Pathophysiology Of Pain

Neurobiology of Pain

Pathophysiology of the Pain Response Peripheral and Central Nervous System Involvement

The Pain Response Tissue Damage

Transmission of the Pain Signal to the Brain

Activation of the Peripheral Nervous System

Activation of the Central Nervous System at the Spinal Cord Level

Pain Samad TA et al. Nature. 2001;410:471-5.

The Pain Pathway Brain Dorsal Root Ganglion

Pain Perception

Dorsal Horn

Spinal Cord Nociceptor

Gottschalk A et al. Am Fam Physician. 2001;63:1979-84. Fields HL et al. Harrison’s Principles of Internal Medicine. 1998:53-8.

Central Pain Transmission

Nociceptors • Nociceptors process and transmit painful stimulation to CNS • Mostly C and Aδ fibers • C fibers unmyelinated and activated by chemical, thermal and mechanical stimulation • Aδ fibers are myelinated and are 25 X faster than C fibers • Mechanical and thermal activation • Somatic structures rich in Aδ fibers and C fibers vs visceral structures with mostly C fibers • Aδ fibers allows rapid precise location of injury • Pain from C fibers more dull, ill-defined and longer lasting

Neuronal Plasticity and Pain Peripheral

Activation

Autosensitization

Central Windup

Modulation Heterosensitization

Central Sensitization Modification

Persistent, Pathologic Pain

Persistent, Pathologic Pain Woolf CJ et al. Science. 2000;288:1765-8. Sivilotti LG et al. J Neurophysiol. 1993;69:162131.

Peripheral Activation

VR1

External

•Heat

Ca

2+

Voltage-Gated Sodium Channels

•Mechanical

Stimuli

•Chemical

Action Potentials

Adapted from Woolf CJ et al. Science. 2000;288:1766.

Peripheral Modulation External Stimulus VR1

HEAT Sensitizing Stimulus

PKA EP Receptor

PGE2

SNS/PN3

PKCε

Bradykinin

TTX-Resistant Sodium Channel

BK Receptor

EP = prostaglandin E; BK = bradykinin.

Adapted from Woolf CJ et al. Science. 2000;288:1766.

Peripheral Modulation • Substance P released from unmyelinated nociceptive nerve treminals • Found in cell bodies of spinal and gasserian ganglia • Presence in PNS is 4X that on CNS • Found in somatic and visceral nervous systems • A vasodilator, it causes local vasodilation and changes in vascular permeability • Results in recruitment of other local nociceptor fibers

Peripheral Modulation • SP causes local tissue edema • Lowers the threshold of surrounding nociceptor fibers thus increasing field of local response and intensity • Capsacin, which depletes SP from peripheral nerve terminals used as local analgesic

Central Sensitization / Modulation • Activation: windup of dorsal horn nociceptors • Modulation: altered synaptic transmission • Modification: altered pain transmission neurons

Woolf CJ et al. Science. 2000;288:1765-8.

Activation of Central Neurons C-Fiber Terminal

Glutamate

P

NMDA

(-)

Substance P AMPA

P

(+)

Ca2+

(+)

Dorsal Horn Neuron

PKC

Woolf CJ et al. Science. 2000;288:1765-8. Schwartzman RJ et al. Arch Neurol. 2001;58:1547-50.

Activation of Central Neurons • • • •

Dorsal horn divided into lamina Lamina I is most superficial and lateral C and Aδ fibers synapse here and in lamina V A fibers which transmit light touch, proprioception and muscle tone synapse mostly in III, IV and V • Wide-dynamic neurons (WDN) also found in V • WDN receive signals from both visceral and somatic structures and may be responsible for referred pain • Interneurons e.g. excitatory stalk cells are located in lamina II and inhibitory islet cells in lamina I

Sensitization 10

Pain Intensity

8

Hyperalgesia

6 Allodynia

Normal Pain Response Injury Hyperalgesia—heightened sense of pain to noxious stimuli

4

Allodynia—pain resulting from normally painless stimuli

2 0 Stimulus Intensity

Gottschalk A et al. Am Fam Physician. 2001;63:1979-84.

Neuropathic Pain

Varies Neuropathic Pain Pain initiated or caused by a primary lesion or dysfunction in the nervous system (either peripheral or central nervous system)1

Pain caused by injury to body tissues (musculoskeletal, cutaneous or visceral)2

Pain with neuropathic and nociceptive components

Examples Peripheral • Post-herpetic neuralgia • Trigeminal neuralgia • Diabetic peripheral neuropathy • Post-surgical neuropathy • Post-traumatic neuropathy Central • Post-stroke pain Common descriptors2 • Burning • Tingling • Hypersensitivity to touch or cold

Nociceptive Pain

Mixed Pain

Examples

• Low back pain with • • •

radiculopathy Cervical radiculopathy Cancer pain Carpal tunnel syndrome

1. International Association for the Study of Pain. IASP Pain Terminology. 2. Raja et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;11-57

Examples

• • • •

Pain due to inflammation Limb pain after a fracture Joint pain in osteoarthritis Post-operative visceral pain

