Towards The Neurobiology of Chronic Pain

270 Pages·1996·12.024 MB·iii-ix, 3-278\270

by  G. Carli and M. Zimmermann (Eds.)

PROGRESS IN BRAIN RESEARCH
VOLUME 110
TOWARDS THE NEUROBIOLOGY
OF CHRONIC PAIN
EDITED BY
G. CARL1
Institute of Human Physiology, University of Siena, Siena, Italy
M. ZIMMERMANN
I1 Institute of Physiology, University of Heidelberg, Heidelberg, Germany
ELSEVIER
AMSTERDAM - LAUSANNE -NEW YORK - OXFORD - SHANNON -TOKYO
1996
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V
List of Contributors
A.M. Aloisi, Istituto di Fisiologia Umana, Universita degli Studi di Siena, Via Aldo Moro, I-
53100 Siena, Italy
A. Berthele, Max-Planck-Institute of Psychiatry, Clinical Institute, Clinical Neuropharmacology,
Kraepelinstrasse 2,80804 Munich, Germany
G. Carli, Istituto di Fisiologia Umana, Universita’ degli Studi di Siena, Via Aldo Moro, I-
53100 Siena, Italy
E. Carstens, Section of Neurobiology, Physiology and Behavior, University of California, Davis,
CA 95616 USA
M. Cavazzuti, Dipartimento di Patologia Neuropsicosensoriale, University of Modena, Via del
Pozzo 71,I-41100 Modena, Italy
F. Cervero, Departamento de Fisiologia y Farmacologia, Universidad de AlcalB de Henares,
Facultad de Medicina, Campus Universitario, AlcalB de Henares, 2887 1 Madrid, Spain
C.R. Chapman, Department of Anesthesiology, RN- 10, University of Washington, Seattle, WA
98195, USA
A.H. Dickenson, Department of Pharmacology, University College, Gower Street, London,
WClE 6BT, UK
A. Dray, Sandoz Institute for Medical Research, 5 Gower Place, London WClE 5BN, UK
A.W. Duggan, Department of Preclinical Veterinary Sciences, Royal (Dick) School of Veterinary
Studies, University of Edinburgh, Summerhall, Edinburgh EH9 IQH, UK
C. Dykstra, Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USA
G.F. Gebhart, Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USA
T. Herdegen, 11. Physiologisches Institut, Universtat Heidelberg. Im Neuenheimer Feld 326, D-
69120 Heidelberg, Germany
A. Herz, Max-Planck-Institute for Psychiatry, Department of Neuropharmacology, Am Klopfer-
spitz 18a, D-82151 Martinsried, Germany
U. Hoheisel, Institut fur Anatomie und Zellbiologie, Im Neuenheimer Feld 307, D-69120 Hei-
delberg, Germany
J.M.A. Laird, Departamento de Fisiologia y Farmacologia, Universidad de Alcall de Henares,
Facultad de Medicina, Campus Universitario, Alcall de Henares, 2887 1 Madrid, Spain
R.H. LaMotte, Department of Anesthesiology, Yale University School of Medicine, New Haven,
CT 065 10, USA
S.T. Meller, Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USA
S. Mense, Institut fur Anatomie und Zellbiologie, Im Neuenheimer Feld 307, D-69120 Heidel-
berg, Germany
M. Petersen, Department of Physiology, University of Wurzburg, Wurzburg, Germany
C.A. Porro, Dipartimento di Scienze Biomediche, University of Udine, Via Gervasutta 48, I-
33100 Udine, Italy
H. Rees, 67 Nant Talwg Way, Barry, South Glamorgan, CF62 6LZ, UK
A. Reinert, Institut fur Anatomie und Zellbiologie, Im Neuenheimer Feld 307, D-69120 Heidel-
berg, Germany
vi
R.C. Riley, Department of Preclinical Veterinary Sciences, Royal (Dick) School of Veterinary
Studies, University of Edinburgh, Summerhall, Edinburgh EH9 lQH, UK
J. Sandkiihler, II. Physiologisches Institut, Ruprecht-Karls-Universitat Heidelberg, Im Neuen-
heimer Feld 326, D-69120 Heidelberg, Germany
J. Schadrack, Max-Planck-Institute of Psychiatry, Clinical Institute, Clinical Neuropharmacol-
ogy, Kraepelinstrasse 2, 80804 Munich, Germany
