Pain Pathophysiology
and Pathways:
a foundation
Emily DeSantis, D.O.
Bassett Healthcare Network, Cooperstown, NY
AOCPMR Mid-year Meeting
April 20, 2012
Disclosures:
No disclosures to report
“That really hurts”

http://youtube.com/watch?v=_OBlgSz8sSM
Pre-Test Questions
1. Which proteins activate primary afferent nociceptor (PAN)
nerve endings?
A. Bradykinins
B. Histamines
C. Prostaglandins
D. Serotonin
E. Substance P
F. All of the above
Pre-Test Questions
1. Which proteins activate primary afferent nociceptor (PAN)
nerve endings?
A. Bradykinins
B. Histamines
C. Prostaglandins
D. Serotonin
E. Substance P
F. All of the above
Pre-Test Questions
2. True or False: Neuropeptides like Substance P are
released from PAN terminals into the dorsal horn of the
spinal cord, AND from (PAN) nerve endings in the
periphery.
Pre-Test Questions
2. True or False: Neuropeptides like Substance P are
released from PAN terminals into the dorsal horn of the
spinal cord, AND from (PAN) nerve endings in the
periphery.
TRUE
Pre-Test Questions
3. The development of pathologic pain states causing
hyperalgesia and allodynia involves which of the
following theorized processes?
A. Spinal sensitization
B. Loss of inhibitory interneurons from excitotoxicity
C. Perpetuation of the inflammatory response/peripheral
nociception cascade
D. Activation of “silent nociceptors”
E. Deficits in the “inflammatory reflex” including the
cholinergic anti-inflammatory pathway
F. All of the above
Pre-Test Questions
3. The development of pathologic pain states causing
hyperalgesia and allodynia involves which of the
following theorized processes?
A. Spinal sensitization
B. Loss of inhibitory interneurons from excitotoxicity
C. Perpetuation of the inflammatory response/peripheral
nociception cascade
D. Activation of “silent nociceptors”
E. Deficits in the “inflammatory reflex” including the
cholinergic anti-inflammatory pathway
F. All of the above
Objectives



Review key neurotransmitters and
neuroanatomical structures involved in peripheral
pain
Discuss proposed hypotheses of pain
mechanisms including the Inflammatory
Cascade, Dorsal Root Reflexes, Gate Control
Theory, and Spinal Facilitation
Briefly review treatment approaches designed to
modify what we understand of these “Ascending”
and “Descending” pathways
Outline
Review nomenclature
 Peripheral pain

 pathways

Spinal cord facilitation
 gate

and pathophysiology
theory, wind-up, and plasticity
Central pain pathways
 ascending

and descending modulators
Treatment strategies
What is Nociception?

Nociception is a mechanical or chemical
event, originating in peripheral tissues.
*
 This
includes bone, intervertebral discs,
muscles, vasculature, and viscera as well as
cutaneous tissue

Nociception is (arguably) consistent
between individuals.
What is Pain?

The International Association for the Study of Pain
Subcommittee on Taxonomy defined pain as “an
unpleasant sensory and emotional experience
associated with actual or potential tissue damage
or described in terms of such damage.” (Merskey &
Bogduk 1994)



Pain is a perception of the activity of nociception
in the spinal cord, brainstem, and cortex.
Pain varies with cognitive and emotional states.
Perception of pain can be modulated.
Types of Pain



Acute pain is a normal condition in which “pain is a
symptom of tissue injury.” (Bloodworth et al in Braddom 2004)
Purpose: Activates the arousal system to form a
protective action or response (ex. wound healing) to
nociceptive event
Result: Changes in the body





Muscle stiffening and altered ROM
Vasodynamic changes, shifting of circulatory compartments
Local release of pro-inflammatory compounds
Metabolic alterations favoring glucose production
New adaptive state, “ALLOSTASIS”

the maintenance of stability through change
Types of Pain



Chronic pain is “an abnormal condition…in which pain
and pain behavior become the primary disease
processes.” (Bloodworth et al in Braddom 2004)
Failure to re-establish homeostasis
Consequences:
repetitive nociceptive input on plastic neurons →
neuromodulation/spinal facilitation → hyperalgesia
(↑gain), allodynia (↓threshold), analgesia (↓output)
 sustained allostasis → slow, progressive organ system damage

Types of Pain

Allodynia refers to pain evoked by a non-painful
stimuli (ie. touch)
 As
acute pain processes progress, “a threshold...is
lowered to the extent that body temperature and the
pressure of edema are adequate stimuli to result in
spontaneous pain.” (Sorkin 1999)

Hyperalgesia refers to an increased pain or
heightened response evoked by a painful stimuli
(out-of-proportion)
Peripheral Pathway
Small Caliber (pain/PT)
 virtually unmyelinated
 naked endings
 high threshold AP
 diffuse projections
 rapidly sensitize to
repetitive stimulation
 synapse in laminas I-III
= warning system
= protection via nociception
Large Caliber (touch/2PV)
 myelinated
 encapsulated endings
 low threshold AP
 precise projections
 adapt to repetitive
stimulation
 synapse in laminas IV-VII
= decrease excitability of
small caliber fibers
= localization
Peripheral Nociception

