outside of the CNS that produce the prohormones may
not possess all of the posttranslational enzymes present in
the brain and thus may be unable to generate the same opi-
ate peptides. For example, proenkephalin A in the brain is
processed to produce the pentapeptides met-enkephalin
(MENK) and leu-enkephalin (LENK); in the adrenal
medulla, however, larger fragments of the prohormone are
produced. Another example is brain-derived POMC which
is processed to form melanocyte-stimulating hormone
(MSH) fragments, whereas adrenohypophyseal POMC is
processed to form large fragments containing the MSH
sequence (e.g., ACTH, y-LPH).
At least three types of opiate receptors have been iden-
tified. The
/x
receptor exhibits greatest affinity for alka-
loid morphine but also recognizes /1-endorphin. There are
two subtypes of the
jx
receptor:
fx
j, which mediates the
analgesic effects of opioids, and
fi2,
which mediates the
respiratory depression and gastrointestinal effects of opi-
oids. The
8
receptor exhibits greatest affinity for the pen-
tapeptides MENK and LENK, while the
k
receptor has
high affinity for the dynorphins but does not recognize the
enkephalins or endorphins. The opiate antagonists nalox-
one and naltrexone bind to
ix
and
8
receptors, but not
to the
k
receptor. Although the endogenous opioid pep-
tides were discovered more than 25 years ago, their phys-
iological functions are still not completely understood.
The biological importance of the endogenous opioids is
primarily attributed to their documented analgesic effects.
Opium and its derivatives (morphine, codeine, etc.) have
long been used to reduce the perception of pain. They are
known to amplify the existing analgesia (pain-modulating)
system of the body, which the endogenous opioid peptides
and their receptors normally operate to modulate the sen-
sation of pain. The endogenous analgesia system consists
of enkephalinergic neurons that inhibit the transmission
of sensory pain signals at multiple levels of the ascending
pain pathway. These neurons originate at three regions
of the CNS: the periaqueductal gray area surrounding the
aqueduct of Sylvius in the mesencephalon; the raphe mag-
nus nucleus in the pons; and the dorsal horn of the spinal
cord. Pain impulses transmitted by either Ad (acute) or C
(slow) fibers can be blocked upon entry in the dorsal horn
and as they ascend through the brain stem. Both /*, and <5
opioid receptor sites are present throughout the analgesia
system and mediate the inhibitory effects of enkephalins
on pain signal transmission.
The cause of death in most cases of opioid overdosage
is respiratory depression, i.e., an effect of opioids on the
respiratory center of the brainstem that inhibits chemore-
ceptor responsiveness to C 02. The medullary ventilatory
control center is said to have a high density of
fx
2
opioid
736
receptors that mediate the depressing effect of opioids on
respiration.
Opioids
increase
appetite
and
stimulate
food in-
take, whereas opiate antagonists inhibit food intake in
food-deprived animals. Although circulating levels of
/
1
-endorphin were found to be higher in obese than in lean
women, there is no evidence that obesity is caused by an
imbalance in endorphin production. However, a relation-
ship between early-onset obesity and inherited defects in
the
POMC
gene that leads to a lack of production of ACTH,
MSH
(a, p, y),
and /1-endorphin has been observed in
humans (discussed later).
The opioids probably do not play an important role in
the regulation of neuroendocrine function because block-
ade of opioid receptor sites has either minor or no effect on
the basal or stimulated release of most pituitary hormones.
However, there is evidence that central opioids may toni-
cally inhibit the rate of hypothalamic GnRH release after
puberty in males.
31.2 Pituitary Gland (Hypophysis)
The pituitary is a small, bilobed gland connected to the
base of the hypothalamus by the infundibular process (pi-
tuitary stalk). Embryologically it derives from Rathke’s
pouch (buccal epithelium) and the infundibulum (neuroec-
toderm). The former gives rise to the anterior lobe (anterior
pituitary or adenohypophysis). The latter is a projection of
the hypothalamus and gives rise to the posterior lobe (pos-
terior pituitary or neurohypophysis). In many species, an
“intermediate lobe” also exists, but in humans this is rudi-
mentary and apparently nonfunctional. The pituitary in an
average-sized adult weighs only about 0.5 g, 75% of which
is anterior pituitary.
The anterior pituitary is not innervated by nerve fibers
from the hypothalamus but is well vascularized by the
portal blood that drains the median eminence. The por-
tal blood flows primarily from the median eminence to
the anterior pituitary; however, some vessels may trans-
port blood in the opposite direction (retrograde flow).
The posterior pituitary consists mainly of nerve end-
ings of hypothalamic magnocellular neurons and con-
tains no portal connections with the hypothalamus; its
vascular connections are largely independent of those
in the anterior pituitary. The hormones of the posterior
pituitary (neurohypophyseal hormones) were discussed
above.
The anterior pituitary has five endocrine cell types, each
of which produces different hormones. In the human, at
least seven are produced: growth hormone (GH), prolactin
chapter 31
Endocrine Metabolism II: Hypothalamus and Pituitary
