Download neuropathic pain models 1 - Pittsburgh Center for Pain Research

PAIN MODELS
RATIONALE, TESTING, AND INTERPRETATION
NEUROPATHIC PAIN
MODELS 1
Martin Oudega, Ph.D.
Departments of Physical Medicine & Rehabilitation, Neurobiology, and Bioengineering
Centers for the Neural Basis of Cognition and Neuroscience
University of Pittsburgh School of Medicine
Pittsburgh, PA 15213, U.S.A.
OUTLINE
GENERAL INTRODUCTION:
- Neuropathic pain.
- SCI, TBI, stroke.
CLINICAL PRESENTATION:
- Manifestation.
- Management.
MODELS:
- Animals.
- Allodynia, hyperalgesia.
- Analyses.
SPONTANEOUS (TONIC) PAIN:
- Assessment.
- Analyses.
OUTLINE
GENERAL INTRODUCTION:
- Neuropathic pain.
- SCI, TBI, stroke.
CLINICAL PRESENTATION:
- Manifestation.
- Management.
MODELS:
- Animals.
- Allodynia, hyperalgesia.
- Analyses.
SPONTANEOUS (TONIC) PAIN:
- Assessment.
- Analyses.
NEUROPATHIC PAIN
Definition:
pain caused by damage or disease affecting any part of the
nervous system involved in bodily feelings (somatosensory
system).
Pain syndromes:
1. spontaneous pain – not dependent on peripheral stimuli
“persistent numbness, burning, cutting, piercing, electric-like”
2. peripherally evoked pain: response to (non-)noxious stimuli
PAIN - ANATOMY
somatosensory system:
peripheral sensors (skin, epithelia,
muscles, bones, joints, organs,
cardiovascular system) to central
processing areas.
Pain: nociception through
nociceptors.
Information pathway: nociceptor
(transduction) - sensory nerve
(transmission) - spinal cord
(modulation) - brain (perception).
Spinothalamic tract (STT)
STT location in spinal cord
PAIN - ANATOMY
Components of the pain pathway:
Neurons:
primary (DRG/trigeminal ganglia: periphery (receptor)-spinal cord)
secondary (spinal cord/brainstem-thalamus)
tertiary (thalamus (ventral posterior nucleus, VPN)-cortex)
Axons:
C fiber: thin, slow (unmyelinated) axon (Lamina II) (less intense)
A fiber: fast, myelinated (sharp)
C fibers in STT: synapse in thalamus
information processing centers:
primary somatosensory area in
postcentral gyrus of parietal lobe
of cerebral cortex.
‘locate’ pain stimulus (homunculus).
Not only neurons involved, also glia, immune cells
PAIN - MODULATION
Modulation happens at different levels. Periaquaductal grey matter plays important role
Descending inhibition to
modulate pain sensation through
hypothalamus-mediated release
of hormones.
Opioid receptors (- analgesic
effects of opioids).
NEUROPATHIC PAIN
Origin:
peripheral nervous system (peripheral neuropathic pain)
central nervous system (central neuropathic pain)
central and peripheral nervous system (mixed neuropathic pain)
NEUROPATHIC PAIN
Origin:
peripheral nervous system (peripheral neuropathic pain)
central nervous system (central neuropathic pain)
central and peripheral nervous system (mixed neuropathic pain)
CENTRAL NEUROPATHIC PAIN (CNP)
Origin:
central nervous system: brain – spinal cord
Neuropathic pain:
was defined as pain caused by damage or disease affecting any part
of the nervous system involved in bodily feelings (the somatosensory
system).
Injury or disease:
spinal cord injury, traumatic brain injury, stroke, multiple sclerosis,
others
NEUROPATHIC PAIN
SCI, TBI, Stroke
Alcoholism
Amputation
Back, leg, and hip
problems
Chemotherapy
Diabetes
Facial nerve problems
HIV infection or AIDS
Multiple sclerosis
Spine surgery
OUTLINE
GENERAL INTRODUCTION:
- Neuropathic pain.
