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Unit for Research on Addictive Drugs,
In the evaluation of the possible physiological roles of new neurotransmitters or
neuromodulators, it is necessary to understand the mechanisms underlying their
biosynthesis, release and metabolism, and interactions with their receptors. There is
now a considerable amount of information on these aspects with regard to the
endogenous opio id pept ides, which has recently been reviewed from the basic and
c1inical points of view (Kosterlitz & McKnight, 1980, 1981). For this reason, it is
intended to deal in this paper mainly with those concepts that are important for an
understanding ofthe principles governing the possible physiological functions ofthe
There is good evidence for the view that the long-chain peptide, ß-endorphin, and
required. There is little doubt that they are derived from large precursors whose
production is prevented by inhibitors of protein synthesis, such as puromycin or
cycloheximide. There is also general consensus that ß-endorphin is not the precursor
of Met-enkephalin although the sequence of Met-enkephalin is present in
It would appear that the primary precursor of ß-endorphin is a large peptide
consisting of 265 amino acid residues, as deterrnined by the sequencing of the
nucleotides formed by cloned cDNA for bovine corticotropin- ß -lipotropin precursor
(Nakanishi, Inoue , Kita, Nakamura, Chang, Cohen & Numa, 1979). The more
immediate precursor is opiocorticotropin consisting of 134 amino acid residues and
cont aining the sequences of ACTH (1-39) and ß-l ipotropin (42-134); from these
may be derived a-MSH (1-13), CLIP (18-39), p-MSH (84-101) and ß -endorphin
(104-134). The proportion of these products varies in the various regions of the
pituitary and hypothalamus (Main s & Eipper, 1978; Pezalla, Seidah , Benjannet,
Crine, Lis & Chretien, 1978; Liotta, Gildersleeve, Brownstein & Krieger, 1979). The
simultaneous presence of p-lipotropin and p-endorphin, on the one hand, and of
ACTH, on the other, in the same cells of the pituitary and the hypothalamus have
their basis in the origin ofthese peptides from a common precursor.
While there is a great deal of information about the biosynthesis of p-endorphin,
our information regarding the origin of the enkephalins is still speculative and
hypothetical. There is good evidence from experiments with incorporation of
labelled amino acids that biosynthesis of enkephalins involves ribosomal synthesis of
large peptide precursors. Thus it has been shown that (3H]-tyrosine is incorporated
into both Met- and Leu-enkephalin in the myenteric plexus-longitudinal muscle of
the guinea-pig ileum and in slices of the guinea-pig corpus striatum and that this
incorporation proceeds linearly after a lag period of one to two hours (Sosa,
McKnight, Hughes & Kosterlitz, 1977; McKnight, Hughes & Kosterlitz, 1979). Since
the incorporation is blocked by protein synthesis inhibitors only when these are
present during the labelling period, it is likely that the enkephalins are produced in
the neurone from larger precursors. Such large peptides (5,000-100,000 daltons) have
been found in guinea-pig, rat and bovine corpus striatum (Lewis, Stein, Gerber,
Rubinstein & Udenfriend, 1979a), in rat and pig brain (Beaumont, Dell, Hughes,
Malfroy & Morris, 1980), in guinea-pig myenteric plexus-longitudinal muscle
(McKnight, Sosa, Corbett & Kosterlitz, 1980) and in bovine adrenal medulla (Lewis,
Stern, Rossier, Stein & Udenfriend, 1979b; Yang, Costa, Di Giulio, Fratta & Hong,
adrenal medulla and purified to homogeneity. One is apparently, a Met-enkephalin
precursor containing two copies of the Met-enkephalin sequence, the other contains
both Leu- and Met-enkephalin sequences and is presumably a common precursor of
the two forms of enkephalin (Kimura, Lewis, Stern, Rossier, Stein & Udenfriend,
1980). However, it has not been proved yet that these larger peptides are enkephalin
precursors because no kinetic relationship has been established between the putative
precursors and the enkephalins.
As far as release of enkephalins is concerned, the main problem is the rapidity with
there is always some residual cross reactivity between Met- and Leu-enkephalin.