Primary Afferent Nociceptors (PANs): pain fibers

FAST Aδ-fibers (warning)


SLOW C-fibers (protection)


Mechanoreceptors and chemoreceptors
Chemoreceptors
30% Aδ, 40% C-fibers = “silent nociceptors”

become active only with tissue damage or inflammation
Peripheral Nociception


Noxious stimuli or tissue damage causes release of proteins
which irritate and activate PANs
PAN Activators: induction of metabolic cascades








*Neuropeptides (PANs): substance P, calcitonin gene-related
polypeptide (CGRP), and somatostatin
Bradykinins (from tissue)
Histamines (mast cells)
Prostaglandins (cell membrane)-increases pain in the PNS,
decreases pain in CNS
ATP (damaged muscles): activate receptors on PAN membrane
H+ (tissue)
Chemokines (immune and nervous system cells)
Serotonin (platelets)
Peripheral Sensitization

The “TRIAD” setup: juxtaposed bare PANs, vessels, and mast cells

Tissue Injury: vasodilation → swelling/edema → activation of stretch receptors
and immunocyte migration to the region → cytokine release (IL, IF, TNF)

Irritation of distal PAN ending → proximal relay to Dorsal Root Ganglia

Dorsal Root Reflexes → distal PAN endings release the same type of
neuropeptides (substance P and CGRP) that initiated the original nerve irritation

“Chemical soup” affecting and activating other adjacent PAN endings → Dorsal
Root Reflex

Consequently, there is a decreased threshold to activate pain fibers, AND an
additional population of pain fibers are “awakened” (silent nociceptor activation)
Dorsal Root Reflexes
Inflammation
-A wave of depolarization enters the dorsal horn and adjacent terminals
become depolarized. A greater population of dorsal horn neurons respond to a
stimulus at the original site of injury
-Small afferent fibers release neuropeptides (SP, CGRP) into the periphery,
(antidromically)
-Thus, silent nociceptors are activated (40% of C-fibers, 30% of Aδ-fibers)
Peripheral Nociception Cascade
Schematic borrowed from Frank Willard, PhD
Peripheral Sensitization Sequelae

Activated PAN stimulate spinal cord pathways via
proximal release of:
 Amino

acids: Glutamate and Aspartate
into the dorsal horn

activates post-synaptic NMDA channels = second messenger system
 Neuropeptides:
Substance P and Calcitonin gene-related
peptide

into the dorsal horn AND peripheral tissue



activates further mast cell degranulation, further vasodilation, &
further immunocyte migration in the periphery
inflammatory chemical soup develops around adjacent PAN endings
activates phosphorylation cascade = second messenger system
Peripheral Sensitization Sequelae

“The peripheral mechanisms responsible for
neuropathic pain are found in the altered
gene/protein expression of primary sensory
neurons [PANs]. With damage to peripheral
sensory fibers, a variety of changes [“plasticity”]
in pain-related gene expression take place in
dorsal root ganglion neurons.”
–H. Ueda (2008)
C
e
r
v
i
c
a
l
Dorsal Root Entry Zone
Lateral (pain) & Medial (touch)
Lamina I (pain)
C
o
r
d
Lamina II and III (pain)
T
o
p
o
g
r
a
p
h
y
Lamina IV (touch)
Lamina V and VI (touch)
Lamina VII (touch)
Dorsal Horn Topography
the Laminas:


I: prickling, tingling, coolness
II/III: burning, itching, nociception






“substantial gelatinosa” = lamina II
generally does not project axons out of the cord, instead they help
integration of multiple segments
IV: light touch
V/VI: referred pain, peripheral cutaneous, visceral input
VII: proprioception from muscles, tendons
Implications: in pain states, second messenger systems
cause large caliber (touch) fibers to sprout, forming
collateral fibers to nociceptive lamina II
Spinal Cord Level Pathways

Dorsal Horn receives input from:
 Pain
fibers
 Touch fibers
 Wide dynamic range (WDR)
Receive large receptive fields (A β, A δ, C) and
stimuli intensities
 Modified by descending pathways
 Selective activation leads to perception of discrete
pain (normally)

Segmental Control

“Gate Control Theory”
 Large
caliber fibers naturally yield collateral fibers,
which synapse on inhibitory interneurons and
presynaptic PAN terminals. Aδ-PAN terminals in the
dorsal horn are surrounded by these GABAnergic
synapses.
 Therefore,
gentle touch inhibits our sensation of pain.
Brain
Schematic borrowed from Frank Willard, PhD
Spinal Facilitation

Repetitive stimulation of a WDR neuron causes
excitotoxicity and cell death.

