Neurobiology of Opioids

452 Pages·1991·12.907 MB·English

by  H. W. Kosterlitz (auth.), Dr. Osborne F. X. Almeida, Dr. Toni S. Shippenberg (eds.)

O.F.X. Almeida T.S. Shippenberg (Eds.)
Neurobiology
ofOpioids
with 57 Figures and 23 Tables
Foreword by A. Goldstein
Springer-Verlag
Berlin Heidelberg New York
London Paris Tokyo
Hong Kong Barcelona
Budapest
Dr. Osborne F.x. Almeida
Department of Neuroendocrinology
Max Planck Institute for Psychiatry
KraepelinstraBe 2
D-8000 Miinchen 40
FRG
Dr. Toni S. Shippenb erg
Department of Neuropharmacology
Max Planck Institute for Psychiatry
D-8033 Martinsried
FRG
Cover photograph:
Immunocytochemical demonstration of opioid receptors on neuroblastoma x glioma cells (NG
108-15 cell line), using an anti-idiotypic antibody against opioid receptors (courtesy of A.H.S.
Hassan and O.F.x. Almeida). See Neuroscience, 1989,32: 269-278, for details.
ISBN-13: 978-3-642-46662-5 e-ISBN-13: 978-3-642-46660-1
DOl: 10.1007/978-3-642-46660-1
Library of Congress Cataloging.in.Publication Data
Neurobiology of opioids/O. Almeida, T. Shippenberg, (eds.). p. cm. Includes bibliographical
references. Includes index.
ISBN-13: 978-3-642-46662-5 I. Endorphins-Congresses.
I. Almeida, O. (Osborne), 1954- . II. Shippenberg, T. (Toni), 1957- . [DNLM: I.
Endorphins-physiology. 2. Neurobiology. 3. Receptors, Endorphin-physiology. QU 68 N4935 1989)
QP552.E53N484 1990 612.8'22-dc20 DNLM/DLC
This work is subject to copyright. All rights are reserved, whether the whole or part of the material
is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,
broadcasting, reproduction on microfilms or in other ways, and storage in data banks. Duplication
oft his publication or parts thereof is only permitted under the provisions oft he German Copyright
Law ofS eptember 9, 1965, in its current version, and a copyright fee must always be paid. Violations
fall under the prosecution act of the German Copyright Law.
© Springer-Verlag Berlin Heidelberg 1991
Softcover reprint of the hardcover 1s t edition 1991
The use ofg eneral descriptive names, registered names, trademarks, etc. in the publication does not
imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
Product Liability: The publisher can give no guarantee for information about drug dosage and
application thereof contained in this book. In every individual case the respective user must check
its accuracy by consulting other pharmaceutical literature.
Typesetting: International Typesetters, Inc., Manila, Philippine~
31/3145-543210 Printed on acid-free paper
Foreword
It is a singular honor to have been asked to write the Foreword to this volume, which
largely consists of the papers presented at the symposium held 2-5 July 1989 at
Ringberg, Federal Republic of Germany, to honor the retirement of our colleague
Albert Herz. I have known Professor Herz for 20 years in his several roles -leading
investigator in the field of opioids, distinguished department head at the basic
science unit of the Max-Planck Institute for Psychiatry at Martinsried, one-time host
and current Secretary of the International Narcotics Research Conference, member
of the Deutsche Akademie der Naturforscher Leopoldina, recipient (1988) of the
prestigious Nathan B. Eddy Memorial Award of the Committee on Problems of
Drug Dependence. Our relations have been sometimes those of friendly collabo
rators and sometimes those offriendly competitors. The field of opioid research has
been an example - in contrast to some other fields - of how, even in a fast-moving
and highly competitive area, friendly collegial relations and mutual respect can be
maintained. Albert Herz exemplifies this quality.
One who writes a Foreword has usually had the opportunity to read the book, so
that the prefatory remarks can be germane and, at least, not contradictory to some
major theme expounded in the main text. Not having seen anything but a Table of
Contents puts me at a distinct disadvantage. But there is this offsetting advantage -
I can stand back and comment on the state of the field and the contributions of the
Herz group to it without the complication ofh aving critically to dissect the individual
chapters. I have watched the field of opioid research develop, and have been
fortunate enough to be a part of that development over a long enough time to have
gained some perspetive. I present these remarks, therefore, not as a scientific review,
but simply as the personal opinions that they are.