It has been shown that the K+-induced release of enkephalins from synaptosomes
obtained from rat brain (Smith, Hughes, Kosterlitz & Sosa, 1976) or rabbit striatum
(Henderson, Hughes & Kosterlitz, 1978), and from slices of rat striatum (Osborne,
Höllt & Herz, 1978) or globus pallidus (lversen, Iversen, Bloorn, Vargo & Guillemin,
Since the myenteric plexus of the small intestine of the guinea-pig contains high
concentrations ofenkephalins, it would, in principle, appear to be a suitable model to
study the effect ofelectrical stimulation ofthe intramural nerves on the release ofthe
enkephalins. However, it has so far been impossible to obtain a consistent release of
enkephalin in the bath fluid , probably because of the readiness with which
enkephalins are degraded by enzymes. Therefore, an indirect method has been used ,
in which new formation of enkephalins is prevented by cycloheximide, an inhibitor
of protein synthesis; any enkephalin which has been released due to electrical
stimulation cannot be repl aced and therefore the decrease in the enkephalin content
is a measure ofthe rate ofrelease. With stimulation with a supramaximal current at I
PHYSIOLOGICAL ROLE OF ENKEPHALINS AND ENDORPHINS 35
or 10 Hz , the release has been found to be 4-5 fmol enkephalin g-I tissue for each
pulse ofstimulation, which corresponds to about 0.001% ofthe enkephalin content of
the tissue, Met-enkephalin being released more readily than Leu-enkephalin
(McKnight, Sosa, Hughes & Kosterlitz, 1978; Corbett, Sosa , McKnight & Kosterlitz,
1980). This rate ofrelease is similar to that found in the noradrenergic system.
The evidence for relea se of endogenous opioids in the whole animal is based on
possible behavioural deficits produced by opiate antagonists. lt is implied that, where
naloxone or naltrexone given without previous administration of opiates produce
such an efTect, it may be due to antagonism ofthe action ofreleased opioid peptides.
Fal se negative or positive results ma y ari se when the dose of antagonist is too low or
when it is raised to a level when non-specific efTectsappear. It is likel y that the action
of an antagonist will be specific when it is obtained with doses not high er than those
required to reverse the efTects ofmorphine; however, larger doses ma y be necessary to
antagonise the efTectsof enkephalins on t5 -receptors to which naloxone or naltrexone
have a relatively low affmity. In such circumstances it is necessary to prove that the
action of the antagonist is specific, that is, the efTect should be seen only with
(-}-naloxone but not with (+}-naloxone. At present direct evidence for release has
been obtained only rarely as indicated by the increase of enkephalin- and
p-endorphin-like immunoreactive material in the CSF after periventricular
stimulation in man (Akil , Richardson, Barchas & Li, 1978; Akil, Richardson, Hughes
& Barchas, 1978; Hosobuchi, Ros sier , Bloom & Guillemin, 1979).
One of the striking difTerences in the inactivation of the enkephalins and
ß-endorphin is the high sensitivity of the enkephalins to hydrolysis by peptidases.
Thus, the half-life of [3H]-Met-enkephalin is only 2-4 s in vivo after intrajugular
injection in the rat (Dupont, Cusan, Garon, Alvarado-Urbina & Labrie, 1977) or
2 min after in vitro incubation in rat plasma (Hambrook, Morgan, Rance & Smith,
1976) and less than I min after intracerebroventricular injection (Meek, Yang &
Costa, 1977). The inactivating enzymes are non-specific carboxypeptidases and more
particularly aminopeptidases, which are widely distributed in the central nervous
system and in pla sma. They are inhibited by puromycin (Vogel & Alste in , 1977;
Barclay & Phillips, 1978; Knight & Klee , 1978). A more specific, membrane-bound
dipeptidase, enkephalinase, splits the Gl y-Phe bond releasing Tyr-Gly-Gly (Malfroy,
Swerts, Guyon , Roques & Schwartz, 1978) and Phe-Met (Guyon, Roques, Guyon,
Foucault, Perdrisot, Swerts & Schwartz, 1979) and is inhibited by Gl y-Gly-Phe-Met
and not by puromycin (Malfroy, Swerts, Llorens & Schwartz, 1979). The distribution
ofenkephalinase in mouse (Malfroy et al., 1978, 1979) and rat brain (Sullivan, Akil &
Barchas, 1979) closely paralleis that of specific opiate binding sites and of
enkephalins, with highest levels of activity in the striatum and hypothalamus and
three to five times lower levels in the cerebellum.
