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Pathophysiology of Acute &

Chronic Pain
Steven Stanos, DO
Center for Pain Management
Rehabilitation Institute of Chicago
Dept. of PM&R, Northwestern
University Medical School
Feinberg School of Medicine
• Nociceptive vs. Neuropathic
• Receptors and channels
• Inflammation
• Peripheral Sensitization
• Central Sensitization
• Temperature Sensation
• Plasticity & Brain Changes
• Muscle Pain
• Cytokines: the Future
Nociceptive vs. Neuropathic Pain
Nociceptive Other “Mixed” Neuropathic
Pain Pain Types? Pain2,3
(Inflammatory?)1

Postherpetic CRPSII*
neuralgia
Postoperative (PHN)
Arthritis Trigeminal
pain
Neuropathic neuralgia
Sickle cell low back pain
Mechanical crisis
low back pain Central post-
Distal stroke pain
polyneuropathy
Sports/exercise
(e.g., diabetic, HIV)
injuries
*Complex regional pain syndrome type II.
1. Portenoy RK, Kanner RM. In: Pain Management: Theory and Practice. Philadelphia, PA: FA Davis Company; 1996:4.
2. Merskey H, Bogduk N, eds. Classification of Chronic Pain. 2nd ed. Seattle, WA: IASP Press; 1994.
3. Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain. Minneapolis, MN: McGraw-Hill; 2000.
The BIOMEDICAL Model
• Pain as a
sensory event
reflecting
underlying
disease or
tissue damage
Gate Control Theory

Melzack R. In: Cousins MJ, Bridenbaugh PO, eds. Neural Blockade in Clinical Anesthesia and Management of
Pain. 3rd ed. Philadelphia, Penn: Lippincott Williams & Wilkins; 1998.
Gate Control Theory

A. Sensory
B. Affective
C. Evaluative

Melzack R, Wall PD. Science. 1965;150:971-976.


Enteroceptive Sensations
• Pain
• Thirst
• Hunger
• Thermoception

• Neurophysiologic changes
• Neurochemical changes
Biological Functions of Pain
Sherrington (1906)

Exteroceptive: Escape and avoidance of


external threats
Interoceptive: protection of injured or
dysfunctional tissues that
disrupt homeostasis

Price DD et al. Pain 2003, 106.


Physiological Pain
• Initiated and by specialized sensory
nociceptors innervating peripheral tissues
and responding only to noxious stimuli
• Projects to spinal cord and cortex
• Activates reflex withdrawal, increase in
arousal, emotional, autonomic and
neurohumoral responses
The Role of Plasticity
in Chronic Pain
Injury
Acute Pain

Normal Healing Healing With Plasticity

Pain Relief Hyperalgesia Allodynia

Chronic
Pain

Adapted from Marcus DM. Am Fam Physician. 2000;61:1331-1338.


Neuronal Plasticity and Pain
• Normal adaptive function
• Neurons detecting and transmitting pain
display “plasticity”
– A capacity to change function, chemical profile,
or structure
– A response to painful stimuli and inflammation
– A contributor to altered sensitivity to pain
• When persistent can lead to permanent
neuropathic pain

Woolf CJ, et al. Science. 2000;288:1765-1768.


Pain Pathophysiology
• Nociceptive pain
– Believed to be related to ongoing activation of an
intact nervous system by tissue injury
• Somatic
• Visceral
• Neuropathic pain
– Believed to be related to aberrant somatosensory
processing in the peripheral nervous system, the
central nervous system, or both
Nociception
• Transduction: detection of noxious or
damaging stimuli
• Conduction: passage of resulting sensory
input from peripheral terminals to the
spinal cord
• Transmission: synaptic transfer of input
to neurones within specific laminae of DH
Physiology of Pain Perception1-3 Brain

