Table Of ContentThe Neuroscience of
PAIN, STRESS, AND
EMOTION
Psychological and
Clinical Implications
Edited by
MUSTAFA AL’ABSI
University of Minnesota Medical School, Minneapolis, Duluth,
MN,USA
MAGNE ARVE FLATEN
Department of Psychology, Norwegian University of Science
andTechnology, Trondheim,Norway
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CONTRIBUTORS
Mustafa al’Absi
University ofMinnesota MedicalSchool,Minneapolis, Duluth,MN,USA
MartinaAmanzio
Department ofPsychology, University ofTurin,Turin, Piedmont,Italy
Emily J.Bartley
University ofFlorida, PainResearch andIntervention Center ofExcellence, Gainesville,
FL,USA
FabrizioBenedetti
Department ofNeuroscience,University ofTurinMedicalSchool,Turin, Piedmont,
Italy
EmmaE.Biggs
Research GroupHealthPsychology, University ofLeuven, Leuven,Belgium;
Department ofCognitiveNeuroscience, MaastrichtUniversity,Maastricht,
TheNetherlands
TavisS.Campbell
Department ofPsychology, University ofCalgary, Calgary,AB,Canada
BlaineDitto
Department ofPsychology, McGillUniversity,Montreal, QC,Canada
RogerB.Fillingim
University ofFlorida, PainResearch andIntervention Center ofExcellence, Gainesville,
FL,USA
Magne ArveFlaten
Department ofPsychology, Norwegian Universityof Scienceand Technology,
Trondheim,Norway
KristinHorsley
Department ofPsychology, McGillUniversity,Montreal, QC,Canada
MariaHrozanova
Department ofNeuroscience,Norwegian University ofScience andTechnology,
Trondheim,Norway
FrancisJ.Keefe
DukeMedical Center,DukeUniversity,Durham,NC,USA
AnnMeulders
Research GroupHealthPsychology, University ofLeuven, Leuven,Belgium;Center for
Excellence onGeneralizationResearch inHealth andPsychopathology, University of
Leuven, Leuven,Belgium
ix
x Contributors
RobertMurison
Department ofBiologicalandMedical Psychology, UniversityofBergen, Bergen,
Norway
Motohiro Nakajima
Universityof Minnesota MedicalSchool,Minneapolis,Duluth, MN,USA
AkikoOkifuji
Department ofAnesthesiology, Universityof Utah,SaltLakeCity,UT,USA
SaraPalermo
Department ofNeuroscience,University ofTurinMedicalSchool,Turin, Piedmont,
Italy
PaulPauli
Department ofPsychology, BiologicalPsychology, Clinical Psychologyand
Psychotherapy, Universityof Würzburg,Würzburg, Germany
DonaldD.Price
Divisionof Neuroscience,Department ofOralandMaxillofacial Surgery,University of
Florida,Gainesville, FL,USA
JamieL.Rhudy
Department ofPsychology, TheUniversity ofTulsa,Tulsa,OK,USA
ToreC.Stiles
Department ofPsychology, Norwegian Universityof ScienceandTechnology,
Trondheim,Norway
DennisC.Turk
Department ofAnesthesiology, Universityof Washington,Seattle, WA,USA
LeneVase
Department ofPsychologyand Behavioural Sciences,Schoolof Businessand Social
Sciences,AarhusUniversity,Aarhus, Denmark
JohanW.S.Vlaeyen
Research GroupHealthPsychology, University ofLeuven, Leuven,Belgium;Center for
Excellence onGeneralizationResearch inHealthand Psychopathology, University of
Leuven,Leuven, Belgium;Departmentof ClinicalPsychological Science,Maastricht
University,Maastricht, TheNetherlands
MatthiasJ.Wieser
Department ofPsychology, BiologicalPsychology, Clinical Psychologyand
Psychotherapy, Universityof Würzburg,Würzburg, Germany
FOREWORD
In the course of my 35years as a pain researcher and clinician I have had
the opportunity to attend numerous international scientific meetings that
featured plenary talks in which the biopsychosocial model of pain was
discussed. Though many of the presenters were well known and their talks
well organized, all too often I have left these sessions with a feeling of
disappointment. For example, a prominent psychologist might give an
overview of the biopsychosocial model and then spend most of his or her
time talking about studies of the psychology of pain. Likewise, a world-
renowned basic scientist giving a plenary talk might briefly mention the
biopsychosocialmodel,butthenfocushisorhertalkonnovelbasicscience
findingsonthebiologyofpainwithlittleattempttorelatethesefindingsto
psychological or social aspects of pain.
