Transcript Pain

Pain and Depression:
Pathophysiological aspect
Zoran Grubič
Institute of Pathophysiology
Medical Faculty, University of Ljubljana,
TOPICS
Stress and depression
neuroendocrine dysregulation
excitotoxicity
the role of BDNF (Brain derived neurothrophic factor)
Depression and pain
BDNF (Brain derived neurothrophic factor)
Cytokine signalling
Neuron – glia interactions
1
Progression of Depression –“Kindling” Phenomenon:
Adverse Effects of Each Successive Episode
Risk (odds ratio)
10
Likelihood of recent life stress precipitating depression
Risk (odds ratio) of depression onset per month
8
Female participants only N=2,395
6
4
2
0
0
1
2
3
4
5
6
7–8
9–11
Number of previous depressive episodes
Kendler KS, et al. Am J Psychiatry. 2000;157:1243–1251. Copyright © 2000 American Psychiatric Association. All rights
reserved.
Key brain areas involved in regulation of
mood
 (A) Ventromedial prefrontal cortex (VMPFC)1
B4
 Modulates pain and aggression, and sexual and
eating behaviors
 Regulates autonomic and neuroendocrine response
A4
 (B) Lateral orbital prefrontal cortex (LOPFC)2
 Activity is increased in depression, obsessive-compulsive
disorder (OCD), posttraumatic stress disorder (PTSD),
and panic disorder
 Corrects and inhibits maladaptive, perseverative, and
emotional responses
 (C) Dorsolateral prefrontal cortex (DLPFC)3
C4
 Cognitive control, solving complex tasks, and
manipulation of information in working memory
 Hypoactivity of DLPFC in depression has been associated
with neuropsychological manifestation of depression
1. Öngür D, Price JL. Cereb Cortex. 2000;10(3):206-219.
2. Drevets WC. Annu Rev Med. 1998;49:341-361.
3. MacDonald AW III, et al. Science. 2000;288(5472):1835-1838.
4. Davidson RJ, et al. Annu Rev Psychol. 2002;53:545-574.
Reprinted with permission from the Annual Review of Psychology.
Key brain areas involved in regulation of
mood (cont.)
 (A) Amygdala: regulates cortical arousal and
neuroendocrine response to surprising and
ambiguous stimuli1
 Role in emotional learning and memory
 Activation of amygdala correlates with degree
of depression2
 Implicated in tendency to ruminate on
negative memories2
 (B) Hippocampus: has a role in episodic,
A6
contextual learning and memory3,4
 Rich in corticosteroid
 Regulatory feedback to hypothalamic-pituitaryadrenal axis
 Hippocampal dysfunction may be responsible for inappropriate
emotional responses
receptors5
1.Davidson RJ. Psychophysiology. 2003;40(5):655-665.
2.Drevets WC. Curr Opin Neurobiol. 2001;11(2):240-249.
3.Squire LR, Knowlton BJ. In: Gazzaniga MS, ed.
The New Cognitive Neurosciences; 2000:765-779.
B6
4. Fanselow MS. Behav Brain Res. 2000;110(1-2):73-81.
5. Reul JM, De Kloet ER. J Steroid Biochem. 1986;24(1):269-272.
6. Davidson RJ, et al. Annu Rev Psychol. 2002;53:545-574.
Reprinted with permission from the Annual Review of Psychology.
Neuronal circuits connecting the areas
involved in depression
Brain atrophy in depression?
Atrophy of the Hippocampus in Depression1
Normal2
1. Bremner JD, et al. Am J Psychiatry. 2000;157(1):115-118.
2. Images courtesy of J Douglas Bremner, MD, Yale University.
Depression2
Correlation between hippocampal volume
and duration of untreated depression*
Total Hippocampal Volume (mm3)
38 Female Outpatients With Recurrent Depression in Remission
6000
R2=.28
*P=.0006
N=38
5500
5000
4500
4000
3500
3000
0
1000
2000
3000
Days of Untreated Depression
*Significant inverse relationship between total hippocampal volume and the
length of time depression went untreated.