Descending Perception
Pathway

Ascending
Pathway
Spinal
C-Fiber
Cord
α-β Fiber
Dorsal
α-δ Fiber Horn

Conduction Transmission/
Dorsal
Root
Modulation
Peripheral
Nerve Ganglion

Transduction Injury

1. Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain. Minneapolis, MN: McGraw-Hill; 2000.
2. Irving GA, Wallace MS. Pain Management for the Practicing Physician. New York, NY: Churchill Livingstone; 1997.
3. Woolf CJ, et al. Ann Intern Med. 2004;140:441-451.
Kidd, Urban. Br J Anaesthesia 2001;87(1).
Pathologic vs. Physiologic
Classification of Fibers in
Peripheral Nerves
Lloyd /Hunt Diameter Letter Conduction Myeli Receptor/ ending
(µm) System velocity n
(m/sec)
12-20 - 70-120 + Muscle spindle
I-a primary endings
12-20 - 70-120 + Golgi Tendon organs
I-b
- 12-20 A-α 70-120 + Muscle efferents
(extrafusal)
II 6-12+ A-β 30-70 + Encapsulated
endings;Merkel
- 2-10 A-γ 10-50 + Muscle efferents
(intrafusal)
III 1-6 A-δ 5-30 + A-δ specific &
polymodal; cold; hair;
visceral (+/-)
- <3 B 3-15 + Preganglionic
autonomic
IV <1.5 C 0.5-2.0 No C-nociceptors; C-polymodal;
warmth, mechano;postganglioic
autonomic; enteric nerve fibers

Adapted from Nolte J. The human bran. St.Louis: Mosby, 1999:213.


Conduction Velocity: Aδ & C fibers
• Aδ (Fast pain)1
• C-fibers (Slow pain)1
• Age related
impairment in fast
pain fibers2

1. Julius D, Basbaum A, Nature 2001(413).


2. Chakour M,, et al. Pain 1996; 64:143.
Receptors
Non-painful stimuli:
• Specificity for a particular stimulus
• High degree of gain to amplify weak signals
• Rapid adaptation to increasing intensities
Painful stimuli:
• Specificity less important
• High threshold receptors: thermal, chemical and
mechanical stimuli (polymodal)
• Threshold for firing may decrease

Kidd, Urban. Br J of Anaesth 87, 2001.


Cutaneous
C-fiber A-δ
• Small diameter • Medium diameter
• Slow conducting • Fast conducting
• Unmyelinated • Lightly myelinated
• Polymodal
1. Proinflammitory peptides
Subst P Type I
CGRP Long response latency
Lamina I/II > 50°C
* tissue inflammation Persistent pain
(NGF) 2. Type II
2. Specific enzymes/ Lectin IB4
Short response
*chronic neuropathic pain
43°C
(GDNF)
Initial burn
Caterina, Cur Op in Neurobiology (9), 1999.
Primary Afferent C & Aβ Fibers
Sensation Mediated
Fibre Threshold Principal Receptors Physiological Pathological
Class For Transmitters Engaged
Activation
C High SP/NKA NK Noxious Highly noxious
CGRP CGRP (pain) (hyperalgesia)
EAA NMDA Cold Allodynia
AMPA (pain)
mGlu

Aβ Low EAA AMPA Innocuous Mechanical


(no pain) allodynia

Millan, Progress in Neurobiology, 1999.


Receptor types on sensory neurons
Transduction mechanism Example Cellular effect

Ligand-gated channel Capsaicin-heat Excitation


H , 5HT, ATP
Glutamate, GABA-A

G-protein linked GABA-B Inhibition of


Opiated, Adenosine transmitter &
Adrenoreceptors peptide release
NPY, 5HT

Bradykinin(B2) Excitation
Histamine (H1) and/or
Adrenoreceptors (α2) sensitization
PGE2
Tyrosine kinase linked NGF (Trk A) Control of gene
expression
Bevan S. Textbook of Pain, 4th ed. Wall, Malzack, 1999.
Ion Channels
• Dynamic, constantly changing
• Plasticity reflects sensitivity needed for
survival
• Injury: amygdala, hippocampus, and DRG
• Normal peripheral nerves (resist)
• Demyelination: density
Receptors
• Capsaicin/ Vanilloid • Purinergic (P2X)
Ion Channel Linked Receptors

Receptors Ion Channels


• Vanilloid (VR-1) • Sodium
• Acid-sensing (ASIC) – TTX-S
• Purinergic (P2X) – TTX-R

• Cannabinoid • Calcium

Kidd BL, Urban LA, Br J of Anaesthesia (1). 2001.