H.-G. Schaible, Physiologisches Institut, Universitat Wiirzburg, RBntgenring 9, D-97070 Wiir-
zburg, Germany
R.F. Schmidt, Physiologisches Institut, Universitat Wiirzburg, RBntgenring 9, D-97070 Wiir-
zburg, Germany
K.A. Sluka, 2600 Steindler Building, Iowa City, IA 52242, USA
T.R. TBlle, Max-Planck-Institute of Psychiatry, Clinical Institute, Clinical Neuropharmacology,
Kraepelinstrasse 2, 80804 Munich, Germany
K.N. Westlund, Marine Biomedical Institute, 301 University Boulevard, Medical Research
Building, Galveston, TX 77555- 1069, USA
Z. Wiesenfeld-Hallin, Karolinska Institute, Department of Medical Laboratory Sciences and
Technology, Section of Clinical Neurophysiology, Huddinge University Hospital, Sweden
W.D. Willis, Marine Biomedical Institute, 301 University Boulevard, Medical Research
Building, Galveston, TX 77555-1069, USA
X.-J. Xu, Karolinska Institute, Department of Medical Laboratory Sciences and Technology,
Section of Clinical Neurophysiology, Huddinge University Hospital, Sweden
J.-m. Zhang, Department of Anesthesiology, Yale University School of Medicine, New Haven,
CT 065 10, USA
W. Zieglgansberger, Max-Planck-Institute of Psychiatry, Clinical Institute, Clinical Neurophar-
macology, Kraepelinstrasse 2,80804 Munich, Germany
M. Zimmermann, II. Physiologisches Institut, Universtat Heidelberg, Im Neuenheimer Feld 326,
D-69 120 Heidelberg, Germany
vii
Preface
Pain research in the past was mostly related to the sensory aspects of acute experi-
mental noxious stimuli in animals and humans and the clinical reality was not suffi-
ciently taken into account. One of the main goals of the foundation of the Interna-
tional Association for the Study of Pain in 1973 was to concentrate the attention of
the scientific community on chronic conditions which elicit enduring suffering and
pain in patients.
The last few years have witnessed a major change in paradigms related to pain.
With the development of a variety of animal models, it is now possible to focus on
slow changes in the nervous system, at systemic, cellular, biochemical, molecular
and genetic levels that occur in response to noxious events such as trauma, inflam-
mation or nervous system lesions. It has become clear that plasticity of neural func-
tions is a common denominator of what is seen following a noxious condition, and
the end point is the increased sensitivity of the nervous system towards pain. This
plasticicty of function bears similarities to the neurobiological mechnaisms of learn-
ing and therefore we may see the ability to learn as a basic nervous system process
involved in the chronicity of pain. Since in some patients the process of pain
chronicity is going on with a progressive severity of the process and with a decreased
efficacy of therapy, the prevention and the early treatment of chronic pain represent
the new tasks to be set out in clinical medicine.
It was, therefore, with the aim of providing a well-balanced review of activity-
dependent modifications of synaptic efficacy which follow noxious events that the
symposium “Towards the Neurobiology of Chronic Pain” was organized in Siena, at
the Certosa di Pontignano. The title of the book was selected hoping that it will con-
tribute to the continuing interest in understanding pain reinforcement by the brain.
This emerging new concept in turn can be expected to have a great impact on the
development of clinical paradigms of pain prevention and rehabilitation.
