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Progress in Neuroendocrinology
Neuroendocrinology 38: 418-426 (1984)
Opioid-Adrenergic-Steroid Connection in Regulation of Luteinizing
Hormone Secretion in the Rat
Satya P. Kalra. Pushpa S. Kalra
Department of Obstetrics and Gynecology, University o f Florida College of Medicine, Gainesville, Fla., USA
Key Words. Gonadal steroids • Epinephrine ■Luteinizing hormone • Norepinephrine • Opioids
Abstract. In this article we have attempted first to summarize the current information on the effects of each of the thre
neuronal systems - gonadal steroid concentrating neurons, catecholamine and opioid producing neurons - on variou
aspects of luteinizing hormone releasing hormone (LHRH) secretion. The salient features of the new information are: ( I >
gonadal steroids are capable of raising LHRFI levels in the median eminence nerve terminals without changing LH (LHRH
secretion; (2) a chain of temporally related neural events in the preoptic-tuberal pathway precede the preovulatory LL
release; (3) catecholamines may provide a permissive environment for appropriate function of LHRH neurons, and (4) th
inhibitory influence of endogenous opioid peptides on LH release may be mediated by adrenergic neurons in th
preoptic-tuberal pathway. Based on this information we have constructed a conceptual model which attempts to integrat
the inputs of these three systems during the episodic basal and cyclic release of LH in the rat.
Received : August 31, 1983
Accepted after revision: November 2,1983
SC Neuronal System
It appears that SC neurons serve as central sensors of th
circulating gonadal steroid milieu in the rat. These neuron
possess specific intracellular receptors for I7f)-estradu
(E 2), progesterone (P) and androgens and avidly accumulai _■
these steroids [64,66, 72], Although found at diverse sites i :
the rat brain [66, 72] there is a regional specificity in th
action of SC neurons in modulating some aspects of th •
secretory activity of LHRH neurons [34, 35, 79]. Dependir. :
upon the strength, duration and nature of the gonadal ste
oid milieu, SC neurons may influence the secretory function
of LHRH neurons in two ways. They may modulate the
episodic discharge of LHRH by evoking a secretion pattei n
different from that prevalent in gonadectomized rats. Wh e
testosterone (T) and E2 predominantly suppress the height <f
the LH pulse in gonadectomized rats [29, 32, 36, 37, 80[. a
combination of E2 and P treatment has been shown o
modify the frequency and amplitude of the LH dischar e
[61]. It is likely that the synergistic action of E2 and P may be
responsible for the distinct episodic pattern of LH secret! n
seen during each phase of the estrous cycle [24, 25, 49, 6 11.
Whether such modulation of episodic LH secretion reflects
changes in LHRH secretion under the direction of gonadal
steroids remains to be ascertained. There is little agreement
on the effects of gonadal steroids on the LHRH release
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There is compelling evidence to show that pituitary LH
secretion is regulated by a distinct neural circuitry in the
diencephalon, the components of which communicate by
diverse chemical signals. Identification of these components
and their organization in coordinating the episodic and
cyclic release patterns of LH has been the subject of inten­
sive investigations for decades. Luteinizing hormone releas­
ing hormone (LHRH) producing neurons, distributed exten­
sively in the diencephalon [56,85], apparently secrete LHRH
episodically into the hypophysial portal veins in the median
eminence (ME) [7,62,74,75] to impart a pulsatile pattern of
pituitary LH secretion in intact and gonadectomized rats [16,
24, 25, 32, 37]. On the basis of recent research it has been
possible to identify three neuronal systems which predic­
tably modulate the output of LHRH neurons by evoking
changes in the intracellular production and secretion of the
neurohormone [49]. These neuronal systems are: the steroid
concentrating (SC) neurons and catecholamine (CA) and
endogenous opioid peptide (EOP) producing neurons. Re­
cent progress in our understanding of the anatomical and
functional relationships among these systems, in modula­
tion of LHRH (LH) secretion, is discussed briefly in this
communication.