First, let me explain a matter of style. I hold the view that the scientific leader of
a research group is responsible (i.e., gets both the credit and the blame) for the
scientific accomplishments of the group. Therefore - and especially since this
volume is a testimonial to that leader - I mention no one else by name, even though
a large number of younger scientists have been associated with (and often have been
the key figures in) the research described here. A number of them are authors of
cha pters in this book, and the names of some others appear in the selected cita tions
I have provided to aid readers who are unfamiliar with the field. The comprehensive
textbook on the opioids (Herz 1978), written as a collective effort of the group, offers
an excellent view of the state of the field and the composition of the Martinsried
department a dozen or so years ago.
VI Foreword
I served as chairman of the international Scientific Advisory Board (Fachbeirat)
that site-visited the basic science departments of the Max-Planck Institute for
Psychiatry in 1986 and 1988. That experience confirmed what I knew already from
the literature, namely, the scientific stature of Professor Herz's Department of
Neuropharmacology on the international scene. After each visit, and based on our
study of the scientific progress reports, we agreed unanimously - and so informed
the president of the Max-Planck Society - that this department's work in the field
ofo pioids was not only ofworld-c1ass quality but actually ranked among the very few
most productive groups anywhere. Let me begin, then, with a straightforward
quantitative analysis of this productivity and then furnish a brief qualitative
assessment.
Figure 1 shows the number of papers published by the Herz group in each of the
past 20 years. There are two reasons why I chose this period oftime for analysis. First,
two decades is a convenient, round number, approximately the second half of the
scientific life of someone who has just reached retirement age. Second, the year 1969
was just about when Herz shifted his interests seriously from other neurophar
macologic problems to the opioids.
A comment is in order concerning the impressive numbers here. The total of36l
publications - the majority, incidentally, in refereed journals of recognized high
quality - does not in itself speak for the significance of the work. Indeed, we tend
nowadays to look with some suspicion on "too big" a list of publications. This list,
however, represents the efforts of a large and extremely talented group, operating
(despite turnover) at a consistently high level of scientific activity. An uninformed
reader might suspect that the old European system (not unknown in some American
institutions) was operating here, whereby the professor routinely appends his name
to every paper, without being truly responsible for the work. But every knowl
edgeable scientist in our field knows of Albert Herz's intimate involvement in the
planning and interpretation of experiments, his talent for recruiting the outstanding
younger scientists who produced the data, and his ability to expound and defend all
aspects of the work of his group.
50
Herz group
40
1969-1988
..!..I..I 30
a.
a0 .
'0 20
0
z
10
O~~~~~~~~~~~~~~~~~~
68697071727374757677787980818283848586878889 Fig. 1. Number of papers pub
lished by the Herz group
Yeor between 1969-1988
Foreword VII
Figure 1 is also an eloquent commentary on the practice of forced retirement at
any age, but especially at the early age of67, when many biological scientists are in
the prime of productive life. The figure speaks so well for itself in this regard that no
more need be said about this mindlessly rigid and foolish policy!
In Table 1 I break down the scientific productivity by subject area. Naturally, this
involved some arbitrary judgments on my part as to how a particular paper was to
be classified, especially when it pertained to more than a single category.
Nevertheless, one can see a kind of ontogenesis of a career in opioid research here.
It begins with studies on the sites of action of morphine and other opiates, especially
in relation to antinociception, and with a heavy emphasis on catecholamines and on
tolerance and physical dependence. Then comes the end of 1975 and beginning of
1976, and the discovery of the enkephalins and fJ-endorphin. The Herz group
jumped in at once, and already in 1976 published several papers on the endogenous
opioid peptides (Blasig and Herz 1976; Schulz and Herz 1976; Zieglgansberger et al.
1976).
Dynorphin comes onto the scene in 1979, and the Herz group - well positioned
now for peptide research - immediately (beginning with Wiister et al. 1980)
becomes a foremost contributor. Then, beginning in 1981 (see below) the group gives
increasing attention to two areas of wider scope: interrelationships of opioid
peptides with other endocrine systems and motivational properties of opioids. It
would be interesting to know more about what factors determined their decision to
undertake these new and very important research problems.