G.C arli and M. Zimmermann
1996
ix
Acknowledgements
The conference “Towards the Neurobiology of Chronic Pain”, which was organized
in Siena, Certosa di Pontignano, on March 4-5, 1994, was made possible by the fi-
nancial support of Bayer AG, Leverkusen; Formenti, Milan; Goedecke AG,
Freiburg; Gruenenthal GmbH, Stolberg; Mundipharma GmbH, Limburg; Deutsche
Gesellschaft zum Studium des Schmerzes and Universith degli Studi di Siena. We
are greatly indebted to the Servizio VI Convegni and Congressi della Universith di
Siena, to the members of the Istituto de Fisiologia Umana della Universith di Siena
and particularly to Dott. Anna Maria Aloisi for taking care of the innumerable organ-
izational details without which neither the conference nor the publication of its Pro-
ceeding would have been possible. The editorial expertise of Almuth Manisali in
helping to edit this volume is gratefully acknowledged.
The Editors
G. Cadi and M. Zimrnermann (Eds.)
Progress in Brain Research, Vol. 110
0 1996 Elsevier Science B.V. All rights reserved
CHAPTER I
From acute to chronic pain: mechanisms and hypotheses
Fernando Cervero and Jennifer M.A. Laird
Departamento de Fisiologia y Farmacologia, Universidad de Alcald de Henares, Facultad de Medicina, Campus Universitario,
Alcala de Henares, 28871 Madrid, Spain
Introduction peripheral neuropathies and central pain states
(Fig. 1). However, it is important to point out that
Some years ago we proposed a conceptual frame- these phases are not exclusive, and that at any
work and a series of models that addressed the given time several of the neurophysiological
mechanisms of both acute and chronic pain and the mechanisms that underlie these pain states may co-
inter-relation between different pain states exist in the same individual.
(Cervero and Laird, 1991a). We argued that the We believe that the basic framework is still
neurophysiological mechanisms responsible for all valid and useful, but we would like to consider in
of the various pain states are different and that this chapter a number of points which were not
normal (nociceptive) and abnormal (neuropathic) covered sufficiently in our original article or that
pain represent the end-points of a sequence of pos- need to be modified due to new experimental evi-
sible changes that can occur in the nervous system. dence obtained in the last 5 years.
Normally, a steady state is maintained in which
there is a close correlation between injury and Phase 1 pain
pain. However, changes or oscillations induced by
nociceptive input or by changes in the environment The mechanisms subserving the processing of
can result in variations in the quality and quantity brief noxious stimuli (Phase 1 pain) can be viewed
of pain sensation produced by a particular noxious as a fairly simple and direct route of transmission
stimulus. Such changes would be temporary, un- centrally towards the thalamus and cortex and thus
less there was further noxious input, as the system the conscious perception of pain, with possibilities
would always tend to restore the normal balance for modulation occurring at synaptic relays along
between injury and pain. However, long-lasting or the way (see Phase 1 model in Fig. 1). The relative
very intense nociceptive input or the removal of a simplicity of this model reflects the experimental
portion of the normal input would distort the no- observation that in humans undergoing Phase 1
ciceptive system to such an extent that the close pain, there is a close correlation between the dis-
correlation between injury and pain would be lost. charges in peripheral nociceptors and the subjec-
We considered three major stages or phases of tive expression of pain. Phase 1 pain is the type
pain and proposed that different neurophysiologi- which has been most studied experimentally, and
cal mechanisms are involved depending on the on the basis of the large body of data from both
nature and time course of the originating stimulus. humans and animals, it is reasonably easy to con-
These three phases are: (1) the processing of a struct plausible and detailed neuronal circuits to
brief noxious stimulus; (2) the consequences of explain the features of Phase 1 pain. In our original
prolonged noxious stimulation leading to tissue proposal we suggested that Phase 1 pain can best
damage and peripheral inflammation; and (3) the be explained by models based on the specificity
consequences of neurological damage, including interpretation of pain mechanisms, that is, the exis-
4
Fig. 1. Three models of pain processing for the three phases of pain discussed in this chapter. For a detailed explanation see text.