Opioid-Adrenergic-Sleroid Connection
I
Proestrus morning
419
Proestrus afternoon
LM surge
rr
2
2.000
-|
♦
LHRH
surge
1
1
ME LHRH
content
(synthesis)
Opioid '
peptide
activity
1
Fig. 1. Depicts a model o f the ongoing sequential neural events
in the preoptic-tuberal pathway on proestrus. See text and refer­
ences 42 and 49 lor details. The model suggests that on the morning
of proestrus, a progressive decrease ( 1), perhaps directed by the
neural clock (see figure 4 also) either directly or through unknown
neural systems, as shown by the empty box on the left, leads to a
gradual augmentation (f) in the adrenergic tone (predominantly in
NE neurons) locally in the hypothalamus. These facilatory events
permit accumulation of LHRH in the MBH prior to the neural
‘trigger' for LHRH and LH release during the critical period (2-4
p.m.) evoked by increased E (and NE) output (from 42].
Fig. 2. Lower: Effects o f various concentrations o fT on the MBH
LHRH levels in orchidectomized rats. Note that extremely low
concentrations o f T (413-638) pg/m l) maximally raised the MBH
LHRH levels without suppressing LH release. *p < 0.05 vs. control.
Upper: Determination o f the duration o f T exposure (519 ± 40
pg/ml) necessary to elicit maximal elevation in the MBH LHRH
levels without adversely affecting LH secretion in orchidectomized
rats. Note that constant exposure for a minimum period of 72 h was
necessary to elicit the MBH LHRH response in the presence of
normal LH secretion in castrated rats [from 37], *p < 0.05 vs.
control.
pattern in ovariectomized rats [17, 62, 63, 74, 75]. Although
Sarkaret al. [74] reported increased levels of LHRH in portal
plasma collected from anesthetized ovariectomized rats, a
similar augmentation in LHRH output from the ME was not
apparent with the push-pull cannula system in freely moving
ovariectomized rats [62,63]. Surprisingly, Dluzen and Ramirez[ 14] recently reported attenuated LHRH output from the
ME of long-term orchidectomized rats. Thus, despite the
prevailing view that gonadal steroids may modulate LHRH
secretion, data correlating the patterns of LH and LHRH
secretion in intact, gonadectomized and gonadectomized
steroid-treated rats is scarce.
On the other hand, recent studies have demonstrated that
gonadal steroids stimulate accumulation of LHRH in the
medial basal hypothalamus (MBH). Extensive evidence
gathered by us suggests that accumulation of LHRH evoked
by gonadal steroids may be due largely to augumented
appearance of new LHRH; alterations either in the amounts
or pattern of neurohormone secretion, if any, may be of little
1,000 4
Hours of exposure to testosterone
Control
¿.13130 638139 1.337151 1,776139
Testosterone, pgim l
consequence [32,35-37,47, 51], These views were formulat­
ed from the results of two diverse experimental designs. Just
prior to the preovulatory LH surge on the afternoon of
proestrus, LHRH begins to accumulate mainly in the axons
and terminals in the MBH [33,51,84](fig. I). That this abrupt
increase, contemporaneous with basal circhoral LH dis­
charge [25], may be facilitated by P is shown by observations
that similar antecedent LHRH responses can be reproduced
with marked facility by P in ovariectomized estrogen-primed
rats [46, 50,79], The circulating concentrations of P between
diestrus II and the critical period on proestrus may be
sufficient to evoke LHRH accumulation in the ME-arcuate
nucleus (ARC) prior to discharge into the hypophysial por­
tal vessels [45,49, 79]. The other line of evidence,in support
of the hypothesis of direct stimulation of LH RH elaboration
by gonadal steroids, was obtained in castrated male rats [32,
36, 37]. It was consistently found that concentrations of T
(400-638 pg/m l) as illustrated in figure 2, or of E2 (5-10
pg/ml), too low to disrupt the characteristic episodic LH
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Adrenergic
activity
NE
f
E
420
show a striking regional similarity in the diencephalon [66,
72,85]. Therefore, it is possible that the peptidergic neuron^
themselves may concentrate steroids and possess intracellu
lar receptors. Kelly and Ronnekleiv[55] have provided elec
trophysiological evidence indicative of steroid membrane
receptors on the MBH LHRH neurons of the guinea pig.
