Ganong's Review of Medical Physiology, 23rd Edition

144 SECTION IIPhysiology of Nerve & Muscle Cells

One contains methionine (met-enkephalin), and one con-
tains leucine (leu-enkephalin). These and other peptides that
bind to opioid receptors are called opioid peptides. The en-
kephalins are found in nerve endings in the gastrointestinal
tract and many different parts of the brain, and they appear to
function as synaptic transmitters. They are found in the sub-
stantia gelatinosa and have analgesic activity when injected
into the brain stem. They also decrease intestinal motility.
Like other small peptides, the opioid peptides are synthe-
sized as part of larger precursor molecules. More than 20
active opioid peptides have been identified. Unlike other pep-
tides, however, the opioid peptides have a number of different
precursors. Each has a prepro form and a pro form from
which the signal peptide has been cleaved. The three precur-
sors that have been characterized, and the opioid peptides
they produce, are shown in Table 7–4. Proenkephalin was
first identified in the adrenal medulla, but it is also the precur-
sor for met-enkephalin and leu-enkephalin in the brain. Each
proenkephalin molecule contains four met-enkephalins, one
leuenkephalin, one octapeptide, and one heptapeptide. Proo-
piomelanocortin, a large precursor molecule found in the
anterior and intermediate lobes of the pituitary gland and the
brain, contains β-endorphin, a polypeptide of 31 amino acid
residues that has metenkephalin at its amino terminal. There
are separate enkephalin-secreting and β endorphin-secreting
systems of neurons in the brain. β-Endorphin is also secreted
into the bloodstream by the pituitary gland. A third precursor
molecule is prodynorphin, a protein that contains three leu-
enkephalin residues associated with dynorphin and neoen-
dorphin. Dynorphin 1-17 is found in the duodenum and
dynorphin 1-8 in the posterior pituitary and hypothalamus.
Alpha- and β-neoendorphins are also found in the hypothala-
mus. The reasons for the existence of multiple opioid peptide
precursors and for the presence of the peptides in the circula-
tion as well as in the brain and the gastrointestinal tract are
presently unknown.
Enkephalins are metabolized primarily by two peptidases:
enkephalinase A, which splits the Gly-Phe bond, and enkephali-
nase B, which splits the Gly-Gly bond. Aminopeptidase, which
splits the Tyr-Gly bond, also contributes to their metabolism.
Opioid receptors have been studied in detail, and three are
now established: μ, κ, and δ. They differ in physiologic effects
(Table 7–5), distribution in the brain and elsewhere, and
affinity for various opioid peptides. All three are G protein-
coupled receptors, and all inhibit adenylyl cyclase. In mice in
which the μ receptors have been knocked out, morphine fails
to produce analgesia, withdrawal symptoms, and self-admin-
istration of nicotine. Selective knockout of the other system
fails to produce this blockade. Activation of μ receptors
increases K+ conductance, hyperpolarizing central neurons
and primary afferents. Activation of κ receptors and δ recep-
tors closes Ca2+ channels.
The affinities of individual ligands for the three types of
receptors are summarized in Figure 7–11. Endorphins bind
only to μ receptors, the main receptors that mediate analgesia.
Other opioid peptides bind to multiple opioid receptors.

Other Polypeptides

Numerous other polypeptides are found in the brain. For ex-

ample, somatostatin is found in various parts of the brain,

where it apparently functions as a neurotransmitter with ef-

fects on sensory input, locomotor activity, and cognitive func-

tion. In the hypothalamus, this growth hormone-inhibiting

hormone is secreted into the portal hypophysial vessels; in the

endocrine pancreas, it inhibits insulin secretion and the secre-

tion of other pancreatic hormones; and in the gastrointestinal

tract, it is an important inhibitory gastrointestinal regulator.

A family of five different somatostatin receptors have been

TABLE 7–5 Physiologic effects produced

by stimulation of opiate receptors.

Receptor Effect

μ Analgesia

Site of action of morphine

Respiratory depression

Constipation

Euphoria

Sedation

Increased secretion of growth hormone and prolactin

Meiosis

κ Analgesia

Diuresis

Sedation

Meiosis

Dysphoria

δ Analgesia

FIGURE 7–11 Opioid receptors. The ligands for the κ, μ, and δ

receptors are shown with the width of the arrows proportionate to the

affinity of the receptor for each ligand. (Reproduced with permission from

Julius DJ: Another spark for the masses? Nature 1997;386:442. Copyright © 1997 by

Macmillan Magazines.)

Dynorphins β-Endorphin Enkephalins

Endomorphins

κ δ