Sheline YI, et al. Am J Psychiatry. 2003;160(8):1516-1518.
4000
Hippocampal dysfunction contributes to
neuroendocrine dysregulation
Hypothalamus
Hippocampus
+
CRF
Amygdala
Pituitary
ACTH
Glucocorticoids
Dexamethasone
Nestler EJ, et al. Neuron. 2002;34(1):13-25.
Hippocampus
Adrenal
cortex
Cortisol levels in patients with depression
predicted executive function and memory
N=26
Patients with
recurrent MDD,
Mean HAM-D=21.4
Wisconsin Card
Sorting Test (WCST)
was used to evaluate
executive function
Saliva Cortisol (nmol/L)
60
50
40
30
20
10
0
0
1
2
3
4
5
6
Failure to Maintain Set Score
Worse Performance
Egeland J, et al. Acta Psychiatr Scand. 2005;112(6):434-441.
7
Excitotoxicity: excessive glutamatergic signalling
Communications in the CNS
Synaptic transmission - neurotransmitters
Growth factors
Activation and inactivation of neurons
Excitotoxicity: excessive glutamatergic signalling
Inhibitory neurotransmitter - GABA
Serotonin (5-HT) and norepinephrine (NE) pathways
Modulate balance between excitatory and inhibitory inputs in key brain areas
Limbic System
Prefrontal
Cortex
Amygdala
Raphe Nuclei
(5-HT source)1
Hippocampus
Locus
Coeruleus
(NE source)1
Descending 5-HT
pathways1
Descending
NE pathways1
Based on: Cooper JR, et al. The Biochemical Basis of Neuropharmacology. 8th ed. New York: Oxford University Press; 2003.
Communications in the CNS
Synaptic transmission - neurotransmitters
Growth factors
Sympathetic ganglion
without NGF
10 ng/ml NGF
Neurotrophins – mode of action
Neurotrophins – intracellular signaling
Neurotrophins
NGF
(nerve growth factor)
BDNF
NT-3
(brain-derived neurotrophic factor – nevrotrofični dejavnik
možganskega izvora)
(neurotrophin-3)
NT-4/5
(neurotrophins-4/5)
The role of antidepressants and neurotrophic factors in the
network hypothesis of depression: Rerouting aberrant
patterns
Nestler EJ, et al. Neuron. 2002;34(1):13-25.
Reprinted with permission from Elsevier.
Beyond synapse: Serotonin and norepinephrine aid BDNF synthesis
(preclinical evidence)
1. Manji HK, et al. Biol Psychiatry. 2003;53(8):707-742.
2. Tsankova NM, et al. Nat Neurosci. 2006;9:519-525.
Recurrent MDD and Suicidal Attempts May
Be Associated with Lower BDNF Levels
BDNF (pg/mL)
1800
1600
1400
1200
1000
800
600
400
Patients with MDD with
or without SA
2000
*P<.001
1800
*
*
*P<.001
1600
BDNF (pg/mL)
2000
Patients with MDD with first episode
or with recurrent episode
1400
1200
*
1000
800
600
400
200
200
100
100
First
Recurrent
Normal Without SA With SA
Normal
episode
episode
control
control
 Plasma BDNF levels were measured in 77 patients with MDD and 95 normal controls
BDNF=brain-derived neurotrophic factor; MDD=major depressive disorder; SA=suicide attempt.
Lee BH. J Affect Disord. 2007;101:239–244. Copyright © 2007, by permission from Elsevier.
Monoamines Regulate BDNF Synthesis in
Cultured Astrocytes in Rodents
Astrocyte response to neurotransmitters†
Increase in BDNF level
(multiple of baseline)
6
5
4
4.7
Baseline
Baseline
NE1mM
1μM
NE
5-HT1mM
1μM
HT-5
DA 150μM
DA
4
3
2
2.3
2.2
1.7
1
1
1
1.4
0
Cortical astrocytes
Cerebellar astrocytes
 NE elevated BDNF levels 4-fold or more in cortical and cerebellum astrocytes; 5-HT and DA
elevated levels roughly 2-fold
†Cultured
astrocytes incubated for 4 hours with monoamine neurotransmitters; 5-HT=serotonin; BDNF=brain-derived
neurotrophic factor; DA=dopamine; NE=norepinephrine.
Juric DM, et al. Brain Research. 2006;1108:54-62.
Relationship Between Change in BDNF Levels, Duration
of Treatment and Treatment Response in MDD Patients
2.0-
BDNF changes versus
days of improvement
