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Physiology of pain

Prof. Vajira Weerasinghe

Professor of Physiology, Faculty of Medicine, University of Peradeniya &


Consultant Neurophysiologist, Teaching Hospital, Peradeniya

www.slideshare.net/vajira54

Topics covered in the lecture


1.

What is pain? (International definition of pain)

2.

Dual nature of pain: fast pain and slow pain

3.

What causes pain : pain stimuli

4.

Nerve pathways carrying pain signals to the brain

5.

Brain areas involved in pain perception

6.

Pain modulatory pathways

7.

Neurochemicals involved in pain pathways

8.

Gate control theory of pain

What is pain?
Pain is a difficult word to define
Patients use different words to
describe pain
eg.

Aching, Pins and needles, Annoying, Pricking, Biting, Hurting,


Radiating, Blunt, Intermittent, Burning, Sore, Miserable, Splitting,
Cutting, Nagging, Stabbing, Crawling, Stinging, Crushing, Tender,
Dragging, Numbness, Throbbing, Dull, Overwhelming, Tingling,
Electric-shock like, Penetrating, Tiring, Excruciating, Piercing,
Unbearable

Different words in Sinhala or in Tamil

What is pain?
There is an International definition of pain
formulated by the IASP (International
Association for the study of pain)
Pain is an unpleasant sensory and
emotional experience associated with
actual or potential tissue damage, or
described in terms of such damage
IASP International Association for the Study
of Pain 2011

What is pain?
Pain is
subjective
protective
and it is modified by developmental, behavioural,
personality and cultural factors

It is a symptom
Associated signs are crying, sweating,
increased heart rate, blood pressure,
behavioural changes etc

Measurement of pain
It is difficult to describe pain although we know
what it is
It is difficult to measure pain
visual analogue scale (VAS) is used

Dual nature of pain


Fast pain

acute
pricking type
well localised
short duration

Thin myelinated nerve


fibres are involved (A
delta)

Slow pain

chronic
throbbing type
poorly localised
long duration

Unmyelinated nerve fibres


are involved (c fibres)

Different situations
No stimuli, but pain is felt
phantom limb pain
eg. in amputated limb
Stimuli present, but no pain felt
eg. soldier in battle field,
sportsman in arena
Pain due to a stimulus that
does not normally provoke pain
Allodynia
Pain caused by a lesion or disease of the
somatosensory nervous system
Neuropathic pain

Pain terminology
International Association for the Study of Pain 2011
Hyperalgesia
Increased pain from a stimulus that normally provokes pain
Hyperaesthesia
Increased sensitivity to stimulation, excluding the special senses (increased
cutaneous sensibility to thermal sensation without pain )
Paraesthesia
An abnormal sensation, whether spontaneous or evoked
Anaesthesia
A loss of sensation resulting from pharmacologic depression of nerve function or
from neurological dysfunction
Neuralgia
Pain in the distribution of a nerve or nerves
Analgesia
Absence of pain in response to a normally painful stimulus
Allodynia
Pain due to a stimulus that does not normally provoke pain

22

Pain terminology

International Association for the Study of Pain 2011


Neuropathic Pain
Pain caused by a lesion or disease of the somatosensory nervous
system
Nociceptive pain
Pain that arises from actual or threatened damage to non-neural tissue
and is due to the activation of nociceptors
Visceral pain
Pain arising from visceral organs (e.g., heart, lungs, gastrointestinal tract,
liver, gallbladder, kidneys, bladder).
Neuropathy
A disturbance of function or pathological change in a nerve: in one nerve,
mononeuropathy; in several nerves, mononeuropathy multiplex; if diffuse
and bilateral, polyneuropathy
Nociception
The neural process of encoding noxious stimuli
Noxious stimulus
A stimulus that is damaging or threatens damage to normal tissues.

