Pathophysiology of PainPathophysiology of PainPathophysiology of PainPathophysiology of Pain

Nociception Nociception Nociception Nociception

The detection of tissue damage by The detection of tissue damage by specialized transducers connected to specialized transducers connected to A-delta and C-fibers A-delta and C-fibers

PainPainPainPain

An unpleasant sensory and emotional An unpleasant sensory and emotional experience which we primarily associate experience which we primarily associate with tissue damage or describe in terms of with tissue damage or describe in terms of such damage, or both such damage, or both

Classification of Pain NociceptionClassification of Pain NociceptionClassification of Pain NociceptionClassification of Pain Nociception

• Proportionate to the stimulation of the Proportionate to the stimulation of the nociceptornociceptor

• When acuteWhen acute– Physiologic painPhysiologic pain

– Serves a protective functionServes a protective function

– Normal painNormal pain

• Pathologic when chronicPathologic when chronic

Classification of Pain:Classification of Pain:Neuropathic PainNeuropathic Pain

Classification of Pain:Classification of Pain:Neuropathic PainNeuropathic Pain

• Sustained by aberrant processes in Sustained by aberrant processes in PNS or CNSPNS or CNS

• Disproportionate to the stimulation of Disproportionate to the stimulation of nociceptornociceptor

• Serves no protective functionServes no protective function

• Pathologic painPathologic pain

Classification of Pain: Mixed PainClassification of Pain: Mixed PainClassification of Pain: Mixed PainClassification of Pain: Mixed Pain

• Nociceptive componentsNociceptive components

• Neuropathic componentsNeuropathic components

• ExamplesExamples– Failed low-back-surgery syndromeFailed low-back-surgery syndrome

– Complex regional pain syndromeComplex regional pain syndrome

Classification of Pain: Idiopathic PainClassification of Pain: Idiopathic PainClassification of Pain: Idiopathic PainClassification of Pain: Idiopathic Pain

• No underlying lesion found yet, despite No underlying lesion found yet, despite investigationinvestigation

• Pain disproportionate to the degree of Pain disproportionate to the degree of clinically discernible tissue injuryclinically discernible tissue injury

Normal Central Pain Normal Central Pain MechanismsMechanisms

Normal Central Pain Normal Central Pain MechanismsMechanisms

Peripheral and Central Pathways for PainPeripheral and Central Pathways for PainPeripheral and Central Pathways for PainPeripheral and Central Pathways for PainAscending TractsAscending Tracts Descending TractsDescending Tracts

Cortex

Midbrain

Medulla

Spinal Cord

Thalamus

Pons

Pain-Inhibitory and Pain-Facilitatory Pain-Inhibitory and Pain-Facilitatory Mechanisms Within the Dorsal HornMechanisms Within the Dorsal HornPain-Inhibitory and Pain-Facilitatory Pain-Inhibitory and Pain-Facilitatory Mechanisms Within the Dorsal HornMechanisms Within the Dorsal Horn

A-DELTAA-BETA C

Neuronal circuitryNeuronal circuitrywithin the dorsal horn.within the dorsal horn.Primary afferent neuronPrimary afferent neuronaxons synapse onto axons synapse onto spinothalamic neurons spinothalamic neurons and onto inhibitory and and onto inhibitory and excitatory neurons.excitatory neurons.

TO BRAIN

+ +

+_ _

+

0

STTSTTNEURONNEURON

STTSTTNEURONNEURON

Rating of First and Second Pain IntensityRating of First and Second Pain IntensityRating of First and Second Pain IntensityRating of First and Second Pain Intensity

Adapted with permission from Cooper BY, et al. Adapted with permission from Cooper BY, et al. Pain.Pain. 1986;24:103 1986;24:103 andand from Lee KH, et al. In: Fields HL, from Lee KH, et al. In: Fields HL, Dubner R, Cervero F, eds. Dubner R, Cervero F, eds. Proceedings of the Fourth World Congress on Pain.Proceedings of the Fourth World Congress on Pain. New York, NY: Raven Press; New York, NY: Raven Press; 1985:204.1985:204.