r = 0.65; P=.02
1.51.00.50-
-0.50
2
4
6
Change in BDNF – effect size
Change in BDNF – effect size
BDNF changes versus
depression improvement
2.0-
r = 0.52; P=.01
1.5-
1.00.50-0.5-
Cohen’s d for depression
0
20
40
60
Period of treatment (days)
80
 Meta-regression based on 10 case control and 13 clinical trial studies assessing 1,504 subjects
 Study analyzed (weighted by inverse variance)
BDNF=brain-derived neurotrophic factor; MDD=major depressive disorder.
Brunoni AR, et al. Int J Neuropsychopharmacol. 2008;11:1169–1180. Copyright © 2008 Cambridge University Press.
Successful antidepressant treatment can
be associated with BDNF increase
35
*P<.01 vs control or treated
Plasma BDNF (ng/mL)
30
25
20
*
15
10
5
(n=50)
(n=16)
(n=17)
0
Control
DepressedDepressed-Treated
Treatment Naive
Mixed group of antidepressants used for treatment.
HAM-D17=27.810.2 and 18.811.4 for untreated and treated groups respectively.
Shimizu E, et al. Biol Psychiatry. 2003;54(1):70-75.
Depression: Multiple Core and Associated
Symptoms
Emotional symptoms
 Feelings of guilt
 Suicidal
 Lack of interest
 Sadness
Associated symptoms
Physical symptoms
 Lack of energy
 Decreased
concentration
 Change in appetite
 Brooding
 Obsessive rumination
 Irritability
 Excessive worry over
physical health
 Change in sleep
 Pain
 Change in psychomotor
skills
 Tearfulness
American Psychiatric Association (APA). DSM-IV-TR; 2000:352,356.
 Anxiety or phobias
What is the Prevalence of Associated Painful
Symptoms in Patients with Depression?
Depressed patients
 Studies addressed both depression
and painful symptoms, including:
 Headaches
MDD without
painful
symptoms
35%
MDD with
painful
symptoms
65%
 Back pain
 Neck pain
 Extremity/joint pain
 Chest pain
 Pelvic pain
Mean prevalence data from 14 studies
focusing on painful symptoms
in patients with depression
 Abdominal pain
 General pain
 Prevalence was not influenced by psychiatric versus primary care settings
MDD=major depressive disorder.
Bair MJ, et al. Arch Intern Med. 2003;163:2433–2445.
% Patients (depressed at baseline)
achieving endpoint recovery
Painful Symptoms Decrease the Chance of
Recovery in Depressed Patients
3-year longitudinal study of adults aged 55–85
80
70
60
50
40
30
20
10
0
47%
9%
N=102
MDD only
N=119
MDD and painful
symptoms
 The close association between painful symptoms and depression
emphasizes the need for progressive treatment strategies
MDD=major depressive disorder.
Geerlings SW, et al. Soc Psychiatry Psychiatr Epidemiol. 2002;37:23–30.
Patients achieving remission
(9-Week studies) (%)
Improving Painful Symptoms in MDD
Increases Chances of Remission
60
100
*P<.001
2 pooled studies
50
*
40
36%
30
18%
20
10
n=77
0
50% improvement in
painful physical symptoms
n=49
50% improvement in
painful physical symptoms
 Remission=HAMD-17 total score 7
 Painful physical symptom improvement measured by the Visual Analog Scale (VAS)
overall pain score
Fava M, et al. J Clin Psychiatry. 2004;65:521–530.
Multiple Types of Pain1
The Good
Noxious
A. Nociceptive pain peripheral
stimuli
Brain
B. Inflammatory pain
Inflammation
Brain
The Bad
C. Neuropathic pain
Brain
Peripheral nerve
damage
Multiple mechanisms
D. Non-inflammatory/
non-neuropathic pain
Brain
No known tissue
or nerve damage
Patients may experience multiple pain states simultaneously2
Abnormal central
processing
1. Figures adapted from: Woolf CJ. Ann Intern Med. 2004;140:441–451. Copyright © 2004, by
permission from American College of Physicians. 2. Chong MS, Bajwa ZH. J Pain Symptom Manage.
2003;25:S4–S11.
Questions