From Cervero and Laird (1991a).
tence within the peripheral and central nervous ify their responsiveness in ways that are not
systems of a series of neuronal elements concerned merely an expression of the changes in their inputs
solely with the processing of these simple noxious from the periphery. These changes mean that the
events. This viewpoint remains unchanged. CNS has moved to a new, more excitable state as a
result of the noxious input generated by tissue in-
Phase 2 pain jury and inflammation. Phase 2 pain is character-
ised by its central drive, a drive that is triggered
The situation changes to what we have called and maintained by peripheral inputs (see Phase 2
Phase 2 pain if a noxious stimulus is very intense, model in Fig. 1).
or prolonged leading to tissue damage and in- In Phase 2 pain, the subject experiences sponta-
flammation. The pain state under these conditions neous pain, a change in the sensations evoked by
is different from that in Phase 1 pain, because the stimulation of the injured area, and also of the un-
response properties of various components of the damaged areas surrounding the injury. This change
nociceptive system change. There is a greatly in- in evoked sensation is known as hyperalgesia, de-
creased afferent inflow to the CNS from the in- fined as a leftward shift in the stimulus-response
jured area as a result of the increased activity and function describing the relationship between stim-
responsiveness of sensitised nociceptors. In addi- uli and pain sensation (Fig. 2, Treede et al., 1992).
tion, nociceptive neurones in the spinal cord mod- In this situation, normally innocuous stimuli like
5
of continuous nociceptive input to the CNS, and
thus spontaneous pain, depending on the site of
injury. For example, the available evidence on the
properties of visceral nociceptors indicates that a
variety of noxious stimuli, evoke not only an acute
excitation of the nociceptors, but also cause pro-
longed sensitisation of both the “normal” and the
“silent” nociceptors (see Cervero, 1994 for re-
view). In the sensitised state, visceral nociceptors
respond to many of the innocuous stimuli that oc-
cur during the normal functioning of internal or-
gans. As a consequence, after inflammation of an
internal organ, the CNS will receive an increased
Fig. 2. Diagram illustrating the changes in pain sensation
barrage from peripheral nociceptors that is related
induced by injury. The normal relationship between stimulus
initially to the extent of the acute injury, but for the
intensity and the magnitude 01 pain sensation is represented
by the curve at the right-hand side of the figure. Pain sensa- duration of the inflammatory process initiated by
tion is only evoked by stimulus intensities in the noxious the injury, will be dependent on the motor (smooth
range (the vertical dotted line indicates the pain threshold). muscle) and secretory activity of that organ until
Injury provokes hyperalgesia, defined as a leftward shift in
the peripheral sensitisation has completely re-
the curve relating stimulus intensity to pain sensation. Under
solved.
these conditions, innocuous stimuli evoke pain (allodynia),
and stimulus intensities that normally evoke mild pain evoke
more intense pain. Central mechanisms contributing to Phase 2 pain
brushing and touch, are painful (allodynia), and The role of continuing afferent input
normally mild painful stimuli like pinprick, are In normal human subjects, intense experimental
more painful (hyperalgesia; Lewis, 1936; LaMotte pain produced by a bum injury or by chemical
et al., 1991). Hyperalgesia in the area of injury is stimulation of nociceptors with capsaicin changes
known as primary hyperalgesia, and in the areas of the responsiveness of an area of undamaged skin
normal tissue surrounding the injury site, as sec- surrounding the injury site such that normally in-
ondary hyperalgesia. nocuous stimuli like brushing and touch, are pain-
ful (allodynia), and normally mild painful stimuli
Peripheral mechanisms contributing to Phase 2 like pinprick, are more painful (hyperalgesia;
pain Lewis, 1936; LaMotte et al., 1991). This phe-
nomenon of “secondary hyperalgesia” is now
The sensitisation of peripheral nociceptors is known to be due to a central change, induced and
characterised by two main changes in their re- maintained by input from nociceptors, such that
sponse properties. Firstly, the appearance of spon- activity in large myelinated afferents connected to
taneous activity, which will provide a continuous low threshold mechanoreceptors provokes painful
nociceptive afferent barrage which probably con- sensations as well as tactile sensations (Torebjork
tributes to spontaneous pain, and secondly a de- et al., 1992), and input from nociceptors evokes
crease in threshold, to an extent that normally non- enhanced pain sensations (Cervero et al., 1994).