Less is known about the catabolism of p-endorphin which is less susceptible to
aminopeptidases and carboxypeptidases than the enkephalins. Thus, c1eavage of the
N-terminal Tyr-Gly bond occurs at a very much slower rate (Grynbaum, Kastin,
Coy & Marks, 1977; Marks, Grynbaum & Neidle, 1977); the half-life in rat plasma
after intravenous administration is about 9 min (Chang, Jagannadha Rao & Li, 1978).
This c1eavage is probably also due to aminopeptidase action since D-Ala2 analogues
of a-, p- and y-endorphin have a more long-Iasting antinociceptive efTect than the
parent peptides (Grynbaum et al., 1977; Walker, Sandman, Berntson, McGivern,
Coy & Kastin, 1977). It has been shown that degradation of p-endorphin occurs
extracellularly and is probably initiated by an endopeptidase acting on the bond
between residues 17 and 18 of ß-endorphin to yield y-endorphin (Austen, Smyth &
Snell , 1977; Graf, Kennessy, Patthy, Grynbaum, Marks & Lajtha, 1979); thereafter
the actions of aminopeptidases and endopeptidases result in the formation of
des-Tyr- y-endorphin, a-endorphin and des-Tyr- a-endorphin (Burbach, Loeber,
Verhoef, Wiegant, de Kloet & de Wied, 1980).
For some years evidence has accumulated in favour ofthe existence ofmore than one
type of receptor for the alkaloid narcotic analgesics. Thi s concept was based on
clinical observations and on neurophysiological observations on the spinal dog
(Martin, 1967; Martin, Eades, Thompson, Huppier & Gilbert, 1976) and was
confirmed by bioassays on the guinea-pig ileum and mouse vas deferens (Hutchinson,
Kosterlitz, Leslie , Waterfield & Terenius, 1975). Morphine was taken to interact with
the p-receptor and another group ofnarcotics, ofwhich ketazocine was the prototype,
with the K-receptor. The importance of the existence of the I(-receptor is due to the
fact that agonists interacting with this receptor do not substitute for morphine in the
The fmdings obtained with the opioid peptides indicated that they interact not only
with the p-receptor but also with the 8-receptor which is ditTerent from the
I(-receptor. The two enkephalins have no K-agonist activity but are not pure
u-agonists when tested in a set of four parallel assays (Lord, Waterfield , Hughes &
Kosterlitz, 1977). These consist oftwo pharmacological assay s, the guinea-pig ileum
(Kosterlitz, Lord, Paterson & Waterfield, 1980).
As far as the natural opioid peptides are concerned, p-endorphin is equipotent in
the guinea-pig ileum and mouse vas deferens and also in its ab ility to inhibit binding
of[3H]-Leu-enkephalin and [3H]-naloxone or [3H]-naltrexone. Leu-enkephalin is 50
times more potent in the mouse vas deferens than in the guinea-pig ileum and its
ability to inhibit [3H]-Leu-enkephalin binding is 25 time s greater than that to inhibit
[3H]-naltrexone. The receptor atTmities ofMet-enkephalin are intermediate between
those of p-endorphin and Leu-enkephalin.
An important observation is the fact that in the mouse vas deferens the interaction
with the 8-receptor is much less readily reversed by the antagonists available at
present, such as naloxone or naltrexone, than the interaction with the u-receptor.