Caterina. Cur Op in Neurobiology (9), 1999.
Nociception in Other Organs
• Less differentiation
• Autonomic component
• Poorly localized
• Referred pain
• Absence of Aβ in viscera
• Skeletal muscle: group III, group IV
• Joint: group III & group IV respond to
stretch
Visceral Pain
Psychophysics Neurobiology
• Not evoked from all • Not all innervated by
viscera “sensory receptors”
• Not always linked to • Functional properties of
injury afferents
• Referred to body wall • Viscerosomatic
• Diffuse & poorly convergence in CNS
localized • Few “sensory” visceral
• Intense motor & afferents, diverge CNS
autonomic reactions • Warning system,
capacity for
amplification
Cervero F, Laird J, Lancet 353, 1999.
Siddal, Cousins. Neural Blockade in Clinical Anesthesia and Management of Pain, Third Ed.,1998.
Milan MJ, Progress in Neurobiology 66, 2002.
Inflammation
• Redness (rubor)
• Heat (calor)
• Swelling (tumor)
• Loss of function (function lasea)
• Pain (dolor)
Inflammation
• Macrophages:
– Cytokines(IL1, IL6, TNF-α)
– Nerve Growth Factor
• Damaged Cells:
– ATP and protons
• Mast Cells:
– Histamine, serotonin, prostaglandins, arachidonic
acid metabolites
• Upregulation of receptors
– VR1, SNS, SNS-2 & Peptides
• Phenotypic Switch ( A-fiber into C-fiber)
Jensen et al. Acat Anaesthesiol Scand 45, 2001.
Inflammation
• Short-term
– Modifications in excitation & sensitization of
peripheral sensory terminals
• Longer-term
– Changes in properties of afferents
– Decrease in threshold for firing
– Increase in excitability of spinal neurons

Mamet et al. J of Neuroscience, 22(24), 2002.


Hyperalgesia Sensitization

pain threshold threshold for response

pain to suprathreshold response to


stimuli suprathreshold stimuli

Spontaneous pain Spontaneous activity


Peripheral Sensitization
Tissue Damage Inflammation Sympathetic Terminals

SENSITIZING ‘SOUP’
Hydrogen Ions Histamine Purines
Noradrenaline Potassium Cytokines
Bradykinin Prostaglandins NGF
Leukotrienes 5-HT Neuropeptides

Woolf, Chong. Anesth. Analgesia (77), 1993.


Peripheral Sensitization
Plasma Extravasation
Vasodilation
SKIN
TNF-α
IL-6
Macrophage LIF
Mast Tissue
Cell Damage

Pressure ?
Heat Bradykinin
5-HT3 Histamine PGE2 IL1ß NGF ATP H+

VR1 5-HT3 H1 EP B1/B2 IL1-R TrkA P2X ASIC


H+
Ca2+

(PKC)
PKA Peripheral
PKC TTXs Nerve
Gene
TTXr
(SNS/SNS2) Regulation Terminal
TTXr
Sub P

Adapted from Woolf CJ, et al. Science. 2000;288:1765-1768.


Central Sensitization: wind up
With permission. Jensen TS et al. Acta Anaesth Scand, 45, 2001.
Mechanisms of Nociceptive
Central Pain
• Autosensitization of receptors
• Ectopic firing of DRG cells
• Calcium-induced molecular cascades from
excess glutamate
• Phenotypic change of A-β cells and DRG
• Changes in gene expression of sodium
channels and neuropeptides
• Anatomic changes at dorsal horn

Schwarzman et al. Neurological Review, 58, 2001.


With Permission. Woolf,2000.
Mechanisms of nociceptive central pain

1. Autosensitization of receptors
2. Ectopic firing of DRG cells
3. Calcium-induced molecular cascades
from excess glutamate
4. Phenotypic change of A-β cells and DRG
5. Changes in gene expression of sodium
channels and neuropeptides
6. Anatomic changes at dorsal horn
Schwarzman et al. Neurological Review, 58, 2001.
Neuropathic Pain Is Defined
as…
…Pain caused by a lesion or dysfunction
of the nervous system1
• Nerve sensitization or damage
can be located in the peripheral
or central nervous system1
• Manifests with sensory symptoms
and signs2
• May have both positive and
negative sensory and motor symptoms and
signs2

1. Merskey H, Bogduk N, eds. Classification of Chronic Pain. 2nd ed. Seattle, WA: IASP Press; 1994.
2. Backonja MM. Anesth Analg. 2003;97:785-790.
Examples of Peripheral vs. Central
Sensitization
Sensory function after nerve injury with spontaneous firing along axon

To Brain
No
Pain
Stimulus Nociceptor Sensation
Dorsal Horn
Neuron

Central sensitization occurs as a result of increased nociceptor drive or disinhibition


after nerve injury, leading to exaggerated dorsal horn response
Inhibitory Input Is
Downregulated

To
Brain
Innocuous
Innocuous Dorsal Horn or Noxious Dorsal Horn
Stimulus Neuron Stimulus Neuron

Increased Nociceptor Drive Disinhibition

Adapted from Woolf CJ, Mannion RJ. Lancet. 1999;353:1959-1964.


