Perception and Response to Pain

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Endogenous Opioid Neurotransmission Interfacing
Reward and Stress Regulation
Jon-Kar Zubieta, M.D., Ph.D. Associate Professor,
Senior Associate Research Scientist Departments
of Psychiatry and Radiology, Mental Health
Research Institute and Neurosciences Program The
University of Michigan
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Most complex illnesses are characterized by an
interaction between biological vulnerabilities
and environmental factors
Depression, Substance Use
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D. Hamer, Science 2002
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Genetic Variations
Early Stress
Sex Hormones
Behavioral Phenotypes
Cross-sensitization to substance use
Behavioral Dysregulation
Emotional Dysregulation
Males more vulnerable to addiction
Dysregulation of HPA axis

• DA to PFC
• PFC suppression of Amygdala
• Amygdala function
• Striatal function

• PFC function
• ? Amygdala function

• striatal DA response to drug
• PFC dysregulation

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MAO-Apromoter polymorphism
COMTval158met polymorphism
Caspi et al., 2002
Enoch et al., 2003
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QuestionCan we detect the points of
interaction between reward and reinforcement
circuits and stress?
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Mu Opioid Neurotransmission

• Experimental evidence (animal models and humans)
  and transgenic models implicate them in
• Stress responses and stress-induced analgesia
• Endogenous opioid analgesia and effects of opiate
  drugs
• Regulation of amygdala and nucleus
  accumbens-mediated
• responses to salient stimuli, including drugs
  of abuse
• Direction of modulation is typically suppressive
  of the relevant response (e.g., stress, anxiety,
  locomotion)

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Mu Opioid Receptor-Mediated Neurotransmission
BP
4
3
2
1
CING
Distributed in affective / motivational
circuits - neuronal nuclei involved in responses
to rewarding and salient stimuli.
THA
CAU/ NAC/ VP
AMY
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Receptor Quantification with PET
Tracer Transport (rCBF x Tracer Extraction)
Incorporation to Specific Binding Sites
1 min
2 min
3 min
5 min
10 min
30 min
70 min
Data Analysis
Generation of Parametric Maps e.g., Logan Plots
(K1, DVR)
Non-Linear Anatomical Standardization (ICBM
Coordinates)
Coregistration with Anatomical MRI
Z-VALUE
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3
STATISTICAL PARAMETRIC MAPS OF SIGNIFICANCE (SPM9
9)
2
1
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Activation of µ-Opioid Neurotransmission by a
Pain Stressor
PFCTX BA 8
INS
A THA
NAC/VP
ACING
Z-VALUE
HYPO
AMY
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Note the interindividual variations in binding
and release
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2
1
Zubieta et al., Science 293 311-315, 2001
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Parallel HPA and µ-Opioid System Activation
Cortisol
ACTH
VP, NAC
VP, NAC
? Activation
r0.55
r0.59
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µ-Opioid System Suppression of Sensory and
Affective Qualities of Pain
ACING
NAC/ VP
AMY
THA
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µ-Opioid System Suppression of Sensory and
Affective Qualities of Pain

• During sustained pain/stress, µ-opioid
  neurotransmission is activated to suppress
  responses to the stressor

• This activation takes place in numerous cortical
  and subcortical regions

• Some of them are involved in the perception and
  regulation of sensory aspects of pain (i.e.,
  intensity and localization -lateral thalamus,
  PAG-)

• But also in the regulation of stimulus salience,
  reward-motivation and emotional states -anterior
  cingulate, insula, nucleus accumbens and ventral
  pallidum, amygdala-)

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Activation of Dopamine Neurotransmission by a
Pain Stressor Reductions in 11Craclopride BP
during sustained pain
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Monoamine-Opioid Interactions
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Effects of GenotypeCOMT Val158Met Polymorphism

• Substitution of val by met, codon 158
• 4-fold reduction in enzyme activity
• Co-dominant alleles
• Frequent met allele frequency 0.4
• Linked with trait anxiety in women (met/met,
  Enoch et al., 2003), cognitive function (Egan et
  al., 2001), polysubstance abuse (val/val,
  Vandenbergh et al., 1997).
• Gene activity also reduced by estradiol

Enoch et al., 2003
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Dopamine D2 Effects on Opioid Neurotransmission

• Reduction in enkephalin mRNA
• Increase in µ-opioid receptor binding
• PFCTX, striatopallidal pathway
• Models Cocaine use, D2 agonists
• Met158met COMT alleles ?