Thus, in the mouse vas deferens, the opioid peptides interact mainly with the
8-receptors; in the guinea-pig ileum, on the other hand, the y interact mainly with the
u-receptor because the y are readil y reversed by naloxone (Lord et al., 1977; Kosterlitz
Since the natural enkephalins are very sensitive to the degrading action of
enzymes, stable analogues have to be used for experiments in animals and
observations in man. As the natural opioid peptides have ditTerential atTmities to the
various receptor binding sites , it is of importance to establish the binding and
thc othcr hand, Tyr-D-Ala-Gly-MePhe-Met(O)-ol, (FK 33-824 , Sandoz) (Roemer,
Buescher, Hili, Pless, Bauer, Cardinaux, Closse , Hauser & Huguenin, 1977), has a
very ditTerent pattern.Comparcd with its parent compound, Met-enkephalin , the
affinity to the p-receptor is unchanged but that to the 8 -receptor is decreased to 6.4%;
its acti vity in the guinea-pig ileum is increased 20-fold but that in the mou se vas
defcrens is unchanged (Kosterl itz et al., 1980). FK 33-824 is a much more potent
antinociceptive agent than Tyr-D-Ala-Gly-Phe-D-Leu, a fact which suggests that for
this action the u-receptor is more important than the 8 -receptor. All analogues
PHYSIOLOGICAL ROLE OF ENKEPHALINS AND ENDORPHINS 37
whieh have good antinoeieeptive aetivities show preferential interaetion with the
p-receptor rather than the t5-reeeptor, for example, Tyr-Dvlvlet-Gly-Phe-ProNllr
(Szekely, R6nai, Dunai-Kov äcs, Miglecz , Berzetei, Bajusz & Graf, 1977).
Binding assays in whieh saturation is aehieved give information on the maximal
number of binding sites, provided eross-reaetivity between binding sites is low. The
enkephalins bind preferentially with t5-sites but ean also interaet with u-sites; the
maximal binding of either ofthe two enkephalins in guinea-pig brain is between 5-6
pmol g-I brain tissue and that of dihydromorphine 4 pmol g-I. Amidation of the
similar to that found for one of the most potent nareotie analgesie drugs, etorphine.
This fmding would indieate that these eompounds interaet with both the and
t5-reeeptors, and possibly with an as yet unknown binding site (Gillan, Kosterlitz &
Further evidenee for multiplieity of opiate receptors has been obtained from the
differential effeets of GTP on binding (Pert & Taylor, 1980). It is possible that the
GTP-sensitive binding sites may be eorrelated to the u-receptor and the
GTP-insensitive sites to the t5-reeeptor. When the number of u-binding sites was
estimated by low eoneentrations of (12SI]-D-Ala2-MePhe 4-Met(O)-oIS-enkephalin and
the t5-binding sites by low eoneentrations of ['2SI]-D-Ala2-D-Leus-enkephalin
(Chang, Cooper, Hazum & Cuatreeasas, 1979), the distribution of the u-sites was
different from that of the t5-sites. On the whole, the p-receptors appear to be
preponderant in sites assoeiated with antinoeieeption while the t5-reeeptors are
prevalent in the limbie system as will be detailed later.
The earlier literature has been obtained without referenee to the multiplieity of
opiate reeeptors and will therefore have to be revised and arnplified.
etorphine in homogenates of various region s of the central nervous system (Hiller,
Pearson & Simon, 1973; Kuhar, Pert & Snyder, 1973) or (2) autoradiographic
visual izat ion of (lH]-diprenorphine after intravenous injection (Atweh & Kuhar,
The binding sites are distributed widely and unevenl y throughout the brain and
spinal cord. Detailed examination with [3H]-etorphine or [3H]-dihydromorphine in
the monkey and human brain showed the highest eoneentrations usually in the areas
periaqueduetal grey, and the dorsal horn of the spinal cord, particularly laminae
I-I1I. The exception is the eaudate whieh has many receptors but is relatively sparse
in enkephalin-containing fibres . The results obtained with the autoradiographic
determination of deposition ofthe potent opiate (3H]-diprenorphine are qualitatively
similar to these fmdings but permit a more detailed analysis of the distribution of
Possible physiological functions
The analysis of the physiologieal functions of the opioid peptides has encountered a
number of difficulties. First, the peptides do not penetrate the blood-brain barrier
readily. Moreover, the resistanee to the passage across this barrier is uneven, the
hypothalamic region being particularly leaky. Compared with the action ofthe more
lipophilic alkaloid nar cotics, parenteral ad ministration of opioid pepti des has a
relative ly grea ter effect on the hypoth alamus and thus on endocrine function than on
th e funct ion s of other parts of the centra l nervou s system.