Enough about the numbers. What has always struck me about the work of the
Herz group is the originality and broad impact of their discoveries. Obviously, every
scientist would choose differently in assessing which were the most important
contributions; these are my own subjective judgments.
Twenty years ago it was unclear where morphine and other opiates acted to
produce their antinociceptive effects. The differentiation between spinal and supra
spinal sites was especially unclear. As the receptors had not yet been identified,
sites of action had to be localized by direct pharmacologic means - injecting at local
sites and assaying the effects. Herz devised ingenious ways to confine microinjections
of morphine to discrete regions of the central core of the brains tern (Herz et al. 1968,
1970). These early studies focused attention on the ventricular system, especially the
floor of the fourth ventricle and the periaqueductal gray (PAG) as key sites (though
by no means the only ones) of the antinociceptive actions of morphine. This work
may have stimulated Liebeskind's experiments showing that analgesia could be
produced by electrical stimulation in the PAG. Those, in tum, led to AkiI's discovery
(in Liebeskind's laboratory) that the effect of such stimulation could be blocked by
naloxone, a result that foreshadowed the discovery of the endogenous opioids.
Before the opioid receptor types (p., 8, K, e) had been well characterized, and
without sufficiently type-selective opioid ligands available, most investigators
regarded tolerance as a generalized reaction to chronic administration ofa ny opioid.
It was therefore not regarded as surprising that opioid peptides should produce
tolerance and dependence themselves, as well as cross-tolerance and cross-depen
dence to morphine; indeed, the Herz group was among the first to demonstrate
that (Blasig and Herz 1976; Schulz and Herz 1976). The subsequent discovery of
9 "r1 0 ~ :Ii 0 a
al
Tot 28 19 62 24 53 14 35 24 30 20 4 24 24 361
8
198 I 6 2 2 3 I 2 I 4 22
1987 4 2 5 3 2 7 3 2 3 31 ptides; bution, pioids;
1980 1981 1982 1983 1984 1985 1986 1 2 2 3 2 4 2 6 5 I 2 3 3 4 2 5 7 2 6 3 5 6 5 2 2 4 3 6 9 2 2 2 2 2 2 2 2 6 5 6 4 2 3 I 5 2 3 3 I 1 2 3 2 2 2 1 I 4 2 I 42 21 30 26 17 25 28 dependence, addiction; D localization of opioid peansduction; G opioid receptors, regulation, distrins, pathophysiology; J motivational properties of oher neuropharmacology, not opioid.
Table 1. Herz group: analysis of productivity 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 Year: CategorY' 4 2 2 5 4 2 2 3 A B I I I 9 14 4 2 3 2 7 C 2 1 D I 4 3 E I 1 F 3 G H 1 2 4 J K 2 2 2 3 L 4 2 2 M 7 12 7 20 14 15 24 7 2 4 7 Total • A Opioid sites of ction, relation to biogenic amines; B antinociception; C opioid tolerance, E expression and release of opioid peptides; F opioid receptors, properties, and signal trbinding; H opioids and other hormones, endocrine interrelatioships; I opioid peptide functioK antibodies to opioids and opioid receptors; L opioids: general, theoretical, reviews; M ot
Foreword IX
selective tolerance was therefore unexpected. It was found (Schulz et al. 1980) that
a tissue preparation like the mouse vas deferens could be treated chronically (in vivo
by means of an osmotic minipump) with a type-selective opioid agonist and thereby
made selectively tolerant to agonists of that receptor type.
The phenomenon of selective tolerance was found to apply quite generally, both
in brain and in peripheral tissues, and more dramatically as more selective ligands
came to hand. It was employed to confirm that there is a receptor type,e, thatis highly
selective for p-endorphin. The presence of such a receptor in rat vas deferens,
previously reported, was confirmed; and it was demonstrated that a tissue made
tolerant to other opioid agonists remained sensitive to p-endorphin (Schulz et al.
1981 ).
The Herz group raised the first monoclonal anti-idiotypic antibodies that would
recognize opioid receptors (Gramsch et al. 1988). An antibody was first raised
against an opioid pharmacophore. In this case the known structure-activity relations
among the various opioid pep tides led to the rational decisions to use p-endorphin
as hapten, and then to select a monoclonal antibody that would recognize the
essential N-terminal YGGF sequence, shared by all three families of opioid
peptides. Then a monoclonal anti-idiotypic antibody was raised against this primary
(idiotypic) antibody. Consistent with the way immunoglobin hypervariable regions
are thought to fit the three-dimensional shapes of antigens, the anti-idiotypic
antibody did, indeed, behave as though it were the "internal image" of the idiotypic
binding site; it mimicked opioid ligands in interacting with the binding site of opioid
receptors.