- SCI, TBI, stroke.
CLINICAL PRESENTATION:
- Manifestation.
- Management.
MODELS:
- Animals.
- Allodynia, hyperalgesia.
- Analyses.
SPONTANEOUS (TONIC) PAIN:
- Assessment.
- Analyses.
SPINAL CORD INJURY
etiology
Updated: June 2009
National SCI Statistical Center
Birmingham, Alabama
Other
Sports
8%
Violence
Traffic accidents
9%
42%
15%
27%
Falls
 Incidence: Over 12,000 spinal cord injuries in U.S.A. every year
 Prevalence: 229,000-306,000 persons with spinal cord injury
 Gender: 81% of all spinal cord injuries occur in men
 Age: Between 16-20 (55%). Average age = 40.
 Neurologic level: 51% tetraplegic (cervical injury; 30%, incomplete)
 Over 75% of SCI are contusive injuries.
SPINAL CORD INJURY
CONTUSION
C2
C5
C7
T2
Uninjured
Over 75% of SCI
is a contusive injury
Contusion, solid, no cyst
15%
Contusion, cyst
33%
Maceration
29%
Laceration
23%
Bunge et al., 1993, Kakulas, 1999
SPINAL CORD CONTUSION
Demyelination
Oligodendrocyte death
Cyst formation
No growth substrate
Glial Scar
Surrounding the injury site
Spinal cord contusion
CELLULAR CONSEQUENCES
DEMYELINATION
ABORTIVE SPROUTING
INFLAMMATION
SCARRING
GLIOSIS
CELL DEATH
LOSS BLOOD VESSELS
HYPER EXCITABILITY
CYSTS
ISCHEMIA
APOPTOSIS
EDEMA
Impaired function
INITIALLY
SECONDARY
Cell death
Axonal dieback
Axonal damage
Demyelination
Hemorrhage
Scar formation
Inflammation
Cyst formation
FUNCTIONAL CONSEQUENCES
X
Sensory
Information
To brain
Loss of motor function
Loss of sensory function
Loss of autonomic function
injury
Degenerating
Distal part of
damaged axon
Interruption of
descending (motor) and
ascending (sensory)
pathways
Loss of bowel/bladder function
Loss of sexual function
Spasticity
Central Neuropathic Pain
Motor
information
to periphery
X
ENDOGENOUS REPARATIVE EVENTS
UPREGULATION RAGs
REMYELINATION
AXON SPROUTING
DEBRIS REMOVAL
ANGIOGENESIS
PLASTICITY STEM CELL BIRTH /
PROLIFERATION
SCHWANN CELL
INVASION
TROPHIC FACTORS
FAILS TO RESTORE ANATOMY / FUNCTION
FAILS TO ALLEVIATE NEUROPATHIC PAIN
TRAUMATIC BRAIN INJURY
Similar as SCI…
Insult to head causing brain tissue damage.
Secondary injury progressively worsens injury resulting in loss of tissue.
Location of injury determines deficits.
TRAUMATIC BRAIN INJURY
TRAUMATIC BRAIN INJURY
Symptoms short-term:
Headaches, vomiting, nausea, convulsions, inability to awaken,
pupil dilation, slurred speech, aphasia (difficulty in word finding), etc.
Symptoms long-term:
Changes in appropriate social behavior, deficits in social judgment,
cognitive changes, attention problems, etc.
STROKE
Loss of brain function due to disturbance in blood
supply to the brain
Causes:
ischemia (lack of blood flow) (80%).
hemorrhage (20%)
Epidemiology:
frequent cause of death (>6 million/world)
95% in people over 45 years old.
Symptoms:
starts suddenly, lasts seconds/minutes.
symptoms depend on area affected.
additional symptoms due to compression of
other areas
STROKE
Pathophysiology is ‘similar’ as in SCI and TBI with progressive loss of nervous tissue.
