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9/7/2010
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Neurobiology of Pain
Miles Belgrade, MDFairview Pain Management CenterUniversity of Minnesota Medical center
We’ve come a long way…Still a long way to go
History of Pain Science
• Prehistoric– Brain vs. heart as the seat of sensory processing– DaVinciDescartes– Descartes
• Specificity theory• Gate Control theory• Receptors and ligands• Opioids 1969
15th Century DaVinci
• The brain is the organ that receives and processes sensations including pain
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17th Century‐‐ Descartes
• Pain reflex• Pain pathway
Specificity Theory vs. Pattern theory
• Specific peripheral nerves and endorgansfor different sensations
• Vs. pain as a result of intensity and pattern of stimulation
History of Pain Science
• Neuroanatomy– Single cell elctrodes– The dorsal horn and substantia gelatinosa
D di i i hibit t l (DNIC)• Descending noxious inhibitory control (DNIC)• TRPV1 receptor physiology 1997• Ca3+ and Na+ channels• Genetics of pain
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History of Pain Science
• Plasticity in the CNS• Pain facilitation and hyperalgesia
– On‐cells and off‐cellsO i id i d d h l i– Opioid‐induced hyperalgesia
– Sensitization
• Glial cells and pain
C Pol modal nociceptor
TRPV‐1 (Vanilloid) receptor
HeatAcid (H+)CapsaicinAnandamide
To spinal
d C‐Polymodal nociceptorcord
Nociception: The Transduction of Pain Stimuli
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The 1st Synapse
C‐polymodal nociceptor
= glutamate vesicles
Post‐synaptic membrane of dorsal horn neuron
= dense core vesicleswith substance P, CGRP,CCK, BDNF
Dorsal horn
The 1st Synapse
C‐polymodal nociceptor
= glutamate vesicles
Post‐synaptic membrane of dorsal horn neuron
= dense core vesicleswith substance P, CGRP,CCK, BDNF
Dorsal horn
NK‐1 AMPA NMDA
Immune‐Mediated Peripheral Nociception
Hist=histamine. TNF-α=tumor necrosis factor- α. IL-1β=interleukin-1β. IL-6=interleukin-6. NO=nitric oxide. ATP=adenosine triphosphate. PGs=prostaglandins. CCL2=C-chemokine ligand 2.Thacker MA, et al. Anesth Analg. 2007;105(3):838-847.
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Pressure Ulcer on CoccyxTreated with Topical Morphine
4 cm long X 4.5 cm wide
BoneInflammation
Pain Types by Physiology
Muscular
PsychogenicMechanical
Neuropathic
Gate Theory– Melzack & Wall 1965
+ +
Aβ myelinated
I T- +
C, Aδ pain fibers
Dorsal horn
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Neuropathic Pain Mechanisms
Dorsal HornEctopic impulse generatorAutomatic firing
A-BEphaptic impulse
C-PMNSecond order neuron Wind-up
NMDA
Receptor
Periventricular posterior hypothalamus
Opioids and acupuncture
Hypnosis and behavioral therapy
Descending Inhibitory Pathway for Pain
Dopamine agonists
Locus ceruleus
Benarroch EE. Neurology. 2008;71(3):217-221.
SNRIs
TCAs
Monoamines in the Dorsal Horn
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Aβ‐Fiber Reorganization
Komori FEBS Lett 2003. 55(3):125-128.
Glial Hypertrophy in Response to Sarcoma
Vehicle
Dorsal Horn
OPG
Sham Sarcoma
Alterations in Spinal Cord
• Increased dynorphin expression (III‐VI)• Increased # of neurons expressing c‐fos• Massive astrocyte hypertrophy
– Release growth factors, cytokines– Stimulate 2nd order dorsal horn neurons
• All changes correlate with the degree of osteoclast‐induced bone destruction
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Functional Brain Imaging Techniques
• F‐MRI– Images blood flow to particular brain areas
• PET Scan– Images metabolic activity– Requires radionuclide injectionRequires radionuclide injection
• MEG– Images magnetic field activity
• EEG– Images electrical field activity
F‐MRI
PET Scan
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Pain Affect Encoded in Human Anterior Cingulate But Not Somatosensory Cortex
Rainville. Science 1997
• Unpleasantness vs. intensity• Unpleasantness modified by hypnosis• PET scan localization of unpleasantness
– Anterior cingulate– Rostral insula
• Pain intensity localization to SI, SII
The Neural Matrix
• Ronald Melzack• Experiences are codified in a matrix or “web” that is activated as a unith f h i• Theory of phantom pain
• Pain and memory• possible mechanism for long‐lasting response to acupuncture
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The ‘Remapping Hypothesis’ and Neural Plasticity
• Touching ‘Tom’s’ face produced sensation in his phantom hand
• Modality‐specific sensations felt on hand– ‘Tom’ would feel water dripping
d hi h d if t d i d
Ramachandran & Blakeslee (1998)
down his hand if water was dripped down his face
• Complete representation of phantom hand was ‘mapped’ onto face
• Another representation mapped onto upper arm
• Hand is between arm and face on Penfield map
Somatotopic Organization
Neurobiology of Pain: What Does the Future Hold?
• Brain and spinal cord plasticity– making it work for us instead of against us
• Glial cell deactivation• Genetic modificationP di i i QST d• Predicting response to treatment using QST and genetic testing
• Making the connection between Pain and the mind
• Preventing pain through education, public health measures, occupational health measures
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