However, several experimental and morphological studies
conflict with the notion of LHRH neurons as being the
classical target cells of gonadal steroids. Steroid concentrat
ing neurons outnumber LHRH neurons in the diencephalon, and more importantly, the distribution of these two
groups of cells does not strictly overlap in critical areas in th
preoptic-tuberal pathway where LHRH neurons are abund­
ant. Furthermore, we have found that intracranial implant.:
tion of T or 5a-dihydrotestosterone (DHT) in the medial
preoptic area (MPOA) of castrated rats, which would un­
doubtedly elevate steroid concentrations in the vicinity of
LHRH perikarya and fibers to a high range, failed to raise
LHRH levels either locally in the POA or to prevent th
postcastration depletion caudally in the MBH [34,35]. How
ever, similar intracranial implants of steroids in the MBH
much like systemic treatment with T or DHT, apparentl
promoted accumulation of LHRH locally without adversel
affecting LH secretion. Similary, P-induced accumulation of
LHRH prior to the LH surge in estrogen-primed ovaries
tomized rats is confined to the ME-ARC region [79]. Thes
findings led us to suggest that there may be a distinct popul.
tion of SC neurons in the MBH which underthe influence c
steroids, either directly or through other neuronal system .
regulate LHRH storage in the axons and nerve endings in the
ME. Admittedly, such an interlink with LHRH neurons may
involve neurochemical signalling, the nature of which is not
known.
CA Neurons: Adrenergic System
A large body of evidence shows that hypothalamic pr<
jections of norepinephrine (NE) and epinephrine (E) pro
ducing neurons of the brain stem [19] are apparently capable
of evoking changes in LH secretion [23,26,44], presumably
by altering LHRH output [59], Although true synaptic links
between CA and LHRH neurons have not yet been docu­
mented, the adrenergic neurons appear to terminate in such
close proximation of the dentrites, perikarya and axons of
peptidergic neurons [30, 49] that one can assume that CAs
may evoke LHRH secretion by activating «-adrenergic re­
ceptors in the preoptic-tuberal pathway [38, 86]. What is the
physiological significance of the adrenergic-LHRH link in
LH release in the rat? Results from a variety of experiments
have implicated the adrenergic-LHRH connection in pre­
ovulatory and episodic LH secretion during the estrous cycle
[27,52], in the stimulatory and inhibitory feedback effects of
gonadal steroids on LH release [4 ,13,38]and in pulsatile LH
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secretion pattern in castrated rats, were maximally effective
in elevating the MBH LHRH levels [36,37]. Another notable
feature of steroid action was that the LHRH response dis­
played 'all or none’ characteristics requiring continuous
exposure for a minimum period of 72-96 h. This prolonged
time requirement for the MBH LHRH response could not be
reduced even by continuous supply of high levels of steroids
which drastically suppressed LH (LHRH) release [32, 36,
37]. Careful monitoring of blood E2 and T concentrations
revealed that the threshold of responsiveness was higher, by
2- to 3-fold magnitude, for LH (LHRH) release than for
LHRH accumulation, a disclosure again favoring indepen­
dent actions of the steroids on these neurosecretory re­
sponses.
