Pathophysiology of Acute & Chronic Pain

Steven Stanos, DOCenter for Pain Management

Rehabilitation Institute of ChicagoDept. of PM&R, Northwestern

University Medical SchoolFeinberg 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

*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.

Other “Mixed” Pain Types?

NociceptivePain

(Inflammatory?)1

Neuropathic Pain2,3

Postoperativepain

Mechanicallow back pain

Sickle cellcrisis

Arthritis

Postherpeticneuralgia

(PHN)

Neuropathic low back pain

CRPSII*

Sports/exerciseinjuries

Central post-stroke pain

Trigeminalneuralgia

Distalpolyneuropathy (e.g., diabetic, HIV)

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

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

A. Sensory

B. Affective

C. Evaluative

Enteroceptive Sensations

• Pain

• Thirst

• Hunger

• Thermoception

• Neurophysiologic changes

• Neurochemical changes

Biological Functions of Pain

Sherrington (1906)

Exteroceptive:

Interoceptive:

Escape and avoidance of external threats

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

Chronic Pain

Hyperalgesia Allodynia

The Role of Plasticity in Chronic Pain

Injury

Acute Pain

Healing With PlasticityNormal Healing

Pain Relief

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

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.

Injury

PeripheralNerve

Brain

DescendingPathway

AscendingPathway

SpinalCord

DorsalHorn

DorsalRoot

Ganglion

C-Fiber

α-β Fiber

α-δ Fiber

Conduction

Transduction

Transmission/Modulation

Perception

Kidd, Urban. Br J Anaesthesia 2001;87(1).

Pathologic vs. PhysiologicPathologic vs. Physiologic

C-nociceptors; C-polymodal; warmth, mechano;postganglioic autonomic; enteric nerve fibers

No0.5-2.0C <1.5IV

Preganglionic autonomic

+3-15B<3-

A-δ specific & polymodal; cold; hair; visceral (+/-)

+5-30A-δ1-6III

Muscle efferents (intrafusal)

+10-50A-γ2-10-

Encapsulated endings;Merkel

+30-70A-β6-12+II

Muscle efferents

(extrafusal)+70-120A-α12-20-

Golgi Tendon organs+70-120-12-20I-b

Muscle spindle primary endings

+70-120-12-20I-a

Receptor/ endingMyelin

Conduction velocity

(m/sec)

Letter

System

Diameter

(µm)

Lloyd /Hunt

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

Classification of Fibers in Peripheral Nerves

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.

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

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

Caterina, Cur Op in Neurobiology (9), 1999.

CutaneousC-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)

A-δ• Medium diameter• Fast conducting• Lightly myelinated• Polymodal

Type I

Long response latency

> 50°C

Persistent pain

2. Type II

Short response

43°C

Initial burn

Millan, Progress in Neurobiology, 1999.

Primary Afferent C & Aβ Fibers

Sensation MediatedFibre Class

Threshold For Activation

Principal Transmitters

Receptors Engaged

Physiological Pathological

C High SP/NKA

CGRP

EAA

NK

CGRP

NMDA

AMPA

mGlu

Noxious (pain)

Highly noxious

(hyperalgesia)

Cold Allodynia

(pain)

Aβ Low EAA AMPA Innocuous (no pain)

Mechanical

allodynia

Receptor types on sensory neurons

Transduction mechanism Example Cellular effect

Ligand-gated channel Capsaicin-heat ExcitationH , 5HT, ATPGlutamate, GABA-A

G-protein linked GABA-B Inhibition ofOpiated, Adenosine transmitter &Adrenoreceptors peptide releaseNPY, 5HT

Bradykinin(B2) Excitation Histamine (H1) and/or Adrenoreceptors (α2) sensitizationPGE2

Tyrosine kinase linked NGF (Trk A) Control of geneexpression

Bevan S. Textbook of Pain, 4th ed. Wall, Malzack, 1999.

• Dynamic, constantly changing

• Plasticity reflects sensitivity needed for survival

• Injury: amygdala, hippocampus, and DRG

• Normal peripheral nerves (resist)

• Demyelination: density

Ion Channels

Receptors

• Capsaicin/ Vanilloid • Purinergic (P2X)

Ion Channel Linked Receptors

Receptors• Vanilloid (VR-1)• Acid-sensing (ASIC)• Purinergic (P2X)• Cannabinoid

Ion Channels• Sodium

– TTX-S– TTX-R

• 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

Cervero F, Laird J, Lancet 353, 1999.

Visceral PainPsychophysics• 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

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

SENSITIZING ‘SOUP’Hydrogen Ions Histamine Purines

Noradrenaline Potassium Cytokines

Bradykinin Prostaglandins NGF

Leukotrienes 5-HTNeuropeptides

Tissue Damage

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

Peripheral Sensitization

Inflammation Sympathetic Terminals

SKIN

Peripheral Sensitization

PeripheralNerve

Terminal

Pressure ?

Plasma ExtravasationVasodilation

Heat 5-HT3 PGE2

Bradykinin

VR1 5-HT3 EP B1/B2

IL1ß

MastCell

Macrophage

(PKC)

TNF-α IL-6LIF

IL1-R TrkAH+

PKC

TTXr(SNS/SNS2)

Sub P

Gene Regulation

TTXr

TTXs

H+

P2X ASIC

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

TissueDamage

ATPNGF

H1

Histamine

Ca2+

PKA

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

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

Sensory function after nerve injury with spontaneous firing along axon

No Stimulus Pain

SensationNociceptorDorsal Horn

Neuron

To Brain

Central sensitization occurs as a result of increased nociceptor drive or disinhibition after nerve injury, leading to exaggerated dorsal horn response

Disinhibition

Innocuous or Noxious Stimulus

Dorsal Horn Neuron

To Brain

Increased Nociceptor Drive

Innocuous Stimulus

Dorsal Horn Neuron

Inhibitory Input Is Downregulated

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.

ThermosensationCold• 10-15% C & A-delta• Specificity vs. modulation

of excitatory & inhibitory channels

• K, Na, Ca channels• CMRI (cold- and menthol-

sensitive receptor) cloned• TRP (transient receptor

potential)

Heat• Capsaicin• Vanilloid receptor subtype

1 (VR1 or TRPV1)• Thermal activation

threshold ~43°C• Polymodal, influenced by

a variety of substances

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

To brain

Dorsal horn

Substance P, aspartate, neurotensin, glutamate

Spinal cord

Dorsal root ganglion

Tissue injury

Bradykinin

Leukotrienes

Ion fluxes (H+/ K+)

Prostaglandins

Transmission via spinothalamic tract

to brain

Substance P

Histamine Sensitized nociceptor

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.

INJURY SYMPTOMS

Tissue Damage

Nerve Damage

HyperalgesiaSpontaneous

PainAllodynia

PERIPHERAL ACTIVITY

CENTRAL

SENSITIZATION

Decreased threshold to

peripheral stimuli Expansion of

Receptive field

Increased

Spontaneous

activity

Tracey, 2008

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