The studies on the motivational properties of opioids have truly opened new
prospects for understanding "reward systems" in the brain. I have long been puzzled
by a curious fact concerning the historical development of opioid research. From
early times a strong impetus was the desire to understand opiate addiction. The
central point about drug addiction is that people - some people, at least - seek out
certain drugs and self-administer them. Tolerance and physical dependence, al
though they are fascinating neuropharmacological phenomena, are consequences,
not causes, of opiate addiction. But nevertheless, studies on self-administration and
on other ways of directly studying opioid primary reinforcement (reward) lagged far
behind research on tolerance and physical dependence. Until relatively recently
they remained entirely in the domain of experimental behavioral psychology,
unconnected with neuroanatomy or neurochemistry. This is not the place to analyze
the scientific, sociologic, and psychologic reasons for this strange imbalance in
opioid research. Suffice it to say that - belated though it may have been - when the
Herz group turned their attention to this area, they struck gold.
One of the central questions about the opioid receptor types is whether their
functions are highly differentiated, or whether they serve largely redundant pur
poses. Herz found that whereas fL-receptors mediate positive reinforcement, ac
tivation of K-receptors is clearly aversive. This has been established not only in the
hard data of animal experiments using the conditioned place preference technique
(Mucha and Herz 1985), but even in human experiments in which Albert Herz
himself was one of the volunteer subjects (Pfeiffer et al. 1986). Here, the demon
strated psychotomimetic effects of a K-agonist were shown to be stereospecific and
X Foreword
to be abolished by naloxone, two important properties essential to the definition of
an opioid effect.
The group's studies on a possible role of endogenous opioid dysfunction in
psychosis, through therapeutic trials with naloxone (Emrich et al. 1977), suggested
- in accord with many similar studies by others - that sometimes, in some
patients, to some degree, some endogenous opioids may play some role. Not a
very illuminating conclusion, that, and deja vu for those of us old enough to have
lived through the biogenic amine hypotheses. It is a reminder of how complex the
chemical pathology is, of such multifaceted "diseases" as schizophrenia or bipolar
depression. There must be hundreds of different genetic-biochemical ways to go
crazy! However, the evidence of "aversion systems" that counteract "reward sys
tems" (both systems, perhaps, tonically active to maintain a delicate balance) strikes
me as of seminal importance in modifying our thinking about the chemical
regulation of behavior.
The group's work over the years on the endogenous opioid peptides and their
receptors has been extraordinarily productive. They discovered amidorphin
(Liebisch et al. 1985), a previously unknown product of the enkephalin gene, which
is amidated at its C-terminus. They discovered opioid activity in fragments of
cytochrome (Brantl et al. 1985) and hemoglobin (Brantl et al. 1986); these are
interesting as examples of sequences other than YGGF (here, YPWT and YPFT)
with affinity for opioid receptors. Analogous discoveries in other laboratories
include the casomorphins (and morphiceptin), a-gliadin, dermorphin, and
Erspamer's recently discovered deltorphins.
At this writing none of the opioid receptors have yet been cloned and sequenced,
but the Herz group has been in the forefront of the attempt to understand their
physical properties. Those investigations employed target size techniques to es
timate molecular size (Ott et al. 1986) and, over many years, have sought to clarify
the signal transduction mechanisms that operate through G-protein and adenylate
cyclase interactions (Costa et al. 1988).
Sometimes advances in our knowledge come not from startlingly novel dis
coveries but from years of patient effort to understand complexity. In this category
I would put the numerous contributions of the Herz group to a field in which I have
a special fatherly interest - the dynorphin pep tides, their distribution, regulation,
and physiologic functions (e.g., Przewlocki et al. 1983; H611t et al. 1987). This
research was part of a broad effort to understand how the various opioid peptides
regulate the transcription and secretion of other hormones, and reciprocally, how
other hormones regulate the opioid peptides (Pfeiffer and Herz 1984).