The steroid-induced increments in LHRH levels may
represent a balance of release, synthesis and degradation of
the neurohormone in peptidergic neurons. The evidence
outlined in the preceding section clearly eliminated change
in the LHRH release rate, if any, as a significant factor
contributing towards the rise in LHRH levels. Recently,
Advis et al. [3] have shown a decrease in the activity of LH RH
degrading enzymes in the ME concomitant with the rise in
LHRH levels after P treatment in estrogen-primed ovariectomized rats. While other such mechanisms are likely to be
involved, the long time course of action required to elicit the
LHRH response is in accord with the view that steroids may
stimulate formation of new LHRH either by stepping up
synthesis of the precursor peptide an d /o r by augmenting
liberation of immunoreactive LHRH from a preexisting
high molecular weight precursor peptide [12, 22, 28, 32, 36,
37]. It is important to note that higher concentrations of
LHRH after steroid treatment are observed only in axons
and nerve terminals in the ME-ARC region [39,79],
The physiological significance of the steroid-induced
MBH LHRH increase is speculative. It is possible that the
neurohormone may exist in more than one pool in the ME
nerve terminals. The contents of one such pool, available for
rapid release, can be readily elevated by steroids, as seen
after P injection in estrogen-primed ovariectomized rats [45,
46,79,83] or on proestrus preceding the afternoon preovula­
tory LH surge [33,51,84]. Further, there may be a more stable
LHRH pool, the contents of which are maintained at maxi­
mally elevated levels by gonadal steroids in intact rats. The
sluggishness of the LHRH response after steroid treatment
in castrated rats is consistent with the idea that formation of
new hormone may be evoked by steroid-dependent tran­
scription-translation action at the level of LHRH perikarya
[22] and assembling of the biologically active secretory form
from the precursor hormone predominantly in the ME [47,
49].
The preeminent question posed by the foregoing discus­
sion is where and which SC neurons in the brain participate
in accumulation of LHRH in the ME nerve terminals. Dis­
tribution patterns of SC and LHRH producing neurons
Kalra/Kalru
421
Opioid-Adrenergic-Steroid Connection
in NE neurons observed at this time (fig. 1). It is possible that
E may participate in subsequent steps that evoke abrupt
LHRH discharge and a prolonged LH surge in the afternoon
[1,41].
Additional studies show that even in a gonadal steroidfree environment, adrenergic systems may provide a permis­
sive environment for episodic LH secretion [ 18]. When hypo­
thalamic NE and E levels were acutely suppressed in ovari­
ectomized rats, a marked suppression in the frequency and
height of LH episodes followed. Activation only once of
postsynaptic a-adrenergic receptors with clonidine induced
immediate LH release and resumption of pulsatile LH secre­
tion. Seemingly, the neural mechanisms which trigger the
episodic LHRH and LH secretions are resident in LHRH
neurons and they do not appear to be tightly coupled with or
driven by regular episodic a-adrenergic stimulation and
thus, the adrenergic system may ‘provide a permissive envi­
ronment to optimally allow LH secretion to occur in a
pulsatile fashion’ [18].
Endogenous Opioid Peptides
Although opiates are among the oldest pharmacological
substances known to man, and their effects on reproduction
have been known for some time, the recent discovery of
naturally occuring morphine-like substances in the proximi­
ty of LHRH, SC and CA neurons in the septal-preoptic-tuberal pathway has aroused considerable interest regarding
their physiological role in control of LH secretion [42]. There
are at least three types of EOP - (3-endorphin, enkephalins
and dynorphins - which have the potential of playing im­
portant roles in regulation of pituitary gonadotropin secre­
tion. The chemical and structural relationships among these
neuropeptides and their distribution in the rat brain have
been extensively reviewed elsewhere [8, 42, 49]. The EOP
secreting neurons in the septal-preoptic-tuberal pathway
represent a family of neurons which exert a profound inhibi­
tory influence on LH secretion, perhaps involving more than
one opiate receptor subtype [42, 60, 67]. (3-Endorphin, a
3 1-amino acid peptide, produced in perkarya located exclu­
sively in the arcuate nucleus-periventricular nucleus re­
gions, is apparently the most potent inhibitor of LH release
[57,60]. Intraventricular infusions of [3-endorphin, unlike E2
or T, promptly suppressed the amplitude and frequency of
LH discharge in ovariectomized rats and blocked preovula­
tory LH release and ovulation when administered on proes­
