Transcript Pathophysiology of Pain

Pathophysiology of Pain
Dr. Catherine Smyth
Pain Core Program
April 12th, 2007
What is Pain?
 IASP
 “An unpleasant
sensory and
emotional
experience
associated with
actual or potential
tissue damage, or
described in terms
of such damage”
Descartes (1644) Concept of the
Pain Pathway
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“If for example fire (A)
comes near the foot
(B), the minute
particles of this fire,
which as you know
move with great
velocity, have the
power to set in motion
the spot of the skin of
the foot which they
touch, and by this
means pulling upon
the delicate thread
(cc), which is attached
to the spot of the skin,
they open at the same
instant the pore (de)
against which the
delicate thread ends,
just as by pulling at
one end of a rope one
makes to strike at the
same instant a bell
which hangs at the
other end.”
Processing of Pain
Normal pain
 Nociceptive pain
involves the normal
activation of the
nociceptive system by
noxious stimuli.
 Nociception consists of
four processes:
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transduction
transmission
perception
modulation
Med School
Model of Pain
Multiple afferents
Multiple receptors
Multiple mediators
Multiple
neurotransmitters
 Ascending,
descending,
crossing over
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Throw Away (part) of the Old
Model!
 Pain is a dynamic interlocking series of
biological reactive mechanisms that
changes with time
 The experience of pain alters the
pathophysiology
 Pain mechanisms may be as varied as the
individuals with pain (despite the same
complaint!)
 There is no such thing as a hard-wired,
line-labelled, modality-specific, single
pathway which leads from stimulus to
sensation (Editorial, BJA 75(2) 1995)
Outline
 Nociceptors
 Inflammation
 Peripheral Sensitization
 Afferent Mechanisms
 Tracts
 Neurotransmitters
 The Dorsal Horn and Spinal Cord
 The Gate Theory
 NMDA Receptors
 Central “Wind-Up”
 Secondary Hyperalgesia
 Descending Inhibition and Facilitation
 Opioid Induced Hyperalgesia
Nociceptors
 Pain sensors/receptors = nociceptors
 Located in skin, muscle, joints, viscera
 Closely linked to peripheral sensory and
sympathetic neurons (“free nerve
endings”)
 Convert sensory information into
electrochemical signal (action
potentional)
 Many and varied types of nociceptors
 Distinct sensory channels for different
types of pain
Ad versus C Fibres
 High threshold
 Mechanoreceptors and
temperature (painful)
 Fast, myelinated
 5 to 30 m/sec
 First pain; transient
 Well localized
 Sharp, stinging, pricking
 Uniform from
person:person
 Low threshold
 Polymodal (various
stimuli – mechanical,
thermal, metabolic)
 Slow, unmyelinated
 0.4-1 m/sec
 Second pain; persistent
 Diffuse
 Burning, aching
 Tolerance varies from
person:person
First Pain
Second Pain
Inflammatory “Soup”
 Tissue mediators released by cellular injury
 Neuromediators released by nerves
 Blood vessels, mast cells, fibroblasts, macrophages,
neutrophils add other compounds to the mix
 Significant bi-directional interaction of mediators
 Pool of chemical irritants “excite” the nociceptors
 The list of tissue mediators includes: K+, lactate,
H+, adenosine, bradykinin, serotonin, histamine,
prostaglandins, and leukotrienes
 The list of neuromediators includes:Glutamate,
Neurokinins, Substance P, CGRP, serotonin,
norepinephrine, somatostatin, cholecystokinin, VIP,
GRP and Galanin
Tissue-Chemical-Cellular
Interactions
Ions and Lactate
Physical damage to cells
Changes in membrane permeability
Failure of sodium-ionic pump
Intense irritation and excitation of afferent
nerve endings from high concentrations of K+
 H+ ions from celluluar efflux favour the release
of bradykinin from plasma proteins
 Lactate produced during injury (esp. ischemia)
causes direct excitation of nociceptors
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Bradykinin
 Nonapeptide derived from plasma protein
 Its release is increased when tissue pH decreases (ie.