Common descriptors2 • Aching • Sharp • Throbbing

Proposed Neuropathic Pain Mechanisms

Nociceptors Skin Aβ -fibers * = Ectopic activity

Primary afferent fibers: ■ Ectopic discharge ■ Sensitization ■ Fiber loss/neuroma formation

Dorsal root ganglion: ■ Loss of neuronal cell bodies and scarring ■ Ectopic discharge

Dorsal horn: ■ Central sensitization ■ Loss of central inhibition ■ Deafferentationinduced rewiring

Peripherally and Centrally Induced COX-2 Peripheral Trauma/Inflammation

Central Central Sensitization

Release of Arachidonic Acid

Pain COX-2  Prostaglandins

 Prostaglandins

Pain

COX-2

Peripheral Sensitization

Samad TA et al. Nature. 2001;410:471-5. Smith CJ et al. Proc Natl Acad Sci USA. 1998;95:13313-8.

COX-2 and Peripheral Mechanisms of Pain Tissue Injury COX-2

EP Receptor

PGE2

PKA PKCε P

SNS/PN3 TTX-Resistant Sodium Channel

Resting Membrane Potential Increases Neuron Firing Threshold Decreases

Samad TA et al. Nature. 2001;410:471-5. Woolf CJ et al. Science. 2000;288:1765-8. Byers MR et al. In: Bonica’s Management of Pain. 2001:26-72.

Peripherally and Centrally Induced COX-2 Peripheral Trauma/Inflammation

Central IL-6?

Central Sensitization

Release of Arachidonic Acid IL-1ß

Pain

COX-2  Prostaglandins

 Prostaglandins

Pain

COX-2

Peripheral Sensitization

Samad TA et al. Nature. 2001;410:471-5. Smith CJ et al. Proc Natl Acad Sci USA. 1998;95:13313-8.

COX-2–Dependent Central Modulation C-Fiber Terminal Glutamate

NMDA

(-)

P

Substance P

AMPA

P

Ca2+

(+)

(+)

Dorsal Horn Neuron

PKC (+)

Na+

PGE2

PGE2

COX-2 Induction Samad TA et al. Nature. 2001;410:471-5. Woolf CJ et al. Science. 2000;288:1765-8.

Modulation of Central Neurons C-Fiber Terminal GABA Glycine

Glutamate

NMDA

(-)

P

Substance P AMPA

P

(+)

Ca2+

(+)

Dorsal Horn Neuron

PKC

Woolf CJ et al. Science. 2000;288:1765-8. Schwartzman RJ et al. Arch Neurol. 2001;58:1547-50. Terman GW et al. Bonica’s Management of Pain. 2001:92-3.

Role of COX-2 in Inflammatory Pain Summary • Peripheral induction – at site of injury – local prostaglandin synthesis → pain, inflammation

• Central induction – via PNS – independent of PNS transmission • occurs even following complete sensory nerve block • blood-borne • humorally mediated (IL-1β, IL-6) • long lasting Samad TA et al. Nature. 2001;410:471-5.

COX-2 Induction Hypothesis and COX-2 Specific Inhibitors • COX-2 specific inhibitor therapy may – work at both peripheral and central sites • must readily cross blood-brain barrier for CNS effects1 – prevent COX-2 up-regulation in the CNS with early use2 • inhibition of central sensitization caused by COX-2 induction (↓ prostaglandin synthesis, neurotransmitter release, neuronal excitability) 1. Samad TA et al. Trends Mol Med. 2002;8:390-6. 2. Samad TA et al. Nature. 2001;410:471-5.

Gate Control Theory • Proposed by Melzack and Wall in 1960’s • Non-nociceptive transmission via large myelinated fibers • Nociceptive transmission via C and Aδ fibers • Enters dorsal horn and substantia gelatinosa and via dorsal column and T cells mediating transmission of signals to brain • Theory states that transfer of information to T cells and then to brain depends of type of signal received • If activity of large fibers greater than activity of small fiber neurons, gate closed and no pain transmission • Descending influences from the brain also affects this cycle

Ascending Pain Pathways • 2nd order neurons cross over to contralateral anterior and anterolateral cord • Ascending tracts are spinothalamic, spinoreticular and spinomesencehalic tracts • Further divided into neospinolthalamic and paleospinothalamic tracts • Neospinolthalamic tract comprise of large myelinated fibers that synapse in ventral, posterior and lateral thalamus • Few synapses and quick transmission for localisation of injury • Paleospinothalamic tracts not so well myelinated and has multiple synapse in periaqueductal grey, hypothalamus and medial thalamus • Invokes emotions and memories and protective against recurrence of injury

Descending pathways • Descending systems arrives at lamina I, II and V of spinal cord via dorsolateral funiculus • Inhibitory actions involve use of serotonergic and norepinephrine neurotransmitters • TCAs are believe to enhance these pathways by increasing these chemicals • Higher brain structures e.g. cortical, medulla, PAG and periventricular gray areas also input into the descending systems

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