trus [Leadem and Kalra, unpubl.]. Dynorphin, a 17-amino
acid peptide, predominantly produced in the perikarya of
the magnocellular system [81], is relatively less effective
while methionine-enkephalin, a pentapeptide produced in
cells located at various regions in the diencephalon, was
ineffective in suppressing LH release [60]. Surprisingly, leu­
cine-enkephalin - another pentapeptide with a rather scarce
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secretion in gonadectomized rats [23]. It is generally believed
that increased influx of NE signals plays an important part
in the neurogenic stimuli which excite LHRH release for
episodic basal, preovulatory and steroid-induced LH re­
lease: similar participation of E is limited perhaps to the LH
surge on proestrus and that elicited by ovarian steroids in
ovariectomized rats [11,41],
Careful perusal of these studies has revealed that adren­
ergic systems may participate in the regulation of LH release
in several ways. In a classical neurotransmitter mode there
may be augmented NE discharge in the proximity of LHRH
neurons preceding and during the episodes of LH hyperse­
cretion in intact and gonadectomized rats. In support of this
mode are the reports of increased NE turnover in crucial
sites in the preoptic-tuberal pathway in association with the
LH surge on proestrus or that induced by ovarian steroids in
estrogen-primed ovariectomized rats and during LH hyper­
secretion in gonadectomized rats [9. 10, 68, 76, 83]. Also,
when LH release was suppressed by gonadal steroid replace­
ment in gonadectomized rats, NE turnover decreased in
important sites in the hypothalamus [4, 13, 78]. On the other
hand, reassessment of the temporal sequence of onset of
increments [I. 68, 69, 76, 83] or decrements [13, 78] in NE
turnover and of changes in LH secretion disclosed an entire­
ly different picture. It was evident that increments in NE
turnover in the ME and MBH generally preceded the in­
crease in LH secretion on proestrus and in steroid-treated
rats. If one assumes that increases in NE turnover imply
increased neurotransmitter reaching the postsynaptic a-adrenergic receptors, then the considerable lag in the temporal
sequence of neuroendocrine events is intriguing and is indi­
cative of roles other than that of classical neurotransmitter
for NE.
An alternative mode of adrenergic involvement that has
recently gained momentum implies that adrenergic neurons
may provide a permissive intrahypothalamic environment
for allowing LHRH neurons to produce and discharge their
product in accordance with either their intrinsic rhythmicity
of that imposed by gonadal steroid milieu [48], This view was
based on observations that suppression of brain NE (E)
neurotransmission with dopamine [3-hydroxylase inhibitors
blocked the increase in ME-ARC LHRH levels that pre­
cedes the LH surge in estrogen, progesterone-treated rats
[50, 79]; an observation reaffirmed independently by two
laboratories [ 1,3]. In fact, localized destruction of N E termi­
nals in the MPOA-suprachiasmatic nucleus area was suffi­
cient to similarly suppress antecedent LHRH increments
caudally in the MBH [77]. Also, drastic reduction in hypo­
thalamic NE turnover following pentobarbital injections
promptly suppressed LHRH levels in ovariectomized rats
[53], These disclosures of attenuated NE activity adversely
affecting LHRH levels have led us to suggest that accumula­
tion of LHRH in the hypothalamus, prior to the critical
period on proestrus, may be facilitated by the increased tone
422
Kalra/Kalru
Minutes
Fig. 3. Effects o f intraventricular infusion o f E on LH release in
the morphine-treated ovariectomized rats previously primed con­
comitantly with estrogen and progesterone. Note that E (and NE)
(see 44] induced a similar pattern of LH secretion in morphine-treat­
ed and control rats (from 44].
Fig. 4. A conceptual model of the neural circuitry involved in
regulation o f LH secretion in the rat. It is postulated that episodic
LHRH secretion into the hypophyseal portal veins, which deter
mines the pattern o f LH secretion (pattern generator), is modulates
by axo-axonic neural links between EOP (opioid) and catecholaminergic (E or NE) neurons; this link may be appropriately mon
tored by the clock (command) as in cycling female rats. As shown on
the left the feedback modulator)' influence may occur at three levels
(for details see text) (from 42],
distribution in the diencephalon, stimulated LH release [60]:
a stimulatory response with methionine-enkephalin was re­
ported by Motta and Martini [65]. A majority of the analogs
of methionine-enkephalin tested so far produced long-last­
ing suppression of LH release in ovariectomized rats and
blocked ovulation in cyclic rats [58,60].