Injury)
 Acts on 2 receptors: B1 (vascular) and B2 (nerves)
 Vasoneuroactive peptide
 One of the most potent nociceptor irritants
 Excites primary sensory neurons provoking the
release of substance P, neurokinin and CGRP (all
neuromediators of pain)
 Actions of BK are non-specific (affects all nerve
endings in the tissue)
 Stimulates sympathetic postganglionic nerve fibres to
produce PGE2
Prostaglandins and Leukotrienes
 Result of arachidonic acid (AA) metabolism
 Again, BK is implicated as it activates
phospholipase A2 which releases AA from
phospholipid complexes (cell membranes)
 AA metabolized into eicosanoids by
cyclooxygenase and lipoxygenase
 Prostaglandins and leukotrienes sensitize
nociceptors to all stimuli (ie. Chemical,
mechanical, heat)
 (action of NSAIDs)
Serotonin/Histamine
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Serotonin derived from platelets
Serotonin is strong nociceptor stimulant
Serotonin causes vasoconstriction
(At the level of the spinal cord, it antagonizes
substanceP)
Histamine is released from mast cells
Tissue damage causes BK, H+, PG to activate C
polymodal nociceptors
Nociceptors release neuromediators such as substance P
and CGRP triggering mast cells to release histamine
Histamine acts on local afferent nerve endings and blood
vessels
Substance P
 Production is increased in most pain states
in primary afferent neurons
 Produced in the nucleus and transported
centrally and peripherally
 Neurotransmitter, edema, vasodilation
 Release of histamine
 Capsaicin (neurotoxin, blocks the release of
substance P at free nerve endings, reduces
number of neurons containing substance P)
CGRP
 Calcitonin-Gene Related Peptide
 Similar action to Substance P
 Enhances responsiveness of afferent nerve
terminals (sensitizes)
 Potent vasodilator
 Causes mast cells to release leukotrienes
 Contributes to wound healing (fibroblasts and
smooth muscle cells proliferate)
What’s happening at the tissue
level??
 Tissue injury results in PG,
K and BK release
 Activated C fibers release
Substance P and CGRP
locally
 This triggers platelets and
mast cells to release 5HT,
H+ and more BK
 Local reactions spread to
other nearby axons
causing hyperalgesia
Peripheral Sensitization
 What is it?
 Decreased threshold for activation
 Increased intensity of response to a
stimulus
 Beginning of spontaneous activity
 Why develop it?
 Reparative role; easier activation of pain
pathway allowing tissue to heal
 How is it activated?
 “inflammatory soup” in damaged tissue
Upregulation in the Periphery
Normal Nociception
Peripheral Sensitization
(Inflammatory Soup)
Ectopic Activity
Action Potential in Ectopic Activity
Pathophysiology of Pain
Peripheral Sensitization
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Injury to peripheral neural axons can result in abnormal nerve
regeneration in the weeks to months following injury. The
damaged axon may grow multiple nerve sprouts, some of
which form neuromas. These nerve sprouts, including those
forming neuromas, can generate spontaneous activity. These
structures are more sensitive to physical distention.