One of the hallmarks of the biopsychosocial model is its insistence that
pain (and other phenomena such as stress) is best understood when bio-
logical, psychological, and social viewpoints are integrated. This book
exemplifies this approach as few others have. It is written by two interna-
tional experts whose own research programs on pain and stress represent a
gold standard against which others are compared. The systematic and pro-
grammatic nature of their work is impressive, with one study building
logically upon another. Dr Magne Flaten, for example, has conducted a
series of important studies on the role of expectations (placebo, nocebo) in
pain and pain regulation. Dr Mustafa al’Absi is widely recognized for his
program of neurobiological research linking pain to stress, appetite, and
addiction.
Inthisbook,DrsFlatenandal’Absihaveassembledasetofwell-written
chaptersprovidedbyauthors,eachofwhomisaworld-classexpertinhisor
her field. Each chapter provides an up-to-date overview of a key topic in
the pain and stress area. Readers will find many of the chapters to be true
gems. To mention a few of these: Robert Mursin provides a superb
overview of the neurobiology of stress. A key message is the importance
that early learning and social status have in the development of stress and
pain-regulation processes. A chapter by Jamie Rhudy critically appraises
recent studies of pain and emotion and highlights emerging findings that
suggest that problems with emotional modulation may be a risk factor for
persistent pain.DrsFlaten andal’Absi’sownchapter on painandplacebois
xi
xii Foreword
one of the best in this book because it brings together state-of-the-art
studies dealing with biological processes (endogenous opioids) and psy-
chological processes (instructions, expectations) that are critical to our
current understanding of placebo effects on pain. This chapter is nicely
complemented by a chapter by Drs Amanzio, Plaermo, and Benedetti on
nocebo and pain. This research team is internationally recognized for the
development of novel methodologies for studying both placebo and
noceboprocessesandlinkingtheseresponsestounderlyingbiochemicaland
anatomical findings. Finally, Blaine Ditto and his colleagues provide an
excellent overview of studies of pain, blood pressure, and hypertension.
ThischapterisoneofthebestI’veseenonthistopicsinceitincludesnovel
insights into how blood pressure-related hypoalgesia can modulate both
pain and stress.
Clinicians working in the areas of pain and stress will find this book
extremely helpful because it provides research that will help them
understand clinical phenomena they deal with every day. For a clinician,
understanding the biological processes by which stress influences pain, or
the neurobiology of stress and addiction in patients suffering from chronic
pain, is important for several reasons. First, it enables the practitioner to
better understand the varied ways that different individuals cope with
persistentpainorstress.Second,itprovidesinformationthatcanbeusedto
educatepatientsinwaysthathelpthemreconceptualizepainandstressand
better understand what they can do to manage problematic responses.
Finally, understanding the current literature on pain and stress can help
clinicians better tailor their interventions so as to best address a given
patient’s concerns.
Researchers interested in pain and stress will find this book to be
invaluable. Each chapter highlights important emerging areas of research
and pinpoints key directions for future research. Those looking to develop
their own research agenda and program of research will want this book in
their personal library.
If you are looking for a book that truly integrates the biological, psy-
chological,andsocialperspectivesonpainandstressIencourageyoutoget
this book. Readers eager to learn about the latest research linking the
different elements of the biopsychosocial model (biological to psycholog-
ical, psychological to social, biological to social) will enjoy this book
immensely. The book exemplifies the best of the biopsychosocial model
and demonstrates how the promise of this model is now being fulfilled.
If you’ve been disappointed by prior plenary talks, review papers, and
Foreword xiii
chaptersonthebiopsychosocialmodelofpainandstressIencourageyouto
give this book a read. This book will not disappoint you. Instead, it will
enlighten, energize, and excite you.
Francis J. Keefe, PhD
Professor, Psychiatry and Behavioral Sciences, Duke Medical Center
Professor of Psychology and Neuroscience, Duke University
CHAPTER 1
Neuroscience of Pain and
Emotion
Matthias J. Wieser, Paul Pauli
DepartmentofPsychology,BiologicalPsychology,ClinicalPsychologyandPsychotherapy,
UniversityofWürzburg,Würzburg,Germany
NEUROANATOMY OF PAIN AND EMOTION
The International Association for the Study of Pain defines pain as an
“unpleasant sensory and emotional experience associated with actual or
potential tissue damage, or described in terms of such damage”
(International Association for the Study of Pain, 1994, pp. 209–214). This
definition implies that pain and nociception have to be differentiated, with
thelatterreferringtothephysiologicalprocessestriggeredbytissuedamage.
Although nociception normally results in pain, this is not mandatory, and
vice versa, pain may be experienced without nociception. This definition
alsoclarifiesthatnegativeemotionsareaconstituentofthepainexperience,
and therefore a close interaction or overlap between brain processes related
to pain and emotions has to be expected. As a matter of fact, it may be
argued that pain is an emotion, an emotion that requires the presence of a
bodily sensation with qualities like those reported during tissue-damaging
stimulation (Price, 1999).
