DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

482 the existence of three main receptor types with an opioid pharmacology
(Waldhoer et al., 2004). In 2000, the Committee on Receptor
Nomenclature and Drug Classification of the International Union of
Pharmacology adopted the terms MOP, DOP, and KOP receptors
(mu opi oid peptide receptor, etc). In concert with identification of
these opioid receptors, Kostelitz and associates (Hughes et al., 1975)
identified an endogenous opiate-like factor that they called
enkephalin (“from the head”). Soon afterward, two more classes of
endogenous opioid peptides were isolated, the endorphins and
dynorphins (Akil et al., 1984).
In the early work by Martin, a sigma (σ) receptor was identified
and was thought to represent a site that accounted for the paradoxical
excitatory effects of opiates; this site is now thought to be
the phencyclidine binding site and is not strictly speaking an opiate
receptor or an opiate site.
SECTION II
NEUROPHARMACOLOGY
ENDOGENOUS OPIOID SYSTEMS:
AGONISTS AND RECEPTORS
An agent found within the brain that acts through an opioid
receptor is an endogenous opioid. Several distinct
families of endogenous opioids peptides have been identified:
principally the enkephalins, endorphins, and dynorphins.
These families have several common properties:
• Each derives from a distinct large precursor protein,
prepro-opiomelanocortin (POMC), preproenkephalin,
and preprodynorphin, respectively, encoded by a corresponding
gene.
• Each precursor is subject to complex cleavages by distinct
trypsin-like enzymes, typically at sites designated
by pairs of dibasic amino acids, and to a variety of
post-translational modifications resulting in the synthesis
of multiple peptides, some of which are active.
• Most opioid peptides with activity at a receptor share
the common amino-terminal sequence of Tyr-Gly-
Gly-Phe-(Met or Leu) followed by various C-terminal
extensions yielding peptides ranging from a few
(5) to many residues (Table 18–1; the endomorphins,
with different terminal sequences, are exceptions).
The POMC sequence contains a variety of non-opioid peptides
including adrenocorticotropic hormone (ACTH), melanocytestimulating
hormone (αMSH), and β-lipotropin (β-LPH), all of
which are generated by proteolytic cleavage of POMC. The major
opioid peptide derived from further cleavage of β-lipotropin is the
potent opioid agonist, β-endorphin. Although β-endorphin contains
the sequence for met-enkephalin at its amino terminus, it is not
converted to this peptide. The anatomical distribution of POMCproducing
cells is relatively limited within the CNS, occurring
mainly in the arcuate nucleus of the hypothalamus and the nucleus
tractus solitarius. These neurons project widely to limbic and brainstem
areas and to the spinal cord. POMC expression also occurs in
the anterior and intermediate lobes of the pituitary and also are contained
in pancreatic islet cells. Circulating β-endorphin derives primarily
from the pituitary, from which it and other pituitary hormones are
released (Chapter 38).
Proenkephalin contains multiple copies of met-enkephalin,
as well as a single copy of leu-enkephalin. Proenkephalin peptides
are present in areas of the CNS believed to be related to the processing
of pain information (e.g., laminae I and II of the spinal cord, the
spinal trigeminal nucleus, and the periaqueductal gray), to the modulation
of affective behavior (e.g., amygdala, hippocampus, locus
ceruleus, and the frontal cerebral cortex), to the modulation of motor
control (e.g., caudate nucleus and globus pallidus), to the regulation
of the autonomic nervous system (e.g., medulla oblongata), and to
neuroendocrinological functions (e.g., median eminence). Although
there are a few long enkephalinergic fiber tracts, these peptides are
contained primarily in interneurons with short axons. The peptides
from proenkephalin also are found in chromaffin cells of the adrenal
medulla and in nerve plexuses and exocrine glands of the stomach
and intestine. Circulating proenkephalin products are considered to
be largely derived from these sites.
Prodynorphin contains three peptides of differing lengths that
all begin with the leu-enkephalin sequence: dynorphin A, dynorphin B,
and neoendorphin (Figure 18–1). The peptides derived from prodynorphin
are distributed widely in neurons and to a lesser extent in
astrocytes throughout the brain and spinal cord and are frequently
found co-expressed with other opioid peptide precursors.
Nociceptin peptide is present in neurons widely distributed
throughout brain (cortex, hippocampus, brainstem, and to a lesser
degree, hypothalamus, thalamus, raphe nuclei, and periaqueductal
gray matter) and spinal cord structures. It has been observed in neurons
as well as astrocytes and neutrophils.
More recently, a family of peptides has been identified and
named endomorphins, endomorphin-1 (Tyr–Pro–Trp–Phe–NH 2
) and
endomorphin-2 (Tyr–Pro–Phe–Phe–NH 2
) (Zadina et al., 1997). By
comparison with other opioid peptides, endomorphins have an atypical
structure and display selectivity towards the μ opioid receptor
(Fichna et al., 2007).
Several points should be stressed:
• Not all cells that make a given opioid pro-hormone precursor
store and release the same mixture of opioid peptides; this results
from differential processing secondary to variations in the cellular
complement of peptidases that produce and degrade the active
opioid fragments (Hook et al., 2008).
• Processing of these peptides is altered by physiological demands,
leading to the release of a different mix of post-translationally
derived peptides by a given cell under different conditions.
• Opioid peptides are found in plasma and reflect release from
secretory systems such as the pituitary and the adrenals that do
not reflect neuraxial release. Conversely, levels of these peptides
in brain/spinal cord and in CSF arise from neuraxial systems and
not from peripheral systems.
OPIOID RECEPTORS
Principal Receptor Classes; Distribution
The three opioid receptors—δ, μ, and κ—belong to the
rhodopsin family of GPCRs (Chapter 3) and share