Persistent Pain as a Disease
Entity:
• Increase peripheral input: increase DH
firing
• Increase firing: increased NMDA, Ca,
PKC, Nitric Oxide
• Increase PKC, Ca: genetic changes
• Increase NO: decreased GABA neurons
• Increase Neurotrophins: sprouting
Cousins, MJ, 2009 AAPM
Beydoun A, Backonja. J Pain Symp Management 2003.
Temperature
Thermosensation

Julius D, Proc 10th Word Conference of Pain, 2003.


Thermosensation
TRP channel family
• TRV2 >53 C Noxious heat
• TRPV1 (Vanilloid) >43 C Heat, capsaicin, acid
• TRPV3/TRPV4 >30-40 C Warm
• TRPM8 (CMRI) >25 C Cold, menthol
• TRPA1 <17 C Noxious cold

Szalassi et al. Nature Rev 2007;6.


Thermosensation
Cold Heat
• 10-15% C & A-delta • Capsaicin
• Specificity vs. modulation • Vanilloid receptor
of excitatory & inhibitory subtype 1 (VR1 or
channels TRPV1)
• K, Na, Ca channels • Thermal activation
• CMRI (cold- and menthol- threshold ~43°C
sensitive receptor) cloned • Polymodal, influenced by
• TRP (transient receptor a variety of substances
potential)

Julius D, Proc 10th Word Conference of Pain, 2003.


Capsaicin
genus Capsicum:
mildest (bell) to hottest (habanero)
Capsaicin: 16,000,000 SHU habanero: 200,000 SHU
Classic:
• Activates, desensitize (Ca²), and exert neurotoxic
effects on polymodal nociceptors
• release of Subst P & CGRP, nerve degeneration
(NGF), loss of intraepidermal fibers
• “pharmacological” & “functional desensitization” via
VR1 receptor

Anand P. Gut 52, 2003. Robbins


W. Clin J Pain 16(2), 2000.
TRPV Channels:

Szalassi et al. Nature Rev 2007;6.


Menthol: natural analgesic

• Mentha species
• peppermint plant, cornmint oil,
citronella, eucalyptus & Indian
turpentine oil
• “coolness”: stimulation of cold
receptors by (-) Calcium currents of
neuronal membranes, increasing
pain thresholds
• Activation of central “κ” Opioid
system

Galeotti N. Neuroscience Letters 322 (2002). McKeny, Nature 416, 2002.


Pain Neurochemistry
Transmission via
spinothalamic tract Dorsal Ion fluxes Tissue injury
to brain horn (H+/ K+)
Dorsal root
ganglion Bradykinin
Prostaglandins

Leukotrienes

Spinal cord

Substance P

To brain

Histamine Sensitized
nociceptor
Substance P, aspartate,
neurotensin, glutamate
Neuromatrix
Apkarian AV, et al. J of Neuroscience, 24(46), 2004.
Price DD. Science 2000.

Price DD. Science. 2000;288:1769-1772.


Price DD. Science. 2000;288:1769-1772.
“Pain Matrix”

Moseley GL. Man Ther. 2003;8(3):130-140.


“Pain Matrix”
• Anterior cingulate cortex (ACC)
• Insular cortex (IC)
• Thalamus
• Sensorimotor cortex (SSI, SSII)
• Cerebellum

Moseley GL. Man Ther. 2003;8(3):130-140.


Petrovic P, et al. Science 2002;295:1737-1740.
Petrovic P, et al. Science. 2002;295:1737-1740.
Opioid Systems
• Reynolds: (1969)
• Endogenous opioid system
• PAG & NMM: “funnel”
• Homeostatic and
behavioral adjustments

Mason P. J Neurophysiol. 2005;94:1659-1663.


Finniss DB, Benedetti F. Pain. 2005;114:3-6.
Petrovic P, Ingvar M. Pain. 2002;95:1-5.
Tracey, 2008

INJURY SYMPTOMS
Spontaneous
Tissue Damage Hyperalgesia Allodynia
Pain

CENTRAL
PERIPHERAL
ACTIVITY SENSITIZATION

Decreased Increased
threshold to
peripheral stimuli Expansion of Spontaneous
Nerve Damage Receptive field activity
Summary: “a gain in pain”
• Nociceptive vs. Neuropathic pain
• Chronic changes in the nervous system
may not be reversible
• Understanding of channels and receptors
evolving
• Medications and therapies targeted at
specific mechanisms
• Pain is not just a passive transfer of input
along a fixed system