The pain–emotion interaction is also emphasized by the fact that both
pain and emotions are adaptive responses to survival-relevant challenges in
theenvironment.Whereaspain’smainfunctionalsignificanceistoalertthe
organism that its body integrity is threatened in order to attend to the
sourceofpainandpossiblyavoidit,emotion’sfunctionalsignificanceliesin
the detection of motivationally relevant stimuli that may trigger avoidance
or approach behavior. Both pain and emotions thus have an adaptive value
that ensures the survival of the organism.
Nociceptive Pathways
Human nociception is the process of encoding specific somatosensory
information in the periphery and its transduction to the brain. Nociceptors
are peripheral neurons that respond to noxious stimulation and detect
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4 TheNeuroscienceofPain,Stress,andEmotion
potentiallydamagingstimuli(Basbaum&Jessell,2000).Nociceptorscanbe
specific to a particular type of stimulus (e.g., mechanical, chemical, or
temperature)orcanrespondtoavarietyofnoxiousstimulations.Thelatter
nociceptive neurons are referred to as polymodal nociceptors and are more
abundant in the human body in comparison to the stimulation-specific
nociceptors (Ringkamp & Meyer, 2008). The nociceptive signal is trans-
duced to the central nervous system (CNS) by two main types of
nociceptive fibers constituting the starting point of the nociceptive signal
cascade and found throughout the body tissue: the thinly myelinated Ad
neurons, which transmit information about acute and localized pain at fast
conduction speed, and the unmyelinated C fibers, which signal more
widespread pain with slower conduction speeds (Campbell & Meyer,
2006).
After nociceptive stimulation, the Ad and C fibers transmit the noci-
ceptive signals to the CNS. The peripheral Ad and C fibers terminate in
the dorsal horn of the spinal cord. In turn, second-order neurons are
activated, and the axons of these neurons cross the midline of the spinal
cord directly to the ventral surface of the spinal cord. Ascending pain
signals are then sent to the brain via the spinothalamic tract, whose fibers
project to the intralaminar and ventroposterior nuclei of the thalamus
(Ringkamp & Meyer, 2008). Then two supraspinal neuronal systems can
be differentiated with regard to their primary role within the processing of
nociceptive information: the lateral system, mainly encoding sensory
discriminative components of pain, and the medial system encoding the
affective, motivational component of the resulting pain percept (Apkarian,
2013; Price, 2000).
Itisimportanttonotethattheseascendingnociceptivepathwayscanbe
modulatedbydescendingpathwaysstartinginthebrain.Thesemainlyalter
the transmission of nociceptive inputs at the spinal dorsal horn (Kwon,
Altin, Duenas, & Alev, 2014). The periaqueductal gray (PAG) and the
rostroventral medulla (RVM) are two regions known to play a role in the
endogenous control of pain via the inhibitory PAG–RVM–dorsal horn
pathway (Fields & Basbaum, 1994). Receiving inputs from frontal and
insular cortices,hypothalamus, and amygdala, thePAGhas acritical role in
the descending modulation of pain by interacting with the RVM and the
dorsolateral pontine tegmentum (Fields & Basbaum, 1994). The PAG,
parabrachial nucleus, and nucleus tractus solitaries provide input to the
RVM, which has direct connections to the laminae of the dorsal horn
(Millan, 1999, 2002).
NeuroscienceofPainandEmotion 5
Central Representation of Pain
In the brain, pain is represented in neuronal networks that encompass a
number of subcortical and cortical structures that code various aspects of
pain (Apkarian, Bushnell, Treede, & Zubieta, 2005; Peyron, Laurent, &
Garcia-Larrea,2000).Functionalimagingstudiesmostconsistentlyrevealed
thefollowingmainbrainareasconstitutingthebrainnetworkforacutepain
(seeFigure1):primaryandsecondarysomatosensorycortices,insularcortex
(INS), anterior cingulate cortex (ACC), prefrontal cortex (PFC), and
thalamus (Th) (Apkarian et al., 2005; Price, 2000). The somatosensory
cortex receives input from the lateral nuclei of the Th, whereas the ACC
receives input mainly from the medial portions of the Th via the INS and
further provides the PFC with nociceptive information. The cerebellum
receives direct input from the spinothalamic tract and is one of the
subcortical pain-coding structures together with the caudate putamen,
amygdala, and PAG. Accordingly, sensory and discriminatory aspects of
painareencodedinsomatosensory,lateralthalamic,andcerebellarportions
of the brain, whereas affective and cognitive components of pain are
represented dominantly in the cingulate, insular, and prefrontal areas
(cid:1)
(Apkarian et al., 2005; Bushnell, Ceko, & Low, 2013).
Figure 1 The brain network for acute pain. ACC, anterior cingulate cortex; AMY,
amygdala;BG,basalganglia;PAG,periaqueductalgray;PB,parabrachialnucleus;PFC,
prefrontalcortex;S1andS2,primaryandsecondarysomatosensorycortices.(Adapted
fromBushnellet al.(2013).)