Mechanisms of Pathologic PainMechanisms of Pathologic PainMechanisms of Pathologic PainMechanisms of Pathologic Pain

Mechanisms of Pathologic Pain: Mechanisms of Pathologic Pain: General ConsiderationsGeneral Considerations

Mechanisms of Pathologic Pain: Mechanisms of Pathologic Pain: General ConsiderationsGeneral Considerations

• Pain-processing mechanisms function Pain-processing mechanisms function abnormallyabnormally– Examples: neuropathic pain syndromesExamples: neuropathic pain syndromes

• Nociception is sustained by chronic injuryNociception is sustained by chronic injury– Example: arthritisExample: arthritis

  Mechanisms of Pathophysiologic Pain: Mechanisms of Pathophysiologic Pain: Peripheral ProcessesPeripheral Processes

  Mechanisms of Pathophysiologic Pain: Mechanisms of Pathophysiologic Pain: Peripheral ProcessesPeripheral Processes

•   Injured or diseased nerve(s)Injured or diseased nerve(s)

• Growth of axonal sproutsGrowth of axonal sprouts

• Formation of ectopic fociFormation of ectopic foci

Mechanisms of Pathophysiologic Pain: Mechanisms of Pathophysiologic Pain: Central Sensitization ProcessesCentral Sensitization Processes

Mechanisms of Pathophysiologic Pain: Mechanisms of Pathophysiologic Pain: Central Sensitization ProcessesCentral Sensitization Processes

• Repeated impulse activity in C nociceptive Repeated impulse activity in C nociceptive neurons produces sensitization of STT neurons neurons produces sensitization of STT neurons over timeover time

• Sensitization of STT neurons leads toSensitization of STT neurons leads to– Increased spontaneous impulse activity Increased spontaneous impulse activity – Enhanced responses to impulses in nociceptive and Enhanced responses to impulses in nociceptive and

non-nociceptive primary afferentsnon-nociceptive primary afferents

• Causes hyperalgesia, allodynia, and spontaneous Causes hyperalgesia, allodynia, and spontaneous painpain

Temporal summation of second pain (second pain summation is a result of repeated input from C-fiber).

Temporal summation of responses of a dorsal horn (STT) neuron to repeated C-fiber stimulation and the effects of the NMDA-receptor antagonist ketamine.

Reproduced with permission from Price DD, et al. In: Fields HL, Liebeskind JC, eds. Pharmacological Approaches to the Treatment of Chronic Pain: New Concepts and Critical Issues. Seattle, Wash: IASP Press; 1994:66.

Mechanism of Central Sensitization Associated Mechanism of Central Sensitization Associated With Tonic C Nociceptor InputWith Tonic C Nociceptor Input

Mechanism of Central Sensitization Associated Mechanism of Central Sensitization Associated With Tonic C Nociceptor InputWith Tonic C Nociceptor Input

Enhanced postsynaptic effects by NMDA-receptor sensitization

Tonic activity in C nociceptors

A-DELTAA-BETA

TO BRAIN

+ +

+_ _

+

0

STTSTTNEURONNEURON

STTSTTNEURONNEURON

+

+++ +

C

Intracellular Intracellular Mechanisms Mechanisms of of SensitizationSensitization

Intracellular Intracellular Mechanisms Mechanisms of of SensitizationSensitization

Reproduced with permission from Mao J, et al. Pain. 1995;61:361.

Enhanced postsynaptic effects by NMDA-receptor sensitization

Tonic activity in C nociceptors

A-DELTAA-BETA

TO BRAIN

+ +

+_ _

+

0

STTSTTNEURONNEURON

STTSTTNEURONNEURON

+++ +

Loss of Inhibitory ILoss of Inhibitory Interneuron Functionnterneuron FunctionLoss of Inhibitory ILoss of Inhibitory Interneuron Functionnterneuron Function

C

Brain-to-Spinal-Cord Brain-to-Spinal-Cord Modulation of PainModulation of Pain

Brain-to-Spinal-Cord Brain-to-Spinal-Cord Modulation of PainModulation of Pain

Pain Modulation MechanismsPain Modulation MechanismsPain Modulation MechanismsPain Modulation Mechanisms

• Brain centers/pathways that descend to the Brain centers/pathways that descend to the spinal cord and modulate painspinal cord and modulate pain

• ““Tail-flick test”Tail-flick test”

• ““Off-cells” inhibit transmission of pain-Off-cells” inhibit transmission of pain-related information to the brainrelated information to the brain

• ““On-cells” facilitate transmission of pain-On-cells” facilitate transmission of pain-related signals to the brainrelated signals to the brain

Pathophysiology of Pain: ConclusionPathophysiology of Pain: ConclusionPathophysiology of Pain: ConclusionPathophysiology of Pain: Conclusion

• Neuronal plasticityNeuronal plasticity– Nociceptor, spinal cord, brainNociceptor, spinal cord, brain

• Pain-facilitatory and pathophysiologic Pain-facilitatory and pathophysiologic mechanismsmechanisms– Wind-up phenomenonWind-up phenomenon

– Central sensitizationCentral sensitization

• Modulating mechanismsModulating mechanisms– AscendingAscending

– DescendingDescending