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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 Pain (Inflammatory?)1 Other Mixed Pain Types? Neuropathic Pain2,3

Postoperative pain
Mechanical low back pain

Arthritis Sickle cell crisis Sports/exercise injuries

Postherpetic neuralgia (PHN) Neuropathic low back pain

CRPSII* Trigeminal neuralgia

Distal polyneuropathy (e.g., diabetic, HIV)

Central poststroke pain

*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.


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 protection of injured or Interoceptive: 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

Acute Pain

Normal Healing

Healing With Plasticity

Pain Relief



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

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 Pathway


Ascending Pathway C-Fiber - Fiber - Fiber Dorsal Horn Dorsal Root Ganglion

Spinal Cord

Peripheral Nerve

Transmission/ Modulation



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 (m) Letter System Conduction velocity (m/sec) Myeli n Receptor/ ending


12-20 12-20 12-20


70-120 70-120 70-120

+ + +

Muscle spindle primary endings Golgi Tendon organs Muscle efferents (extrafusal) Encapsulated endings;Merkel Muscle efferents (intrafusal) A- specific & polymodal; cold; hair; visceral (+/-) Preganglionic autonomic
C-nociceptors; C-polymodal; warmth, mechano;postganglioic autonomic; enteric nerve fibers

2-10 1-6 <3 <1.5

A- A- B C

10-50 5-30 3-15 0.5-2.0

+ + + No

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

Conduction Velocity: A & C fibers

A (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.

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.

C-fiber Small diameter Slow conducting Unmyelinated 1. Proinflammitory peptides Subst P CGRP Lamina I/II * tissue inflammation (NGF) 2. Specific enzymes/ Lectin IB4 *chronic neuropathic pain (GDNF)
Caterina, Cur Op in Neurobiology (9), 1999.

A- Medium diameter Fast conducting Lightly myelinated Polymodal Type I

Long response latency

> 50C Persistent pain 2. Type II Short response 43C Initial burn

Primary Afferent C & A Fibers

Sensation Mediated
Fibre Threshold Principal Class For Transmitters Activation SP/NKA C High CGRP EAA Receptors Physiological Pathological Engaged NK CGRP NMDA AMPA mGlu AMPA Noxious (pain) Highly noxious (hyperalgesia) Cold Allodynia (pain) Mechanical allodynia



Innocuous (no pain)

Millan, Progress in Neurobiology, 1999.

Receptor types on sensory neurons

Transduction mechanism Ligand-gated channel Example Capsaicin-heat H , 5HT, ATP Glutamate, GABA-A GABA-B Opiated, Adenosine Adrenoreceptors NPY, 5HT Bradykinin(B2) Histamine (H1) Adrenoreceptors (2) PGE2 NGF (Trk A) Cellular effect Excitation

G-protein linked

Inhibition of transmitter & peptide release

Excitation and/or sensitization Control of gene expression

Tyrosine kinase linked

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

Capsaicin/ Vanilloid Purinergic (P2X)

Ion Channel Linked Receptors

Receptors Vanilloid (VR-1) Acid-sensing (ASIC) Purinergic (P2X) Cannabinoid Ion Channels Sodium


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 A in viscera Skeletal muscle: group III, group IV Joint: group III & group IV respond to stretch

Visceral Pain
Psychophysics Not evoked from all viscera Not always linked to injury Referred to body wall Diffuse & poorly localized Intense motor & autonomic reactions Neurobiology Not all innervated by sensory receptors Functional properties of afferents Viscerosomatic convergence in CNS Few sensory visceral afferents, diverge CNS 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.

Redness (rubor) Heat (calor) Swelling (tumor) Loss of function (function lasea) Pain (dolor)

Macrophages: Cytokines(IL1, IL6, TNF-) 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.

Modifications in excitation & sensitization of peripheral sensory terminals

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.

pain threshold pain to suprathreshold stimuli Spontaneous pain

threshold for response response to suprathreshold stimuli Spontaneous activity

Peripheral Sensitization
Tissue Damage Inflammation Sympathetic Terminals

Hydrogen Ions Noradrenaline Bradykinin Leukotrienes Histamine Potassium Prostaglandins 5-HT Purines Cytokines NGF Neuropeptides

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

Peripheral Sensitization
Plasma Extravasation Vasodilation Macrophage

Tissue Damage Pressure ?

Mast Cell


5-HT3 Histamine PGE2 VR1 H+ 5-HT3 H1 EP

Bradykinin IL1 NGF ATP B1/B2



Ca2+ (PKC) PKA PKC TTXr (SNS/SNS2) Sub P Gene Regulation TTXr TTXs

Peripheral Nerve Terminal

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- 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- 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 Stimulus Nociceptor Dorsal Horn Neuron Pain Sensation

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 Stimulus Dorsal Horn Neuron Innocuous or Noxious Stimulus Dorsal Horn Neuron

Increased Nociceptor Drive


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.



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

TRP channel family
TRV2 TRPV1 (Vanilloid) >53 C >43 C Noxious heat Heat, capsaicin, acid


>30-40 C Warm
>25 C <17 C Cold, menthol Noxious cold

Szalassi et al. Nature Rev 2007;6.

10-15% C & A-delta Specificity vs. modulation of excitatory & inhibitory channels K, Na, Ca channels CMRI (cold- and mentholsensitive receptor) cloned TRP (transient receptor potential)

Capsaicin Vanilloid receptor subtype 1 (VR1 or TRPV1) Thermal activation threshold ~43C Polymodal, influenced by a variety of substances

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

genus Capsicum:
mildest (bell) to hottest (habanero) Capsaicin: 16,000,000 SHU Classic: habanero: 200,000 SHU

Activates, desensitize (Ca), 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. W. Clin J Pain 16(2), 2000. Robbins

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 Opioid system

Galeotti N. Neuroscience Letters 322 (2002).

McKeny, Nature 416, 2002.

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

Spinal cord
Substance P

To brain
Substance P, aspartate, neurotensin, glutamate

Sensitized nociceptor


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

Tissue Damage

Spontaneous Hyperalgesia Pain Allodynia



Decreased threshold to peripheral stimuli

Increased Expansion of Spontaneous Receptive field activity

Nerve Damage

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