Secondl y, there is so far no antagonist which is specific for the int era ction of th e
opioid peptides with any one ofthe receptors, Naloxon e, which is used most widely,
int era cts with the u-receptor in lO-time s lower concentrations than with the
l5 -receptor. It would be desirable to establish alw ays the stereospecificity of the
antagon ist action of naloxone, particularl y if it is used in large doses, but unfor -
tunately the inacti ve (+)-isom er of naloxone is avai lable only in sma ll quantities. On
the other hand, th e absence ofan effect doe s not necessarily exclude a putati ve role of
the opioid peptides whic h ma y be called into pla y in special circumsta nces.
Moreover , an an tagonist effect ma y be masked by the activating of a non -op ioid
syst em with simi lar ph ysiological functions.
Th irdly, Met - and Leu- en kephalin a re easi ly inac tivated enzy ma tica lly and
therefor e concent ra tions in bod y fluids are a very unreliable mea sure ofthe release of
these pept ides, These conside rations appl y to a much Iesser extent to the mo re sta ble
For th ese reason s, the following assumption has been helpful in the atternpts to
elucidate the functions of the opioid peptides, namely that administration of
morphine in therapeut ic or pharmacological doses mimics th eir ph ysiological
fun ctions, such as lim itation of experience of pa in, cont rol of respirat ion and
intestinal movements, changes in the extrapyramida l mot or system, and euphoric
the dorsal horn of the spina l cord and its connections with the raphe magnus of the
The evidence that Met-enkephalin and possibl y Leu- enkeph alin play an important
role in the control ofthe modulat ion ofthe transm ission ofnoxiou s or pa in ful sti muli
is based on the results of electrophysiological experirn en ts, on the relat ion sh ip
bet ween substance P and the enkephalins in the central ner vou s system and on th e
pa rtial antagonism by naloxone of stimulation ofthe periaqueductal grey .
It has bee n shown (Duggan, Hall & Headl ey, 1977) that, when Met- enkephalin or
its amide are applied iontophoreticall y to the substantia gelatinosa ofthe dorsal horn
of the ca t, they reduce the responses of neurones of laminae IV and V to noxiou s
stim uli but have little effect on the responses to non-nociceptive stimuli . It ma y be of
con siderable ph ysiological significance that enkephalins and sub stance P have a
simi lar distribution in areas related to pain and an algesia , such as the substantia
gelatinosa of the do rsal horn of the spi na l cord, the marg inal layer of the spinal
trigeminal nucleus, th e peri aqueductal grey and, to a lesser extent, the medullary
raphe nuclei (Hökfelt, Ljungdahl, Teren ius, EIde & Nilsson , 1977). Ho wever ,
substa nce P is without effects when applied to sites where Met-enkephalin amide
reduces excitation by no xio us skin stimuli (Duggan, Griersmith, Headley &
Hall ,1979); th is fmd ing does not support the view that enkephali ns a re released at
axo-axonic syna pses on the termi na ls of primary affere nts wit h substa nce P as
neurotransmitter. On the other hand, D-Ala2-Met-enkephalin amide inhibits th e
Kt-induced release of substa nce P from slices contai ning spi nal trigem inal nerve
nuclei (JesseIl & Iversen , 1977). These find ings are not necessarily contradic tory but
rather emphasize the highl y complex nature oftransmi ssion in the dorsal horn.
PHYSIOLOGICAL ROLE OF ENKEPHALINS AND ENDORPHINS 39
In addition, the neurones in the dorsal horn receive inhibitory serotoninergic fibres
from the raphe nuclei and a second inhibitory innervation, which arises in the nuclei
gigantocellularis and paragigantocellularis and possesses an adrenergic component. It
is possible that the fibres originating from these two areas are disinhibited by
enkephalinergic fibres from the periaqueductal grey ; if this view is correct, it would
offer an explanation for the antinociceptive effect caused by electrical stimulation of
the periaqueductal grey or by application of opioids to this area. The complex
evidence for and against this possibility has recently been summarized (Mayer, 1979).