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These neuromas become highly sensitive to norepinephrine
and thus to sympathetic nerve discharge. The nerves develop
active sodium channels that become the sites of tonic impulse
generation, known as ectopic foci
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After a period of time, atypical connections may develop
between nerve sprouts or demyelinated axons in the region of
the nerve damage, permitting “cross-talk” between somatic or
sympathetic efferent nerves and nociceptors. Dorsal root fibers
may also sprout following injury to peripheral nerves
Gate Control Theory
Wall & Melzack ’65
Substantia gelatinosa
interneurons
Balance of:
 Afferent nociception
 Nonnociceptive
 Afferent neural
traffic (touch)
 Central inhibition
 = Final flow of
nociception centrally
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Periphery to Spinal Cord
 Note the close association between sensory
afferents
 Note especially the close association of
somatic and sympathetic nerves
Neural Circuits
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Review of 3 order classic
pain pathway
1st order neurons terminate
in the dorsal horn
2nd order neurons cross and
ascend
2nd order neurons may
terminate in brainstem
OR 2nd order may ascend to
the thalamus
Third order neurons project
to frontal cortex or
somatosensory cortex
(medial vs. lateral
projections)
Pain Pathways
Neural Connections in the Lamina
 Sensory afferents
enter the dorsal horn
 Ascend 1-2 segments
in Lissauer’s tract
 Terminate in the grey
matter of the dorsal
horn
 Nerve fibers terminate
in various laminae
 Adelta = lamina I, V
 C fibers = I through V
 A beta = lamina III
Changes with Nerve Injury in the
Dorsal Horn
 Sprouting of nerve
terminals in
myelinated nonnociceptive Ab
afferents in the dorsal
horn
 Form connections
with nociceptive
neurons in laminae I
and II
 Rewiring = persistent
pain and
hypersensitivity
(?allodynia)
Central Pharmacology and
Nociceptive Transmission
 Afferent transmitters (receptormediated)
 Neurokinins, bradykinins, CGRP,
bombesin, somatostatin, VIP, glutamate
(NMDA and non-NMDA), nitric oxide
 Non-afferent receptor systems
 Opioids, adrenergic, dopamine,
serotonin, adenosine, GABA, cholinergic,
Neuropeptide Y, Neurotensin, glutamate
(NMDA and non-NMDA)
Organization of the Dorsal Horn
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Afferents release
peptides and
“excite” 2nd order
neurons
Afferents excite
interneurons
through NMDA.R
Substance P
causes glia to
release PG
Lg. afferent fibres
release GABA,
glycine and inhibit
2nd order neurons
Some activated
interneurons
release
enkephalins
Bulbospinal
pathways (5-HT,
NE) hyperpolarizes
membrane
Second Order Neurons
 In general, there are two types of
second-order nociceptive neurons in
the dorsal horn
 Those that respond to range of gentle
- intense stimuli and progressively
increase their response (Wide
Dynamic Range Neurons; WDR)
 Those that respond only to noxious
stimuli (Nociceptive-specific; NS)
WDR Neurons
 Predominate in lamina V (also in IV, VI)
 Respond to afferents of both Adelta and C
fibres
 Deafferentation injury leads to classic response
of WDR neurons (work harder)
 With a fixed rate of stimulation from C fibers,
the WDR neurons progressively increase their
response
 This is termed the “wind-up” phenomenon
 Pre-emptive analgesia
Wind Up and the NMDA.R
 Action of opioids
mainly presynaptic
(reduced release
neurotransmitters)
 NMDA.R implicated
in Wind Up
phenomenon
 Dorsal horn
nociceptive neuron
and effects of
repeated stimuli in
two groups
“Wind Up”
 Repetitive noxious stimulation of unmyelinated
C–fibers can result in prolonged discharge of
dorsal horn cells. This phenomenon which is
termed "wind–up", is a progressive increase in
the number of action potentials elicited per
stimulus.
 Repetitive episodes of "wind–up" may
precipitate long–term potentiation (LTP), which
involves a long lasting increase in pain
transmission. This is part of the central
sensitization process involved in many chronic
pain states.
Central Sensitization (Early)
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Neurotransmitte
rs activate their
respective
receptors
Activated
receptors cause
an increase in
2nd messengers
(IP3, PKC,
Ca2+)
Phosphorylation
of their own
receptors
Increased
responsiveness
and sensitivity
Central Sensitization (Late)
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Stimulation of
DRG neurons
cause gene
induction (Cox2)
Production of
prostaglandins
(PGE2)
Directly alter
excitability
neuronal
membrane
PGE2 reduces
inhibitory
transmission
++nociception
decreases
transcription of
inhibitory genes
(DREAM)
Central Sensitization
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Following a peripheral nerve injury, anatomical and neuro–
chemical changes can occur within the central nervous system
(CNS) that can persist long after the injury has healed.
As is the case in the periphery, sensitization of neurons can occur
within the dorsal horn following peripheral tissue damage and
this is characterized by an increased spontaneous activity of the
dorsal horn neurons, a decreased threshold and an increased
responsivity to afferent input,
A beta fibers (large myelinated afferents) penetrate the dorsal
horn, travel ventrally, and terminate in lamina III and deeper. C
fibers (small unmyelinated afferents) penetrate directly and
generally terminate no deeper than lamina II. However, after
peripheral nerve injury there is a prominent sprouting of large
afferents dorsally from lamina III into laminae I and II. After
peripheral nerve injury, these large afferents gain access to
spinal regions involved in transmitting high intensity, noxious
signals, instead of merely encoding low threshold information.