Where and how do EOP participate in regulation of LH
release? There seems to be a general consensus that, while
systemically administered opiates could act at extrahypothalamic sites [31], it is likely that EOP released in the vicinity
of LHRH neurons in the preoptic-tuberal pathway inhibit
LH release [40]. On the basis of their in vitro studies, Rotsztejn et al. [70,71] suggested that EOP may act directly at the
level of LHRH nerve endings to inhibit dopamine-induced
LHRH release. More recently, however, no diminution of
the response of LHRH neurons to excitatory neutrotransmitters, such as NE or E, was seen in morphine-treated,
steroid-primed ovariectomized rats (fig. 3) [44]. When the
preovulatory LH surge was blocked with intraventricular
injections of [Tendorphin, these CAs still induced a normal
LH response [Leadem and Kalra. unpubl.]. It seems likely
that the postsynaptic neurosecretory events normally initiat­
ed by adrenergic agents in LHRH neurons are not compro­
mised by opiates or EOP. On the other hand, EOP may
inhibit LHRH release by decreasing the influx of excitatory
adrenergic signals in the vicinity of LHRH neurons. These
views are supported by the findings that blockade of opiate
receptors with the receptor antagonist, naloxone prompt!
activated LHRH release concomitantly with NE and E from
the POA-MBH tissue in vitro [Leadem et al„ unpubl.]; prior
blockade of ct-adrenergic receptors or suppression of hypo­
thalamic NE and E levels rendered naloxone, administered
intracranially or systemically, ineffective in stimulating LH
release in steroid-primed ovariectomized rats [40, 54]. Re­
cent results implicate E as the predominant neurotransmitter involved in mediation of LH stimulation by naloxone
[43]. Thus, these diverse findings together with current
knowledge of the topography of NE and E neurons in the
brain have led us to postulate that a functional axo-axonic
interaction between EOP and CAs may occur in the close
vicinity of LHRH neurons in the preoptic-tuberal pathway
[42,49, 54],
The next obvious question is how the axo-axonic link
between the EOP and adrenergic systems operates during
the inhibitory and stimulatory feedback actions of gonadal
steroids on LH release. On the basis of the information
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Opioid-Adrenergic-Steroid Connection
Opioid-Adrenergic-Steroid Connection
the afternoon of proestrus. Since a similar sequence of
neural events occurs after progesterone treatment in estro­
gen-primed ovariectomized rats [45,46, 79], this experimen­
tal model has been used to test the opioid-adrenergic in­
volvement in evoking the LHRH and LH responses. Two
lines of evidence suggest some degree of temporary curtail­
ment in the inhibitory EOP influence after P injection. First,
continuous stimulation of opiate receptors with morphine,
which would undoubtedly prevent the decrease in EOP
influence on CA neurons, blocked the expected neural
events that follow P treatment such as increase in adrenegic
turnover [2], accumulation of LHRH in the MBH and the
LHRH and LH surges [54]. Second, increase in the content of
[1-endorphin in the M E in the afternoon of proestrus [5] or in
the MBH after P treatment [Kalra, unpubl.], although diffi­
cult to interpret at this juncture, may result from curtailed
[3-endorphin release. Also, our failure to stimulate LH re­
lease with naloxone 4-6 h after P injection in estrogenprimed ovariectomized or in proestrous rats [21], is reflective
of a lapse in inhibitory influence, perhaps, due to decrease in
EOP release. Evidence shows that some adrenergic neurons
in the brain stem accumulate estradiol [73] thereby raising
the possibility that gonadal steroids may independently, in
some way, influence adrenergic activity in the preoptic-tu­
beral pathway.
It is clearly evident that many gaps remain to be filled
before the nature of involvement of the three systems in
regulation of LH release in the rat is precisely known. Never­
theless, the knowledge that one class of peptidergic neurons
(EOP) can communicate with another(LHRH) by aminergic
neurotransmitters and that the gonadal steroid milieu can
affect this communication, has opened a new level of inquiry
towards our understanding of how the brain controls repro­
duction in animals.
