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Neurobiology of Pain

Pathophysiology of the
Pain Response
Peripheral and Central Nervous
System Involvement
The Pain Response
Activation of the
Tissue Damage
Peripheral Nervous
System

Activation of the Central


Transmission of the Pain
Nervous System
Signal to the Brain
at
the Spinal Cord Level

Pain
Samad TA et al. Nature. 2001;410:471-5.
The Pain Pathway
Pain Perception
Brain

Dorsal Root Dorsal Horn


Ganglion

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 Central

Autosensitization 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;69:1621-
31.
Peripheral Activation

VR1
Voltage-Gated
•Heat
External Ca2+
Sodium Channels

•Mechanical
Stimuli •Chemical
Action Potentials

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


Peripheral Modulation

External Stimulus
VR1
HEAT
PKA
Sensitizing Stimulus EP
Receptor SNS/PN3
PGE2
PKCε TTX-Resistant
Sodium
Bradykinin 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
P
AMPA
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

8 Hyperalgesia Normal
Pain
Pain Intensity

Response
6 Injury
Allodynia
Hyperalgesia—heightened
4 sense of pain to noxious
stimuli
2 Allodynia—pain resulting
from normally painless
stimuli
0

Stimulus Intensity

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


Neuropathic Pain
Varies

Neuropathic Pain Mixed Pain Nociceptive Pain


Pain initiated or caused by a Pain with Pain caused by injury to
primary lesion or dysfunction neuropathic and body tissues
in the nervous system nociceptive (musculoskeletal,
(either peripheral or components cutaneous or visceral)2
central nervous system)1

Examples Examples Examples


Peripheral
• Post-herpetic neuralgia • Low back pain with • Pain due to inflammation
• Trigeminal neuralgia radiculopathy • Limb pain after a fracture
• Diabetic peripheral neuropathy • Cervical radiculopathy • Joint pain in osteoarthritis
• Post-surgical neuropathy • Cancer pain • Post-operative visceral pain
• Post-traumatic neuropathy • Carpal tunnel syndrome
Central Common descriptors2
• Post-stroke pain • Aching
Common descriptors2 • Sharp
• Burning • Throbbing
• Tingling
• Hypersensitivity to touch or cold
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
Proposed Neuropathic Pain
Mechanisms

Nociceptors
Skin

Aβ -fibers
* = Ectopic activity

Primary afferent Dorsal root Dorsal horn:


fibers: ganglion: ■ Central
■ Ectopic ■ Loss of sensitization
discharge neuronal cell ■ Loss of central
■ Sensitization bodies and inhibition
■ Fiber scarring ■ Deafferentation-
loss/neuroma ■ Ectopic induced rewiring
formation discharge
Peripherally and
Centrally Induced COX-2
Peripheral Central
Trauma/Inflammation Central Sensitization

Release of Arachidonic Acid


Pain
COX-2

 Prostaglandins  Prostaglandins

COX-2
Pain

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


Peripheral Sensitization 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 PKA
Receptor PKCε
PGE2
P
Resting
SNS/PN3
Membrane
TTX-Resistant Potential
Sodium Increases
Channel
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 Central
Trauma/Inflammation Central Sensitization
IL-6?

Release of Arachidonic Acid


IL-1ß Pain
COX-2

 Prostaglandins  Prostaglandins

COX-2
Pain

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


Peripheral Sensitization 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
Glutamate Glycine

(-)
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 • Central induction
– at site of injury – via PNS
– local prostaglandin – independent of PNS
synthesis → pain, transmission
inflammation • 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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