noxious stimuli will activate the sensitised recep- It is becoming increasingly clear from both psy-
tor. This drop in threshold is generally agreed to chophysical and animal studies that the expression
underlie the change in the sensation provoked by of both spontaneous pain and of hyperalgesia are
stimulation of an injured area known as primary very dependent on ongoing afferent activity from
hyperalgesia (Treede et al., 1992). A drop in the injury site. The elegant studies of LaMotte and
threshold may also contribute to the development colleagues (LaMotte et al., 1991; Torebjork et al.,
6
1992) have shown that after the appearance of an 40-
area of secondary hyperalgesia around an intrad-
ermal capsaicin injection in normal human sub-
30-
jects, the secondary hyperalgesia disappears within
seconds if the injection site is cooled with a piece
of ice (a procedure known to block the ongoing
20-
activity in the nociceptors), and re-appears if the
ice is removed as the temperature returns to nor-
mal. Similarly, it has been shown that duration of 10- r = 0.94
secondary hyperalgesia after a bum injury
(D
a L
(Moiniche et al., 1993) or the application of mus-
0 0 50 100 150 200 250 300
tard oil (Koltzenburg et al., 1992) is dependent on
the afferent input from the site of injury. The pres- Activity evoked by heat stimuli
(number of impulses)
ence of allodynia and hyperalgesia in patients with
peripheral neuropathy, a phenomenon very similar Fig. 3. Trigeminal neurones with input from the cornea, of
to and perhaps identical to secondary hyperalgesia which 6 responded only to stimulation of the cornea, and one
can also be abolished by the injection of local an- to stimulation of the cornea and to noxious stimulation of
periorbital skin were recorded in anaesthetised rats. After a
aesthetic into a presumed source of nociceptive
series of noxious heat pulses were applied to the cornea, all
ectopic activity (Gracely et al., 1992). In animal
six neurones that previously only had a corneal receptive field
experiments, the magnitude of the changes seen in
now had an additional periorbital receptive field that re-
neurones at the first relay in the CNS also appears sponded to noxious stimulation, and the neurone that had a
to be directly related to the amount of afferent in- cutaneous receptive field before heating showed an enlarged
put received. For example, in a recent study from receptive field. The graph shows the relationship between the
number of impulses evoked in the seven neurones by heat
this laboratory, the central changes in the excit-
stimuli, and the size of the novel or enlarged cutaneous re-
ability of trigeminal neurones in response to cor-
ceptive field after the heat stimuli. A highly significant corre-
neal injury were examined (Pozo and Cervero, lation between the two variables was found. Re-drawn from
1993). In this study we were able to demonstrate a Pozo and Cervero (1993).
close correlation between the size of the nocicep-
tive afferent barrage and the extent of the increase sal horn C-fibre evoked potentials with a time
in excitability of the cells as measured by the in- course similar to that of long term potentiation has
crease in the size of their receptive fields (Fig. 3). also recently been described (Liu and Sandkuhler,
1995). These increases in central excitability are
Central sensitisation also referred to as “central sensitisation” (Woolf,
Experiments in laboratory animals have pro- 1989; Woolf and Thompson, 1991 ).
vided evidence for the concept that noxious input The description of central sensitisation provided
to the CNS sets off a central process of enhance- the rationale behind the procedure known as “pre-
ment of responsiveness that continues independ- emptive analgesia” (Woolf, 1989; Woolf and
ently of peripheral afferent drive. Short periods of Chong, 1993) whereby the administration of anal-
electrical stimulation at noxious intensity produce gesics andor neural blocks prior to a surgical pro-
increases in excitability with a time course similar cedure would reduce or eliminate postoperative
to that of short term potentiation (from a few sec- pain. The idea was that blocking the initial injury-
onds to tens of minutes) in single dorsal horn neu- induced barrage from arriving at the CNS would
rones (Cervero et al., 1984; Cook et al., 1987), in prevent the development of central sensitisation,
C-fibre evoked potentials recorded in the superfi- and therefore the resulting pain state. The results
cial dorsal horn (Schouenborg, 1984) and in spinal of some preliminary clinical trials were initially
reflexes (Wall and Woolf, 1984; Woolf and encouraging, but more recently many serious
Thompson, 1991). Increases in excitability of dor- doubts have been raised about the clinical efficacy