Acknowledgements
Supported by grants from NIH (HD 08634, 14006 [to SPK] and
11362 [to PSK]). The excellent secretarial assistance o f Mrs. Sally
McDonellis gratefully acknowledged.
References
1 Adler, B.A.; Johnson. M.D.; Lynch, C.O.; Crowley, W.R.: Evi­
dence that norepinephrine and epinephrine systems mediate the
stimulatory effects o f ovarian hormones on luteinizing hormone
and luteinizing hormone releasing hormone. Endocrinology
113: 1431 (1983).
2 Adler, B.A.; Crowley, W.R.: Modulation o f luteinizing hormone
release and catecholamine activity by opiates in the female rat.
Neuroendocrinology (in press, 1983).
3 Advis,J.P.: Krause, J.E.; McKelvy, F.: Evidence that endopeptidase-catalysed luteinizing hormone releasing hormone cleavage
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available, a conceptual model is presented in figure 4 which
incorporates the neural clock which governs the preovulato­
ry LH discharge (command) and the postulated axo-axonic
link between EOP and CA neurons in modulating LHRH
secretion (modulatory input). It is possible that SC neurons
(feedback circuitry), under the influence of gonadal steroids,
may monitor the level of opioid influence on CA neurons to
produce a change in adrenergic tone in the preoptic-tuberal
pathway, which, predictably, would influence LHRH and
LH release. Involvement of EOP in the inhibitory gonadal
steroid feedback is suggested by the observations that levels
of some of the EOP in the rat hypothalamus were altered by
steroid treatment [15]. [i-Endorphin levels in the portal stalk
plasma, which may reflect hypothalamic synthesis and re­
lease after affecting LHRH release, fluctuate in accordance
with the steroid milieu [82], Also, transient interruption of
the opioid influence by displacement of EOP from receptor
sites by naloxone, results in activation of LH release in intact
male [6, 54] and cycling female rats [21]. The excitatory
effects of naloxone appear to be due to increased LHRH
release induced by NE and E in the vicinity of LHRH
neurons because we found that naloxone stimulates release
of these catecholamines concomitant with LHRH release
from the hypothalamus in vitro [Leadem et al., unpubl.].
Recent studies of Gabriel et al. [20] also show an involvement
of opiate receptors in the inhibitory feedback effects of T on
LH release. While continuous stimulation of opiate recep­
tors with morphine failed to alter LH release, this treatment
rendered orchidectomized rats hypersensitive to the feed­
back action of T to the extent that extremely small T concen­
trations (200-500 pg/ml), which normally do not interrupt
episodic LH secretion (fig. 2) [37], completely suppressed
LH secretion to basal levels as seen in intact rats. Although
the precise mode of opiate receptor involvement is un­
known, these intriguing findings further reaffirm the in­
volvement of opiate receptors in the inhibitory feedback
effects of steroids and provide a framework for future stud­
ies on the interactions of SC and EOP neurons in inhibiting
LH release.
Experimental evidence also favors the participation of
EOP-adrenergic link in the stimulatory feedback effects of
gonadal steroids in eliciting preovulatory LH release. Figure
1 depicts graphically the sequence of neural events that
occur preceding the preovulatory LH surge on the afternoon
of proestrus. We have suggested that on the morning of
proestrus a component of the neural clock which times the
onset of preovulatory LH release, perhaps facilitated by
steroid action (fig. 4), may transiently curtail the influence of
HOP on adrenergic neurons, either directly or via an un­
known neural system (fig. 1, empty box on the left). This
decrease in inhibitory influence triggers a cascade of neural
events starting with augmentation of adrenergic tone in the
preoptic-tuberal pathway, accumulation of LHRH in the
ME and culminating in hypersecretion of LHRH and LH in
423
424
5
6
7
8
9
10
11
12
13
14
15
16
17
contributes to the regulation o f median eminence LHRH levels
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Opioid-Adrenergic-Steroid Connection
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Dr. Satya P. Kalra,
Department o f Obstetrics and Gynecology,
Box J-294 JHMHC,
University o f Florida College of Medicine,
Gainesville, FL 32610 (USA)
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