Which are the brain areas that may play a role in both MDD and
Pain ?

Are there any characterisitc changes in these common areas in
MDD patients with pain symptoms?

Which pathophysiolgical mechanisms can explain these changes at
the cellular and molecular level?
Questions

Which are the brain areas that may play a role in both MDD and
Pain ?

Are there any characterisitc changes in these common areas in
MDD patients with pain symptoms?

Which pathophysiolgical mechanisms can explain these changes at
the cellular and molecular level?
Some Key Areas of the Brain that May Play
a Role in Both MDD and Pain
Prefrontal
cortex
Insular cortex
Anterior cingulate
cortex
Hippocampus
Amygdala
Brain image courtesy of ATI.
Questions

Which are brain areas that may play a role in both MDD and Pain ?

Are there any characterisitc changes in these common areas in
MDD patients with pain symptoms?

Which pathophysiolgical mechanisms can explain these changes at
the cellular and molecular level?

Kako razložiti v okviru teh mehanizmov delovanje antidepresivov pri
obnovi nevrobiološkega stanja ?
Key Replicated Brain Imaging Findings
 Most brain imaging studies have shown abnormalities in these key
areas: amygdala, hippocampus, prefrontal cortex, anterior cingulate
cortex, and orbitofrontal cortex1–3
 Many studies have found prefrontal cortical hypoactivity4 and limbic
hyperactivity4 More recent studies have focused on network
relationships (limbic, prefrontal) and dynamic changes over time2,4–6
 There is great heterogeneity among patients; scanning is not
predictive or individually diagnostic
1. Sheline YI. Biol Psychiatry. 2000;48:791–800. 2. Sheline YI. Biol Psychiatry. 2003;54:338–352. 3. Nestler EJ, et al. Neuron.
2002;34:13–25. 4. Mayberg HS. Br Med Bull. 2003;65:193–207. 5. Fales CL, et al. Biol Psychiatry. 2008;63:377–384.
6. Siegle GJ, et al. Biol Psychiatry. 2007;61:198–209.
Patients With Pain May Experience Gray
Matter Atrophy
N=26
Areas in red
indicate a
composite of
regions where gray
matter density was
reduced in chronic
back pain (CBP)
patients compared
with controls
A slice of the right
anterior thalamus
at the peak of
decreased thalamic
gray matter
 Patients with CBP had 5–11% less whole-brain gray matter, equivalent to 10–20 years of
normal aging
Images copyright 2006 by the Society for Neuroscience.
Apkarian AV, et al. J Neurosci. 2004;24:10410–10415. Copyright © 2004 Society for Neuroscience.
Mood Alters Pain-Evoked Activity in
Limbic structures
AI=anterior insular region; dACC=dorsal anterior cingulate cortex; DLPFC=dorsolateral prefrontal cortex;
PAG=periaqueductal gray; R=right; rACC=right anterior cingulate cortex.
Strigo IA, et al. Arch Gen Psychiatry. 2008;65:1275–1284. Copyright © 2008 American Medical Association. All rights
reserved.
The Amygdala as a Primary Modulator: Emotions and Stress
Effects Amygdala Response to Pain (Hypothetical Model)
Amygdala
Negative Emotion
Chronic stress,
depression, anxiety
Positive Emotion
music, pleasant odors, etc.
+
–
Increases amygdala activity
Inhibits amygdala activity
Pain
Modified from: Neugebauer V, et al. Neuroscientist. 2004;10:221–234. Brain image courtesy of ATI.
Questions

Which are brain areas that may play a role in both MDD and Pain ?

Are there any characterisitc changes in these areas in MDD
patients with pain symptoms?