The effects ofopiate antagonists on the responses to noxious stimuli in animals and
in man are equivocal. The reasons for this inconsistency have not been satisfactorily
elueidated (Mayer, 1979). Different experimental approaehes may measure changes
in pain threshold of changes in tolerance to pain, which may be affected differently.
Another possibility is the presence ofseveral pain controlling systems; if only one of
these systems is mediated by opioid peptides, then the effects of narcotic antagonists
would be masked by the activation ofthe non-opioid mechanisms. Thus, it has been
suggested that a selective modulation of nociceptive input at the level of the spinal
cord can be mediated by supraspinal systems physiologieally distinct from those
involved in analgesia produced by opiates (Hayes, Bennett, Newlon & Mayer, 1978).
Closely related to th is view may be the fact that analgesia induced by hypnosis is not
reversed by naloxone (Goldstein & Hilgard, 1975). On the other hand, analgesia
induced by acupuncture in man is reversed by naloxone (Mayer, Price & Rafii, 1977).
The analgesie effect of a placebo administered for postoperative pain has been found
to be reversed by naloxone, an observation whieh suggests that at least certain
placebo effects are mediated by the opioid peptidergic systems (Levine, Gordon,
Bornstein & Fields, 1979). However, these mechanisms do not seem to offer
significant protection in chronic pain (Lindbiom & Tegner, 1979).
Important observations were obtained in patients with intractable pain.
cerebrospinal fluid of the third ventricle (Akil et al., 1978a & b; Hosobuchi et al.,
1979). It is possib1e that this type ofstimulation activates the part ofthe ß-endorphin
system that originates in the arcuate region of the hypothalamus. Nothing is known
about the physiological conditions which may lead to the activation ofthe system but
it is an attractive speculation that it might be brought into operation in situations of
extreme stress together with the well-known frght-and-flight response ofthe pituitaryadrenal axis.
The well-known euphoric effects of opiates and the occurrence of enkephalins in the
limbic system suggest the possibility that the opioid peptides are involved in
regulating emotion, mood and associated behaviours. In experiments in which rats
self-administered opioids, they ehose Leu-enkephalin more frequently than either
Met-enkephalin or morphine (Belluzzi & Stein, 1977). It is suggested that such a
putative role ofthe endogenous opioid peptides may be based on an interaetion with
noradrenergic neurones (Stein & Belluzzi, 1979). In rhesus monkey, D-Ala2-MePhe4-
Contro/ 0/neuroendocrine mechanisms
The literature on this important subjeet is now very 1arge. There is general agreement
that enkephalins and various enkephalin analogues and p-endorphin, as weil as
rnorphine, cause increased release of prolactin and growth hormone and that these
increases are inhibited by opiate antagonists (Cusan, Dupont, Kledzik, Labrie, Coy &
Schally, 1977; Rivier, Vale, Ling, Brown & Guillemin, 1977; Shaar, Frederickson,
Dininger & Jackson, 1977). The efTects ofthe opiate antagonists are not quite so clear.
In particular, a reduction of prolactin and growth hormone levels in plasma by
naloxone does not seem to occur in man (Janowsky, Judd, Huey, Roitman & Parker,
1979; Martin, Tolis, Woods & Guyda, 1979). The evidence available at present
indicates that the release of both growth hormone and prolactin by opiates and
opioid peptides is not due to a direct action on the pituitary (Rivier et a!., 1977; Shaar
et a!., 1977) but to an inhibition of dopaminergic inhibitory mechanisms in the
mediobasal hypothalamus since dopamine, but not naltrexone, reduces the release of
prolactin from pituitary halves in vitro. When the dopamine receptors are blocked by
haloperidol, serum prolactin levels are increased and this increase is not prevented by
naltrexone (Grandison & Guidotti, 1977; Guidotti & Grandison, 1978). The
depressant efTect of dopamine on the secretion of prolactin from pituitary halves is
blocked by naloxone (Enjalbert, Ruberg, Arancia, Priam & Kordon, 1979),
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