In the mature male rat, the serum concentration of luteinizing hormone (LH) is
Naloxone also prevents the negative feedback inhibition by testosterone on LH
release in the castrated male rat (Cicero, Schainker & Meyer, 1979). In healthy adult
male volunteers, oral administration of 50 mg naltrexone under double-blind
conditions caused an increase in integrated plasma LH levels with recurrent penile
erections in three subjects, efTects wh ich did not occur after placebo administration
(Mendelson, Ellingboe, Keuhule & Mello, 1979).
Intravenous injection of p-endorphin in rabbits or its injection into the .third
ventricle causes a rise in the plasma level ofarginine vasopressin which so far has not
been shown to be prevented by naloxone (Firemark & Weitzman, 1979) although in
rats the antidiuretic efTect of p-endorphin or DvAlat-Dvl.eut-enkephalin is
prevented by naloxone (Bisset, Chowdrey & Feldberg, 1978).
The analysis ofthe efTects of opioid peptides and of their possible importance in the
control ofbody temperature is very complex. The absence of a significant efTect ofthe
It is weil known that large doses of morphine will produce various states of
immobility in rats described as 'catalepsy' or 'catatonia'. Similar efTects have been
observed by many authors after large doses of p-endorphin. An analysis of these
or etonitazene (Browne, Derrington & Segal, 1979). Intracerebroventricular injection
of Met-enkephalin or p-endorphin in rats leads to non-convulsive limbic seizures
(Urea, Frenk, Liebeskind & Taylor, 1977; Henriksen, Bloom, McCoy, Ling &
Guillemin, 1978). Similar naloxone-reversible efTectswere observed after injection of
large doses of Met-enkephalin into or near the forebrain dorsomedial nucleus ofthe
thalamus (Frenk, McCarty & Liebeskind, 1978).
PH YSIOLOGICAL ROLE OF ENKEPHALINS AN D ENDO RPHINS 41
Effects on circulation and respiration
There are a number of ob servations whic h indica te that opioid peptides take part in
th e control of heart rate and blood pressure. In rats ana esthetized with chloralose,
intracisternal administrat ion of ß-endorphin or ofMet-enkephalin produces a rise or
a fall in blood pre ssure, respectively; both peptides cause brad ycardia (Bolme, Fu xe,
Agna ti, Bradley & Sm ythi es, 1978). Wh en ß-endorphin is given int ravenously, it
causes a naloxone-reversible hypotension in rats an aesth etized with urethan e
(Lemai re, Tseng & Lem aire, 1978). The hypotension cau sed by endotoxins,
hypo volaemic and spinal shock and by inha lation of halothane is reversed by
naloxone (Holaday & Faden , 1978, 1980 ; Faden & Holaday, 1979; Arndt & Fr eye,
1979). In th is context, it is of int erest th at enkephalin-like radio-immunoreact ivity is
present in type I glomus cells and processes of the cat carotid body (Lundberg,
Hökfelt, Fahrenkrug, Nil sson & Teren ius, 1979).
As far as respiration is concern ed, intravenous injection of naloxone increases
resp irator y output in the cat (Lawson, Waldrop & Eldridge, 1979). It also raises the
respiratory rate in the anaesthetized rat after electroconvulsive shock or after section
ofthe spina l cord at C7 (Belenky & Holaday, 1979; Holaday & Faden, 1980). In the
latter serie s ofexperiments, intraventricular injection of(-)--naloxone (48 1Jg), but not
ofits (+)--isomer, increased respiratory rate.
The assessment ofthe possible ph ysiological roles ofopioid peptides is more difficult
in man than in an im als. Apart from behavioural changes, effects on levels in blood
plasma are likel y to give informat ion which will be considered in th is section.
In pla sma, ß-endorphin is of particular interest because it is likel y to indicate
secre tion fro m the pituitary. Methodological difficu lties arise from th e fact that
antibodies against ß -endorphin may show considerable cross-reac tiv ity with
ß-lipotropin . For this reason , highly specific antisera have to be used or ß-lipotropin
has to be separated fro m ß-endorphin by gel filtration chromatography prior to
The level of ß-endorphin-like immunoreactiv ity in rat plasma is about
75-100 pmol mi-I which is increased about 4-fold after adrenalectomy. In normal
human males and females the va lues are much lower, near th e limits of detection,
4-12 fmol ml:"; the ß-lipotropin values are of a similar order of magnitude (Ak il,
Watson, Barchas & Li, 1979; Höllt, Müller & Fahlbusch , 1979). In Nelson's
syndrome and in Addison 's and Cushing's diseases there are marked rises in ß-LPH
and ß -endorphin, the total increase being closely related to the rise in ACTH (Nakai,
Nakao, Oki, Imura & Li, 1978; Suda, Liotta & Krieger, 1978). In pregnancy,
ß-endorphin-like immunoreactivit y in plasma is raised about 6-fold and somewhat
more during the second stage of labour; th is occurs together with an increase in
immunoreactive ß-LPH and ACTH (Akil et al., 1979;Csontos, Rust, HöHt , Mahr,
Kromer & Teschemacher, 1979). The function of the increased ß-endorphin is not
known; the concentration is much too small for an analgesic effect or for an action on
isolated peripheral organs, such as the guinea-pig ileum or mouse vas deferens.