OUTLINE
GENERAL INTRODUCTION:
- Neuropathic pain.
- SCI, TBI, stroke.
CLINICAL PRESENTATION:
- Manifestation.
- Management.
MODELS:
- Animals.
- Allodynia, hyperalgesia.
- Analyses.
SPONTANEOUS (TONIC) PAIN:
- Assessment.
- Analyses.
CNP-CLINIC
After SCI/TBI/Stroke, if damage affects primary somatosensory area
(postcentral gyrus of parietal lobe) or along the STT
Prevalence: SCI, 60-80%;
Stroke, 10%
SCI most common cause for central pain.
Mechanisms include central disinhibition and/or central sensitization (STT
neurons have increased background activity, enlarged receptive fields, and
increased responses to afferent impulses, even non-noxious).
Not completely understood at this time. More later.
CNP - CLINIC
Manifestation:
-develops within weeks/months.
-described as: burning, stabbing, electric-like.
Types of pain responses:
allodynia: response to normally non-noxious stimulus.
hyperalgesia: increased response to noxious stimulus.
spontaneous (tonic) pain.
OUTLINE
GENERAL INTRODUCTION:
- Neuropathic pain.
- SCI, TBI, stroke.
CLINICAL PRESENTATION:
- Manifestation.
- Management.
MODELS:
- Animals.
- Allodynia, hyperalgesia.
- Analyses.
SPONTANEOUS (TONIC) PAIN:
- Assessment.
- Analyses.
CNP - TREATMENT
attempt to influence descending pain modulating pathways.
Neurosurgical, pharmacological, behavioral strategies.
Difficult…..40-60% achieve partial relief.
Pain affects quality of life (depression-suicide).
Anti-depressants
(CNS - common mechanisms/different functions)
tricyclica, anticonvulsants (gabapentin),
topical lidocaine
SNRIs (5Ht-Norepi reuptake inhibitors)
anticonvulsants (pregabalin, gabapentin),
topical lidocaine.
Opioid analgesics (not first line treatment).
OUTLINE
GENERAL INTRODUCTION:
- Neuropathic pain.
- SCI, TBI, stroke.
CLINICAL PRESENTATION:
- Manifestation.
- Management.
MODELS:
- Animals.
- Allodynia, hyperalgesia.
- Analyses.
SPONTANEOUS (TONIC) PAIN:
- Assessment.
- Analyses.
CNP MODELING
Specific models to study pain mechanisms
1. Occlusion of blood vessels-ischemia – mechanical allodynia
2. Anterolateral spinal cord lesions – mechanical allodynia/overgrooming
3. Quisqualic injection – overgrooming
(AMPA/kainate/metabotropic receptor agonist)
SCI/TBI/Stroke models that ‘allow’ studying pain (not always)
1.
2.
3.
4.
SCI contusion, clip compression – mechanical/thermal hyperalgesia, allodynia
Hemisections – hyperalgesia, allodynia (depends on location)
Brain contusions-TBI
Artery occlusions-Stroke
SPINAL CORD INJURY MODELS
CONTUSION
PARTIAL
TRANSECTION
COMPLETE
TRANSECTION
SPINAL CORD LACERATION MODELS
Ad: interpretation clear-cut
DA: technically difficult
SPINAL CORD CONTUSION


Compression
Impact Velocity
NYU Contusion Device
Impact
Contused cord
HUMAN VS RAT SPINAL CORD CONTUSION
3 months
TBI MODELING
Lateral Fluid Percussion
STROKE MODELING
Many mechanisms that lead to (ischemic) stroke
including cardiac arrest, hypoxia,
blood clot embolization, but most used is MCA,
middle cerebral artery occlusion
MCA is one of three major paired arteries
that supply blood to brain.
