † §22.5 argues that this chapter's ❌ for NK1 antagonists in pain and depression is epistemically stronger than most ❌ ratings in the book. Explain the distinction, then find one other compound elsewhere in this book that would receive the weaker kind of ❌ and say what evidence would be needed to move it.

Z. The emetic circuitry NK1 antagonists act on includes the area postrema. Why does that matter for the delivery question, and which chapter introduced this structure?

Part D — Orexin (§22.6)

AA. Why does the literature use two names for the same pair of peptides, and what are they?

BB. State the three independent lines of evidence that linked orexin to narcolepsy, and name the species involved in each.

CC. † Narcolepsy type 1 and type 1 diabetes have the same logical shape as diseases. Lay out that parallel in four points — and then name the one respect in which the treatment stories diverge completely.

DD. What class of drug did the orexin system produce, for what condition, and how does its mechanism differ from that of benzodiazepines and Z-drugs?

EE. † Several adverse effects of orexin receptor antagonists resemble narcolepsy symptoms. Explain why that is expected rather than surprising, and generalize the observation into a statement about neuropeptide drugs as a class.

FF. † Small-molecule orexin agonists are being developed for narcolepsy rather than the peptide itself. Give the delivery reason, and then explain why building an agonist is a harder chemistry problem than building an antagonist.

Part E — CGRP, the barrier, and the comparison (§22.7–22.9)

GG. What does the "calcitonin gene-related" part of CGRP's name describe, and what other peptide comes from the same gene?

HH. Set out the three-part human evidence chain for CGRP in migraine — observation, provocation, blockade — in one sentence each.

II. † A provocation study is the piece of evidence §22.9 says separated CGRP from substance P. Explain what a provocation study can establish that no amount of animal work can, and name one thing it still cannot establish.

JJ. Erenumab, fremanezumab, galcanezumab, eptinezumab, ubrogepant, rimegepant, atogepant, zavegepant. Sort these into two groups by molecular class, and state which group — if either — consists of peptides.

KK. † Explain the sentence "the peptide is the target, not the drug" to someone who has read Chapter 1 but nothing since, and give three different examples from this book of a therapy built around a peptide that is not itself a peptide.

LL. Name the three structural features of the blood-brain barrier, and the three exceptions that allow some peptide signaling to reach or influence the brain.

MM. † The NK1 antagonists did cross the blood-brain barrier. Given that, explain why §22.8 still belongs in this chapter — that is, what work the barrier section does in the argument if it does not explain the NK1 failure.

NN. † Substance P and CGRP are co-expressed in many of the same sensory neurons. Write the strongest possible version of the argument that this makes their divergent clinical fates surprising. Then answer it using §22.9's three differences.

OO. † Take one current claim about a brain peptide — from a news article, a press release, a podcast, or a product page — and run §22.9's four-item checklist against it. Report which items it satisfies, which it does not, and which of the four you could not determine from the source at all. That last category is usually the most informative.

PP. Fill in Field 3 of your Evidence Dossier for every entry you have. For any entry whose claimed effect is not in the brain, write "not applicable" and move on — knowing when a question does not apply is part of the skill.

QQ. † Choose the one compound in your dossier whose Field 3 answer is weakest. Write a paragraph stating what a seller or advocate would need to show you — specifically, in terms of measurements rather than assertions — for the delivery question to be considered answered.

A note on what these exercises are training

Almost every item above is a variation on two questions: what was actually measured? and how does the molecule reach the place where the claimed effect happens? Those two questions resolve more peptide arguments than any amount of mechanistic detail, and this chapter is the clearest demonstration in the book of why. The NK1 program had the mechanism, had the compounds, and had the delivery — and still failed, because it did not have the third thing: direct human evidence that the target mattered for the chosen indication.

If you finish this chapter able to ask all three questions in order, without prompting, the chapter has done its job.