Let me say, in conclusion, something that is suggested by the undiminished
vigorous activity depicted in Fig. I. I am sure I express the feelings of all opioid
researchers in hoping that Albert Herz's influence on the field of opioid research, to
which many of the papers in this volume bear witness, will in some manner be able
to continue for many years to come.
Stanford, California, USA A vram Goldstein
Foreword XI
References
Blasig J, Herz A (1976) Tolerance and dependence induced by morphine-like pituitary peptides in rats.
Naunyn-Schmiedeberg's Arch PharmacoI294:297-300
Brantl V, Gramsch C, Lottspeich F, Henschen A, Jaeger KH, Herz A (1985) Novel opioid peptides
derived from mitochondrial cytochrome b: cytochrophins. Eur J Pharmacol III :293-294
Brantl V, Gramsch C, Lottspeich F, Mertz R, Jaeger KH, Herz A (1986) Novel opioid peptides derived
from hemoglobin: hemorphins. Eur J Pharmacol 125:309-310
Costa T, Klinz F J, Vachon L, Herz A (1988) Opioid receptors are coupled tightly to G proteins but loosely
to adenylate cyclase in NG-108-15 cell membranes. Mol PharmacoI34:744-754
Emrich HM, Cording C, Piree S, Kolling A, von Zerssen D, Herz A (1977) Indication of an antipsychotic
action of the opiate antagonist naloxone. Pharmakopsychiatr NeuropsychopharmakollO:265-270
Gramsch C, Schulz R, Kosin S, Herz A (1988) Monoclonal anti-idiotypic antibodies to opioid receptors.
J BioI Chern 263:5853-5859
Herz A (ed) (1978) Developments in opiate research. Marcel Dekker, New York
Herz A, Metys J, SchondorfN, Hoppe S (1968) Uber den Angriffspunkt der analgetischen Wirkung von
Morphin. Naunyn-Schmiedeberg's Arch Pharmacol260: 143
Herz A, Albus K, Metys J, Schubert P, Teschemacher H (1970) On the central sites for the anti nociceptive
action of morphine and fegtanyl. Neuropharmacology 9:539-551
Hallt V, Haarman I, Millan MJ, HerzA (1987) Prodynorhin gene expression is enhanced in the spinal cord
of chronic arthritic rats. Neurosci Lett 73 :90-94
Liebisch DC, Seizinger BR, Michael G, Herz A (1985) Novel opioid peptide amidorphin: charac
terization and distribution of amidorphin-like immunoreactivity in bovine, ovine, and porcine brain,
pituitary, and adrenal medulla. J Neurochem 45:1495-1503
Mucha RF, Herz A (1985) Motivational properties of kappa and mu opioid receptor agonists studied with
place and taste preference conditioning. Psychopharmacology 86:281-285
Ott S, Costa T, Wiister M, Hietel B, Herz A (1986) Target size analysis of opioid receptors. No difference
between receptor types, but discrimination between two receptor states. Eur J Biochem 155:621-630
Pfeiffer A, Herz A (1984) Endocrine actions of opioids. Horm Metab Res 16:386-397
Pfeiffer A, Brantl V, Herz A, Emrich HM (1986) Psychotomimesis mediated by kappa opiate receptors.
Science 233:774-776
Przewlocki R, Lason W, Konecka AM, Gramsch C, Herz A (1983) The opioid peptide dynorphin,
circadian rhythms, and starvation. Science 219:71-73
Schulz R, Herz A (1976) Dependence liability of enkephalin in the myenteric plexus of the guinea pig.
Eur J PharmacoI39:429-432
Schulz R, Wiister M, Krenss H, Herz A (\ 980) Selective development of tolerance without dependence
in multiple opiate receptors of mouse vas deferens. Nature 285 :242-243
Schulz R, Wiister M, Herz A (1981) Pharmacological characterization of the epsilon-opiate receptor. J
Pharmacol Exp Ther 216:604-606
Wiister M, Schulz R, Herz A (1980) Highly specific opiate receptors for dynorphin-(l-13) in the mouse
vas deferens. Eur J PharmacoI62:235-236
Zieglgansberger W, Fry JP, Herz A, Moroder L, Wunsch E (1976) Enkephalin-induced inhibition of
cortical neurones and the lack of this effect in morphine tolerant/dependent rats. Brain Res
115:160-164