Explaining Allodynia
 The allodynia and hyperalgesia associated with
neuropathic pain may be best explained by:
1) the development of spontaneous activity of afferent
input
2) the sprouting of large primary afferents (eg. A–beta
fibers from lamina 3 into lamina 1 and 2),
3) sprouting of sympathetic efferents into neuromas and
dorsal root and ganglion cells,
4) elimination or reduction of intrinsic modulatory
(inhibitory) systems
5) up regulation of receptors in the dorsal horn which
mediate the excitatory process
Descending Modulation
 Brain stem descending pathways play a
major role in control of pain
transmission
 Well established neural circuit linking
Periaqueductal Gray (PAG), Rostral
Ventromedial Medulla (RVM) and the
spinal cord
 Parallel mechanisms of Descending
Inhibition and Facilitation arise from the
brainstem
The Rostral Ventromedial Medulla
 On-Cells
 Fires before and facilitates a nocifensive response
 Facilitates nociceptive transmission
 Firing of on-cells increases in inflammation
 Off-Cells
 Pause in activity before nocifensive response
 Decrease firing in the face of noxious stimulation
(antinociceptive neurons)
 Pauses reduced in inflammation (i.e.less
antinociception)
 There is a balance between synaptic excitation and
inhibition in various pain conditions
 Severe persistent pain may represent the central
facilitatory network overriding the central inhibition
The Usual Response to Pain and
Inflammation
 Early (within 48-72 hrs)
 Increase in descending facilitation
 Primary hyperalgesia and allodynia
 Enhances nocifensive escape behaviour and
protects the organism
 Secondary hyperalgesia occurs when the
balance favours facilitation of pain (protective)
 Late (> 3 days)
 Increase in descending inhibition
 Movement of the injured site is suppressed or
reduced to aid in healing/recuperation
Upsetting the Balance of
Descending Pathways
 Nerve injury and Neuropathic Pain
 Disrupts the balance between facilitation
and inhibition of pain
 Maintenance of hyperalgesia for prolonged
periods of time is indicative of enhanced
descending facilitation
 The nervous system is inherently plastic;
therefore nerve injury may activate a
descending nociceptive system that is
meant to protect the organism early in
inflammation but actually leads to
persistent pain states.
Disinhibition of Pain
 Reduced synthesis of
GABA and glycine
 Destruction of
inhibitory interneurons
due to the excitotoxic
effects of massive
releases of glutamate
following nerve injury
 Less GABA and glycine
 Leads to increased
excitability of pain
transmission neurons
 Pain response with
innocuous inputs
Opioid-induced abnormal pain
sensitivity
 Opioids as pro-nociceptors
 Not due to “mini-withdrawals”
 Likely due to tonic activation of descending
pain facilitory pathways from the RVM
 NMDA.R implicated in opioid-induced pain
sensitivity (experimental inhibition)
 Spinal dynorphin increases with opiate
infusions and modulates opioid-induced
pain
 How to distinguish opiate pharmacological
tolerance vs. opioid-induced pain sensitivity
Summary
 Nociceptors
 Inflammation
 Peripheral Sensitization
 Afferent Mechanisms
 Tracts
 Neurotransmitters
 The Dorsal Horn and Spinal Cord
 The Gate Theory
 NMDA Receptors
 Central “Wind-Up”
 Secondary Hyperalgesia
 Descending Inhibition and Facilitation
 Opioid Induced Hyperalgesia
Summary
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(We have not discussed central modulation of pain (role of
the cerebral cortex))
Pain is critical for survival but with chronic pain, may
become the disease itself
Targeted approach to analgesia --- We need new drugs and
technologies (however …)
The pain pathways are not static – they are plastic with new
connections forming constantly (just to keep you on your
toes)!
Chemicals that transmit pain can be neurotoxic and lead to
loss of inhibitory controls
Translational then transcriptional changes in neurons
predominate with pain and inflammation and nerve injury
causing hypersensitivity
Any Questions????