Although the adrenal medulla of several species conta ins large amounts of
Lew is, Stern, Stein & Udenfriend, 1979; Viveros, Diliberto, Hazum & Chang, 1979),
it has so far not been possible to allocate a physiological role to th is phenomenon. It
is of interest that, in one single patient investigated for hirsuties, 116pg mI-I
Met-enkephalin was found in the left adrenal vein whereas the level in blood from the
Opioid peptides in cerebrospinal fluid
Several compounds are present in the CSF which interact with the opiate receptor. In
ventricular CSF a Met-enkephalin-like substance is present in a concentration of
3 pmol ml! which is lowered in patients with intractable pain (Akil, Watson,
Sullivan & Barchas, 1978c). In lumbar CSF, two fractions of opiate-receptor active
material has been found, of which Fraction 11 may be enkephalin-Iike (Almay,
Johansson, von Knorring, Terenius & Wahlström, 1978; von Knorring, Almay,
Johansson & Terenius, 1978). From a c1inical point of view, Fraction I seems to be
more significant than Fraction Ir. Fraction I is lowered in patients with organic pain
but not in those with psychogenic pain; there is no correlation with anxiety or motor
retardation. In patients with high levels ofFraction I, pain threshold and tolerance to
pain due to continuous stimulation across the fmgers of the dominant hand were
found to be significantly higher than in patients with low levels of Fraction I (von
Knorring et al., 1978). In about half of the patients in whom acupuncture provided
relief from chronic lumbar pain, there is a concomitant increase in the Fraction I
content oflumbar CSF (Sjölund, Terenius & Eriksson, 1977).
It has already been mentioned that electrical stimulation ofthe periventricular grey
in man increases enkephalin- and p-endorphin-like immunoreactivity in the CSF
(Akil et al., 1978a, b; Hosobuchi et al., 1979).
Opioid peptides and mental health
Since morphine and opioid peptides can intluence mood, the first dose often leading
to dysphoria and later doses to euphoria, great interest was aroused in the roles they
may possibly play in schizophrenia and endogenous depression. Attempts have been
made to alter schizophrenic symptoms with administration of opiate antagonists,
p-endorphin, and dia lysis. A review of a very complex situation has recently been
published (Watson , Akil, Berger & Barchas , 1979).
Effects of opioid peptides in man
The enkephalin analogue, FK 33-824, (Tyr-D-Ala-Gly-MePhe-Met(O)-ol, Sandoz)
when given intramuscularly in doses of 0.25 and I mg increased tolerance to
electrically induced pain without affecting threshold. Self-ratings of an oppressive
feeling increased, as did those of drowsiness; there was also some degree ofdysphoria
(Stacher, Bauer, Steinringer, Schreiber & Schmierer, 1979). As described for
p-endorphin, low doses of FK 33-824 readily produced neuroendocrine and, in
addition, peripheral effects (von Graffenried, dei POlO & Roubicek, 1978, personal
p-endorphin was given intravenously to three patients with malignant tumours
and directly into the CSF in one patient (Foley, Kourides, Inturrissi, Kaiko, Zaroulis,
Posner , Houde & Li, 1979). The half-life of 5-10 mg after intravenous injection was
37 min with a volume of distribution of 178 ml kg-'; the corresponding values after
intraventricular injection were 93 min and 0.74 ml kg-I. There was a rapid rise in
plasma prolactin after both types ofadministration and a reduction in plasma growth
hormone after intraventricular but not after intravenous injection. p-endorphin
increased plasma prolactin at doses smaller than those required for analges ia and
PHYSIOLOGICAL ROLE OF ENKEPHALINS AND ENDORPHINS 43
other behavioural etTects. In contrast to the neuroendocrine etTects, in the doses used
analgesia was observed only after intraventricular administration. Intrathecal
administration of 3 mg p-endorphin gives relieffrom intractable pain for about 33 h
(Oyarna, Jin, Yamaya, Ling & Guillemin, 1980).
A large amount of information has accumulated with regard to the chemical
properties of the opioid peptides, their distribution in the central and peripheral
nervous systems, their receptors, metabolism and pharmacological properties.
However, much less is known about their physiological functions. A number of
reasons have contributed to this situation. The characteristics and distribution ofthe
various receptors are not sufficiently defmed nor are the physiological functions
which they subserve. This is mainly due to the fact that there are so far no antagonists
which interact specifically with only one type of the opiate receptors. Further, we
know little about the incidence and significance of co-existence of opioid peptides
with c1assical transmitters in one and the same neurone. Biosynthesis, turnover and
release of enkephalins are not weIl understood. It is probably correct to ass urne as a
first approximation that at most sites the opioid peptides have an inhibitory action
on neuronal activity and that the etTects mediated by this modulation depend on the
In view ofthis complexity ofthe mechanisms involved in the action ofthe opioid
peptides, further progress in basic research will be of particular importance for a
better understanding oftheir c1inical implications.
Supported by grants from the Medical Research Council, the U .S. National Institute
on Drug Abuse (DA 00662) and the U .S. Committee on Problems of Drug
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