Remnants of an Ancient Past

Very primitive multicellular organisms, such as the hydra (e.g., Chlorohydra viridissima, the ultimate simple feeding
tube), have nervous systems that may only use simple proteins
as neurotransmitters, suggesting that these proteins were the
fi rst signaling molecules used by primordial nervous systems. If
we extract a few of these proteins from the “brain” of a typical
Hydra and inject them in human neurons, they will actually
produce similar signaling responses from those neurons.
In fact, the proteins used by hydra in their nervous systems
are identical to some of the proteins that our brains use to help
us think and feel. These proteins are called neuropeptides.
A neuropeptide is like a string of beads, and each bead is an
amino acid. Neuropeptides may be assembled from only a few
or from hundreds of different amino acids. Your body contains
many different types of neuropeptides that are assembled from
the amino acids found in your diet. Neurons that produce and
release these neuropeptides are found throughout the body and
brain and infl uence a diverse array of body functions, including
the release of hormones and the absorption of nutrients from
our blood.
The evolutionary history of our neuropeptides is quite
interesting and tells us a great deal about their current role and
why they are found in certain places in the body and not others.
One very important neuropeptide is insulin, which is produced
by the pancreas. Some neuroscientists have speculated that an
insulin-like peptide might have been the principal ancestor to
many of our other neuropeptides that are still structurally
related to each other. For example, growth hormone and prolactin, peptides that control breast development and milk production, respectively, may have diverged from a common ancestorabout 350 million years ago. Therefore, it’s not surprising that
growth and nursing are also closely related to each other. As
studies of mammals and hydra have demonstrated, evolution does
not tinker with some molecules. If something works well, it tends
to stay around and continue to be used across eons of time.
Alternatively, some neuropeptides have been modifi ed only
slightly but often for related purposes. For example, most animal
venoms are derived from neuropeptide-related precursors, and
some may have originated from brain peptides that initially
appeared at least 100 million years ago and have since been

undergoing modifi cation and mutation. Yet, some venoms still
retain the ability to perform functions that their evolutionary
parent molecule still performs, such as an insulin-like ability to
control blood glucose levels. Because of this shared evolutionary history, venoms extracted from species that range from very
simple single-celled organisms to very complex animals and
plants have become popular tools for scientists studying how
human neuropeptide neurons function. During the past 30 years,
these studies have demonstrated that there are more than 100
different neuropeptide neurotransmitters in our brain and body.
These neuropeptides are found at very low concentrations and
are very potent.
This chapter focuses on neuropeptide neurotransmitters
whose actions in the brain were discovered through the euphoric
and pain-relieving effects of one of the most powerful and addicting class of drugs ever known. By way of contrast, it also discusses
the pain-relieving effects of a few drugs that do not work through
these neuropeptides but, rather, through a very different mechanism. The contrast is interesting in what it tells us about these
neuropeptides in the context of the full arsenal of mechanisms
that the body uses to protect itself from pain and other distress.
The euphoric and sleep-producing effects of opiates, which are
derived from the poppy plant, were well-known to ancient
civilizations. Around 4000 BCE, for example, the Sumerians
(Babylonians) carved pictures of the poppy plant into tablets
inscribed with the words hul (“joy”) and gil (“plant”). In the
classical literature of Virgil (1st century BCE), Somnus, the
Roman god of sleep (a translation of the Greek Hypnos), was
sometimes described as carrying poppies and an opium container from which he poured juice into the eyes of the sleeper.
Chinese legend has the poppy plant springing up from the earth
where the Buddha’s eyelids had fallen after he cut them off to
prevent sleep.
The fi rst specifi c medical use of opium was described in the
Ebers papyrus of ancient Egypt (about 1500 BCE), where it is
presented as a remedy for excessive crying in children. The substance was important for Greek medicine as well. According to
Galen, the last of the great Greek physicians (2nd century CE),
opium was an antidote to poison and venoms and cured headaches, vertigo, deafness, blindness, muteness, coughs, colic, and
jaundice. He also noted its recreational use at the time, commenting on the widespread sale of opium cakes and candies.
Various opium preparations, usually as extractions into
some type of alcoholic beverage, were later developed, including
Dr. Thomas Sydenham’s version of laudanum during the 17th century, which contained 2 ounces of strained opium, 1 ounce of
saffron, and a dram of cinnamon and cloves dissolved in a pint
of Canary wine. The 19th century author Thomas De Quincey
purchased laudanum for a toothache and then spent rest of his
life taking the drug and writing about his experiences with it (e.g.,
in Confessions of an English Opium-Eater, 1821). Another preparation
was paregoric, a combination of opium, camphor, and anise oil
that was developed in the mid-20th century for the treatment of
diarrhea in infants.

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