Which pathophysiolgical mechanisms can explain these
changes at the cellular and molecular level?
Pathophysiolgical mechanisms to explain changes in MDD and Pain at the
cellular and molecular level?
BDNF (Brain derived neurothrophic factor)
Cytokine signalling
Neuron – glia interactions
Pathophysiolgical mechanisms to explain changes in MDD and Pain at the
cellular and molecular level?
BDNF (Brain derived neurothrophic factor)
Cytokine signalling
Neuron – glia interactions
Stress and Pain Lower BDNF in Rats
BDNF levels
(Pg BDNF mRNA/ng -actin mRNA)
Changes in hippocampal BDNF synthesis
Stress
Pain
*P<.05 compared with control
8
6
6
4
4
*
*
2
Control
n=12
n=12
Acute
Chronic
stress
stress
(45 minutes) (10 days)
*
*
*
n=7
n=7
n=12
*
2
n=12
0
*P<.05 compared with control
8
n=12
n=12
0
Control 2:45 h
24 h 10-day
CFA
(chronic)
Formalin (acute)
BDNF=brain-derived neurotrophic factor; CFA=complete Freund’s adjuvant.
Duric V, et al. Neuroscience. 2005;133:999–1006. Copyright © 2005, by permission from Elsevier.
6h
Pathophysiolgical mechanisms to explain changes in MDD and Pain at the
cellular and molecular level?
BDNF (Brain derived neurothrophic factor)
Cytokine signalling
Neuron – glia interactions
Beyond the Brain: Similar Dysregulation of
HPA Axis and Cytokines
Stress and Depression1,2
Pain3
red=inhibitory pathways to hypothalamus–pituitary–adrenal (HPA) axis; green=stimulatory pathways to HPA axis
Adapted from: 1. Raison CL, et al. Trends in Immunol. 2006;27:24–23. 2. Nestler EJ, et al. Neuron. 2002;34:13–25.
3. Blackburn-Munro G, et al. J Neuroendocrinol. 2001;13:1009–1023. Copyright © 2001, by permission of Blackwell
Publishing Ltd. 4. Maletic V, et al. Int J Clin Pract. 2007;61:2030–2040. Copyright © 2007, by permission of Blackwell
Publishing Ltd.
Psychiatric Symptoms Commonly
Associated with Inflammatory Cytokines1–3
 Fatigue
 Aches and pains
 Depressed mood and anhedonia
 Difficulty concentrating
 Anxiety and irritability
 Sleep, appetite, and libido disturbances
1. Raison CL, et al. CNS Drugs. 2005;19:105–123. 2. Dantzer R, et al. Nat Rev Neurosci. 2008;9:46–56. 3. Kim YK, et al.
Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:1044–1053.
Cytokine signalling
Inflammatory Cytokines May Interfere
With BDNF Signaling
1.2
*P=.05
Relative levels
1.0
0.8
 Primary culture of rat
cerebral cortical neurons
*
0.6
*
0.4
0.2
0
BDNF
BDNF
BDNF
IL-1
(5 ng/mL)
IL-1
(20 ng/mL)
BDNF=brain-derived neurotrophic factor; IL=interleukin.
Tong L. Neurobiol Aging. 2008;29:1380–1393. Copyright © 2008, by permission from Elsevier.
Pathophysiolgical mechanisms to explain changes in MDD and Pain at the
cellular and molecular level?
BDNF (Brain derived neurothrophic factor)
Cytokine signalling
Neuron – glia interactions
Altered Neuron–Glia Communication May
Contribute to MDD
Maletic V, Raison C. 2008, Frontiers in Bioscience, in press. Image used with permission from V. Maletic.
Glial Changes in the Prefrontal Cortex of a
Depressed Patient
Glial immunoreactivity in the prefrontal cortex1
Control (27 years old)
MDD (32 years old)
 Reduction in glial cell density and number is the most prominent
feature of cell pathology in depression1–4
Images courtesy of Bentham Science Publishers.
1. Rajkowska G, et al. CNS Neurol Disord Drug Targets. 2007;6:219–233. Copyright © 2007 Bentham Science Publishing Ltd.
2. Rajkowska G, et al. Biol Psychiatry. 1999;45:1085–1098. 3. Ongür D, et al. Proc Natl Acad Sci USA. 1998;95:13290–
13295. 4. Si X, et al. Neuropsychopharmacol. 2004;29:2088–2096.
Conclusions
2
 Depression
is reflected in the structural and functional changes in the
brain.
 Morphological changes have been observed in the areas which are