Receptor Field Dynamics

Facilitation causes sprouting of PAN terminals to other WDR
neurons.

When PAN-1 sprouts to WDRN-2, WDRN-2 gains the afferent input
from PAN-1’s receptor field in addition to input from PAN-2, thereby
doubling its receptor field.


Detrimental if the receptor field of PAN-1 is already sensitized
May lead to further excitotoxicity of other inhibitory WDR neurons
Receptor Field Dynamics
PAN 1
WDRN 1
(dying)
Receptor Field 1
Sprouting
WDRN 2
PAN 2
Receptor Field 2
Spinal Facilitation

“Wind-up”


Increased Ca+ entry into dorsal horn neuron causes an increase in the
cell’s Ca+ permeability, hyperexcitable state
Gene induction initiating


synthesis of endogenous opioid (Dynorphin)
sprouting

Ephaptic electrical cross talk spreads excitation to neighboring neurons
 Activity-dependent plasticity and structural re-organization: Large
caliber (touch) fibers sprout, forming collaterals to nociceptive
lamina II
 Altered activity of cord segment

Ventral Root Effects:


Changes in skeletal muscle tone, ROM, joint positioning
Enhanced sympathetic tone
Spinal Facilitation: Summary
Activity Dependent Plasticity





Calcium influx (mediated by NMDA receptors)→ decreased
AP threshold, increased excitability, increased sensitivity
Excitotoxicity → death of inhibitory interneurons
Sprouting from PAN terminals to other WDR neurons →
increased receptor field → excitotoxicity → death of other
inhibitory interneurons
Large fiber collaterals to nociceptive laminas, “wind-up”
(due to the second messenger system and gene induction)
Dorsal Root Reflexes: antadromic firing of PANs
Ascending Pathways

Lateral Pain Pathway



Localization
SC(ALS) to VP thalamus to Primary and Secondary
Sensory cortex
Medial Pain Pathway




carries pain perceived as dull, throbbing, achy, diffuse
can be accompanied by nausea, vomiting, fear due to
brainstem and limbic connections
SC(ALS) to Medial thalamus to Pre-frontal and Anterior
Cingulate cortex (Limbic areas)
influences two Descending Pain Modulating Pathways
Descending Pathways
“Endogenous Pain Control”

Limbic System influences dorsal horn
and interneurons via a Serotonergic
pathway.

Norepinephrine stimulates the Arousal
Center of the Hypothalamus, activating:

Sympathetic Nervous System
 Hypothalamic-Pituitary Axis


Cortisol/Glucocorticoids released to facilitate wound healing
Oxytocinergic Pathway (?)

Selective blockade of Aδ and C-fibers, and glutamate
activation
The Inflammatory Reflex:
-A neuro-physiological mechanism that regulates the immune
system
-Inflammatory input activates an anti-inflammatory output
-Can be under conscious control via higher cortical functions

Cholinergic anti-inflammatory mechanisms (activated by
limbic system and hypothalamic projections)



Acetylcholine inhibits activation of macrophages and cytokine
release (TNF-α, IL-1)
Ach binds receptors on macrophages and other cytokine producing
cells. Binding suppresses pro-inflammatory cytokines.
Vagus nerve (90% of fibers are afferents)


Stimulated by TNF and other cytokines, mechano- and chemoreceptors, temp sensors, and osmolarity sensors
Stimulation prevents inflammation and inhibits cytokine release
Summary: Normal Pain Fxn

Lateral Pain Pathway:
 Localization

Medial Pain Pathway:
 Activate
 Activate
inhibitory pathways for pain control
arousal system for protection and wound
healing

Inflammatory reflex acting in peripheral tissues
 Cholinergic neurons inhibit acute inflammation
 “Health [is] restored when inflammation is limited
by
anti-inflammatory responses that are redundant, rapid,
reversible, localized, adaptive to changes in input and
integrated by the nervous system.” (Tracey 2002)

Return to homeostasis
Summary: Abnormal Pain Fxn



Perpetuation of inflammatory cascade
Activation of “silent nociceptors” in the periphery
Spinal sensitization: increased input of nociceptive dorsal
horn cells





Loss of inhibitory interneurons 2° excitotoxicity
Increasing receptive field size as previously innocuous sites now
evoke response at cord level
Wind-up: progressive and sustained partial depolarization of the
cell, lowers its threshold, allowing smaller afferent impulses to
result in action potentials.
Impaired descending pain modulators, ie “inflammatory
reflex”
Failure to re-establish homeostasis
Pain Generators of the Spine
Intervertebral Discs
HIZ on MRI: 89% specificity for
symptomatic annular tear when present
at the level of chronic LBP
Spinal Stenosis
Boney Pathology
Compression Fracture
Spondylolysis
Spondylolisthesis
Zygopophysial (Facet) Joints
innervated by Medial Branch Nerves
Referred Pain
Sacral Stress Fx: incidence 2-4% in
athletes, up to 20% in runners
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Thank you.