Occlusion leads to MCA syndrome:
damage to brain hemisphere
paralysis of (contralateral) face/arm
sensory loss (contralateral) face/arm
OUTLINE
GENERAL INTRODUCTION:
- Neuropathic pain.
- SCI, TBI, stroke.
CLINICAL PRESENTATION:
- Manifestation.
- Management.
MODELS:
- Animals.
- Allodynia, hyperalgesia.
- Analyses.
SPONTANEOUS (TONIC) PAIN:
- Assessment.
- Analyses.
HOW DO WE ASSESS CNP AFTER
SCI/TBI/STROKE
Types of responses:
allodynia: response to normally non-noxious stimulus.
hyperalgesia: increased response to noxious stimulus.
Types of assessments:
allodynia: Von Frey aesthesiometer.
hyperalgesia: Hargreaves method.
ALLODYNIA: VON FREY AESTHESIOMETER
Maximilian von Frey
ALLODYNIA: VON FREY AESTHESIOMETER
THERMAL HYPERALGESIA: HARGREAVES
THERMAL HYPERALGESIA: HARGREAVES
OUTLINE
GENERAL INTRODUCTION:
- Neuropathic pain.
- SCI, TBI, stroke.
CLINICAL PRESENTATION:
- Manifestation.
- Management.
MODELS:
- Animals.
- Allodynia, hyperalgesia.
- Analyses.
SPONTANEOUS (TONIC) PAIN:
- Assessment.
- Analyses.
ANALYSES
TIME (seconds, Hargreaves) or PRESSURE (grams, von Frey)
Allodynia and hyperalgesia can be assessed using the pressure/time
it takes to cause withdrawal of paw in response to tactile/thermal
stimulus.
In case of CNP, the time/pressure will be shorter/smaller.
An effective treatment would lengthen time/increase pressure until
withdrawal.
EXAMPLE
BMSC PRESENCE RESULTS IN IMPROVED SENSORY FUNCTION
IN THE ADULT RAT WITH A CONTUSED SPINAL CORD
Thermal hyperalgesia:
Hargreave’s heat source.
Paw withdrawal to noxious
stimulus.
Thermal hyperalgesia
(seconds ± SEM)
16
14
12
BMSC
DMEM
*
10
*
8
6
4
2
0
4 weeks
8 weeks
Mechanical allodynia:
Von Frey aneasthesiometer.
Paw withdrawal to otherwise
innocuous stimulus.
Mechanical Allodynia
(grams ± SEM)
160
140
BMSC
DMEM
120
100
*
*
80
60
40
20
0
4 weeks
8 weeks
OUTLINE
GENERAL INTRODUCTION:
- Neuropathic pain.
- SCI, TBI, stroke.
CLINICAL PRESENTATION:
- Manifestation.
- Management.
MODELS:
- Animals.
- Allodynia, hyperalgesia.
- Analyses.
SPONTANEOUS (TONIC) PAIN:
- Assessment.
- Analyses.
SPONTANEOUS PAIN
Von Frey, Hargreaves are used to assess allodynia, hyperalgesia
“withdrawal responses” to evoked pain or hypersensitivity
In rats, are they reflecting CNP? Is it maybe a reflex to the
sensation rather than a pain-related behavior?
Spontaneous pain is the single most common and debilitating
complaint of people with SCI
How to measure spontaneous pain in rats?
CPP: conditioned place preference
CPP
conditioned place preference:
Based on the fact that relief from pain is rewarding, analgesics
that are not rewarding themselves in the absence of pain should
become rewarding in the presence of pain.
OUTLINE
GENERAL INTRODUCTION:
- Neuropathic pain.
- SCI, TBI, stroke.
CLINICAL PRESENTATION:
- Manifestation.
- Management.
MODELS:
- Animals.
- Allodynia, hyperalgesia.
- Analyses.
SPONTANEOUS (TONIC) PAIN:
- Assessment.
- Analyses.
ANALYSES
TIME spend in drug-associated chamber
In case of spontaneous pain, should be increased