• Increase in enkephalin mRNA
• Reduction in µ-opioid receptor binding
• Models 6OHDA, D2 antagonists
• Val158val COMT alleles ?

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BINDING
BINDING
THAL
BINDING
NAC
VP
RELEASE
ACING
RELEASE
RELEASE
THAL
NAC
VP
Zubieta et al., Science 299 1240-1243, 2003
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What about the influences of novelty and
anticipation?After all, these circuits are
thought to mediate responses to saliency
(whether rewarding or aversive)
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Volunteer Instructions
You will receive two PET studies, one with pain,
the other without. You will not know which one
comes first
Pain Order Novelty
Saline Control Order Anticipation
AMY
AMY (trend)
NAC/VP
NAC/VP
ACING
Post THA
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Sex Differences in µ-Opioid System Responses to a
Pain Stressor
NAC
NAC
VP
AMY, VP, HypoTHA
AMY, VP
THA
Zubieta et al., J Neurosci. 22 5100-5107, 2002
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• Sex Differences
• Follicular Phase (low Estradiol, low
  Progesterone)
• Thalamus
• Nucleus Accumbens
• Ventral Pallidum
• Amygdala

Z VALUE
4
3
2
1

• Psychophysical Implications
• Hyperalgesia
• Nucleus Accumbens, Amygdala
• Enhanced Pain Affect
• Anterior Thalamus
• Enhanced Internal Negative Affective State
• Ventral Pallidum

V/V
V/V
V/V
Zubieta et al., J Neurosci. 22 5100-5107, 2002
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Conclusions

• We demonstrate the feasibility of examining the
  interaction of genetic, sex and cognitive
  influences on neurochemical systems implicated in
  the human response to salient stimuli, both
  rewarding and aversive.
• Reciprocal interactions between dopaminergic and
  opioid systems in striatopallidal and associated
  circuits appear to be of importance to understand
  interindividual variations in the vulnerability
  and resilience to stress and stress-substance
  abuse relationships.
• Further examination of the involvement of these
  circuits in the time course of addiction
  development and withdrawal symptoms appears
  warranted.

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The Team
PAIN MODEL
POST-DOCTORAL FELLOWS
Christian S. Stohler, DDS, PhD
STATISTICAL MODELS
Mary H. Heitzeg, PhD Ke Xu, PhD
Thomas Nichols, PhD
RADIOCHEMISTRY
Michael A. Kilbourn, PhD Douglas M. Jewett, PhD
GRADUATE STUDENTS
WARPING METHODS
Charles R. Meyer, PhD
RADIOTRACER KINETIC MODELING
Susan E. Kennedy, PhD
Robert A. Koeppe, PhD
GENOTYPING
NURSING STAFF
David Goldman, MD Margit Burmeister, PhD
Teresa M. Woike, RN, CCRT Virginia M. Weinberg,
RN, MS
REPRODUCTIVE ENDOCRINOLOGY
Yolanda R. Smith, MD, MS
PROGRAMMING
RESEARCH ASSISTANT
Yanjun Xu, PhD
Joshua A. Bueller, BA
NEUROENDOCRINOLOGY
Elizabeth A. Young, MD
and the technologists of the PET Center and
fMRI Laboratory
Supported by NIDCR, NCCAM, Dana Foundation,
Pritzker Foundation, NARSAD
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