responsible for the impaired functions of depressed patients and which
can be caused by stress (neuroendocrine dysfunction and excitotoxicity).
 Depression can be improved by modifying neurochemical signalling in the
affected areas.
 5-HT in NA are responsible for the balance between excitatory
1
(glutamatergic) and inhibitory
(GABAergic) activities in the prefontal
cortex and limbic system
 Activation of NA and/or 5-HT pathways increases BDNF level and in
this way improves structural damage in depressed patients. 3 N effect
Conclusions
 Pain is a serious problem of depressed patients and must be approached
as a part of the treatment.
 Emotional symptoms and pain might have a common pathophysiological
background - brain areas involved in both emotional reactions and pain
processing are damaged.
 Structural changes in these areas are likely to be a consequence of
insufficient neurotrophic effects (BDNF) due to neuroendocrine
impairment, proinflammatory factors and some other factors.
 There is accumulating evidence that the actions of antidepressives acting
at the level of NA and 5-HT transmitter systems can be explained in the
terms of improved and restored neuroprotection, neuroplasticity and
neurogenesis.
Hippokampus – Šempeter v Savinjski dolini
NEVROBIOLOGIJA DEPRESIJE
prof. dr. Zoran Grubič, dr. med.,
Medicinska fakulteta Ljubljana,
Oddelek za patofiziologijo
Antidepressants Modulate Complex,
Interconnected Signaling Cascades
5-HT
NE
synaptogenesis
PKA
neuroplasticity
cell
survival
CaMK
BDNF
CREB
neurogenesis
5-HT=serotonin; BDNF=brain-derived neurotrophic factor; CaMK=calcium-calmodulin-dependent kinase; CREB=cAMP
response element binding protein; NE=norepinephrine; PKA=protein kinase A.
Adapted from: Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3rd ed.
Cambridge UP: New York, NY; 2008. Copyright permission granted by Neuroscience Education Institute.
Serotonin and Norepinephrine: Modulation
of Mood and Pain Perception1–3
Limbic System
Raphe nuclei
(5-HT source)
Prefrontal
cortex
Locus
coeruleus
(NE source)
Amygdala
Descending
5-HT pathways
Hippocampus
Descending
NE pathways
Ascending
pain pathways
5-HT=serotonin; NE=norepinephrine.
Adapted from: 1. Bymaster FP, et al. Curr Pharm Des. 2005;11:1475–1493. 2. Fields H. Nat Rev Neurosci. 2004;5:565–575.
3. Fields HL, et al. Annu Rev Neurosci. 1991;14:219–245.
Synaptic transmission in the CNS
Common Symptoms of Neuropathic Pain
• burning
• numbness
• shooting pain
• pins and needles
• electric shock-like pain
• sensitivity to touch or cold
• tingling
• a crushing sensation
• a deep, aching pain
• swelling along with temperature changes
• skin discoloration
Key Replicated Brain Imaging Findings
 Most brain imaging studies have shown abnormalities in these key
areas: amygdala, hippocampus, prefrontal cortex, anterior
cingulate cortex, and orbitofrontal cortex1–3
 Many studies have found prefrontal cortical hypoactivity at
baseline improved after treatment4
 Many studies have found limbic hyperactivity (especially cingulate)
at baseline normalized after treatment4
 More recent studies have focused on network relationships
(limbic, prefrontal) and dynamic changes over time2,4–6
 There is great heterogeneity among patients; scanning is not
predictive or individually diagnostic
1. Sheline YI. Biol Psychiatry. 2000;48:791–800. 2. Sheline YI. Biol Psychiatry. 2003;54:338–352. 3. Nestler EJ, et al. Neuron.
2002;34:13–25. 4. Mayberg HS. Br Med Bull. 2003;65:193–207. 5. Fales CL, et al. Biol Psychiatry. 2008;63:377–384.
6. Siegle GJ, et al. Biol Psychiatry. 2007;61:198–209.
Antidepressant Use can be Associated with
Normalization in Brain Activity
Areas of increased activation in patients with MDD after antidepressant treatment (red)
and decreased activation (blue) compared with baseline.
Increased activity: DLPFC, dACC, posterior cingulate
Decreased activity: sgACC, VMPFC, amygdala, hippocampus, insula
ACC=anterior cingulate cortex; DLPFC=dorso-lateral prefrontal cortex; VMPFC=ventromedial prefrontal cortex.
Fitzgerald PB, et al. Hum Brain Mapp. 2008;29:683–695. Copyright © 2008, by permission of John Wiley & Sons, Inc.
Patients with Chronic Back Pain
Gray matter density is reduced in patients with CLBP
compared with controls and degree of reduction is related
to duration of symptoms
CLBP=chronic low back pain; nuCBP=neuropathic chronic back pain.
Apkarian AV, et al. J Neurosci. 2004;24:10410–10415. Copyright © 2004 Society for Neuroscience.
Neuroplasticity in Peripheral Pain
Transmission: Peripheral Sensitization
Voltage-gated
sodium channels
Several neurochemicals may be released
following tissue injury (inflammatory soup),
leading to peripheral sensitization
Na+
PKA
Erk1/2
Cytokine
receptor
IL-1
IL-6
TrkA
B1/2 MOR
PKC
TRPV1
EP
COX-2
TNF
Ca2+
NGF BK
PGE2
AA
IL-1
Tissue injury
Mast cell
Macrophage
AA=arachidonic acid; BK=bradykinin; COX-2=cyclooxygenase-2; EP=prostaglandin E receptor;
Erk1/2=extracellular signal-regulated kinases; IL=interleukin; MOR=m opioid receptor; NGF=nerve
growth factor; PGE2=prostaglandin E2; PKC, PKA=protein kinases C, A; TNF-=tumor necrosis factorα; TrkA=neurotrophic tyrosine kinase A receptor; TRPV1=transient receptor potential vanilloid 1.
Woolf CJ. Ann Intern Med. 2004;140:441–451. Copyright © 2004, by permission from American College
of Physicians. Baron R. Nat Clin Pract Neurol. 2006;2:95–106.
Inflammatory Cytokine Potentiation of Pain
May be Mediated by Glia
TNF IL-6
IL-1
IL-1
TNF
Sciatic
nerve
Dorsal
IL-6
Glia
Pathogen
Phagocytic
immune
cell
Hyperalgesia
Dorsal
horn
Dorsal
horn
Gray matter
Ventral
Ventral
horn
horn
White matter
Ventral
IL=interleukin; TNF=tumor necrosis factor.
Wieseler-Frank J, et al. Brain Behav Immun. 2005;19:104–111. Copyright © 2005, by permission from Elsevier.
Major depressive disorder: The
consequences
 MDD can have emotional, cognitive, behavioral, and
physical manifestations1,2,4
 MDD is associated with metabolic changes in the prefrontal cortex
and limbic system2,3
 Structural changes in the hippocampus and prefrontal cortex often
accompany MDD1
 Compromised neuroendocrine regulation in MDD can lead to
widespread systemic consequences1,3
 MDD may be associated with diminished neurotrophic support,
resulting in impaired neuroplasticity, neurogenesis, and cellular
resilience3
 Cerebral areas affected by MDD have significant noradrenergic
3
and
innervation
1. Sheline
YI.serotonergic
Biol Psychiatry. 2000;48(8):791-800.
2. Drevets WC. Annu Rev Med. 1998;49:341-361.
3. Manji HK, et al. Nat Med. 2001;7(5):541-547.
4. APA. DSM-IV-TR; 2000.
1968: First growth factor discovered (NGF)
Rita Levi-Montalcini; Nobel prize 1986
Major depressive disorder may have
systemic consequences
2. The adrenal gland releases
excessive amounts of
catecholamines and cortisol
3. Increase in catecholamines can
lead to myocardial ischemia,
diminished heart rate variability,
and can contribute to ventricular
arrhythmias
ACTH
1. Hypothalamus stimulates
the pituitary gland to
release excessive ACTH,
continuously driving the
adrenal gland
4. Increase in catecholamines
causes platelet activation;
increase in cytokines and
interleukins may also
contribute to atherosclerosis
and eventual hypertension
5. Cortisol antagonizes insulin and
contributes to dyslipidemia, type
2 diabetes, and obesity;
increases in cortisol also
suppress the immune system
Adapted from: Musselman DL, et al. Arch Gen Psychiatry. 1998;55(7):580-592.