Pain
Pain as a sensation
physiologically (nociception)
Nociceptive pain

Pain as an emotional experience


Psychologically
Psychogenic pain

Pain caused by damage to nerve


Neuropathic pain

Transduction and perception


Transduction
Process of converting noxious stimulus to action
potentials

Perception
Central processing of nociceptive impulses in order
to interpret pain

Stimuli
Physical
pressure etc

Electrical
Thermal
cold, hot

Chemical
H+, lactic acid, K+, histamine, bradykinin, serotonin, leucotrines,
acetylcholine, proteolytic enzymes, capsiacin
Prostaglandins (PGE2)
Cannot directly stimulate nociceptors
Increase the sensitivity of nociceptors for other stimuli (decrease the
threshold)

Receptors
There are no specialised receptors
Pain receptors are called nociceptors
A sensory receptor that is capable of transducing and
encoding noxious stimuli (actually or potentially tissue
damaging stimuli)

Nociceptors are free nerve endings

Free nerve endings are distributed everywhere


both somatic and visceral tissues
except brain tissue and lung parenchyma

Receptors
Nociceptors are very slowly adapting type
Different types of nociceptors
Some respond to one stimulus
Some respond to many stimuli (polymodal)
Some may not respond to the standard stimuli (silent
nociceptors)
they respond only when inflammatory substances are present

Capsaicin receptor (TRPV1 receptor)


Respond to capsaicin, heat, low pH
Stimulation leads to painful, burning sensation

Nerve pathways carrying pain signals to


the brain
Pain signals enter the spinal cord
First synapse is present in the dorsal horn of
the spinal cord
Then the second order neuron travels through
the lateral spinothalamic tracts

afferent fibres
two types
A (thin myelinated)
C (unmyelinated)

central connections
afferent fibre enters the spinal cord
synapses in laminae ii,iii
substantia gelatinosa
substantia
gelatinosa

Neurotransmitter at the first synapse of the


pain pathway is substance P
Acute pain : glutamate
Chronic pain: substance P
Pain inhibitory neurotransmitters: enkephalin, GABA

ascending pathway
crosses the midline
ascends up as the lateral spinothalamic
tract

Pain
C fibre

substantia
gelatinosa

lateral
spinothalamic
tract

n
se
r
so
x
te
or
yc

thalamo
cortical
tracts

thalamus

lateral
spinothalamic
tract
C fibre

Pain perception
This occurs at different levels
thalamus is an important centre of
pain perception
lesions of thalamus produces severe
type of pain known as thalamic pain

Sensory cortex is necessary for the


localisation of pain
Other areas are also important
reticular formation, limbic areas,
hypothalamus and other subcortical
areas

Pathophysiology of pain
Pain sensations could arise due to
Inflammation of the nerves (neuritis)
Injury to the nerves and nerve endings with scar
formation (disk prolapse)
Injury to the structures in the spinal cord, thalamus
or cortical areas that process pain information
(spinal trauma)
Abnormal activity in the nerve circuits that is
perceived as pain (phantom limb pain)
Nerve invasion, for example by cancer (brachial
plexopathy)

Descending pain modulatory system


several lines of experimental evidence
show the presence of descending pain
modulatory system
stimulus produced analgesia (Reynolds)
stimulation of certain areas in the brain stem was
known to decrease the neuronal transmission along
the spinothalamic tract

discovery of morphine receptors


they were known to be present in the brain stem
areas

discovery of endogenous opioid peptides


eg. Endorphines, enkephalins, dynorphin

periaqueductal
grey nucleus

midbrain

pons
nucleus raphe
magnus

medulla

spinal cord

substantia gelatinosa

opioid peptides
short peptides originally known to be secreted
in CNS and later found to be present in GIT etc

opioid peptides
endorphin
Earliest to discover, present in pituitary

encephalins - met & leu


widely distributed

dynorphin
Endomorphine 1 & 2
Pronociceptins

Receptors: mu, kappa, delta, recently discovered ORL1 receptor

descending tracts involving opioid peptides as


neurotransmitter were discovered
these were known to modify (inhibit) pain
impulse transmission at the first synapse at the
substantia gelatinosa

first tract was discovered in 1981 by Fields and


Basbaum
it involves enkephalin secreting neurons in the
reticular formation
starting from the PAG (periaqueductal grey area) of
the midbrain
ending in the NRM (nucleus raphe magnus) of the
medulla
from their ending in the substantia gelatinosa of the
dorsal horn

in the subtantia gelatinosa


enkephalin secreting neuron is involved in
presynaptic inhibition of the pain impulse
transmission by blocking substance P release

substantia
gelatinosa

descending inhibitory tract


dorsal horn

c fibre input

substantia
gelatinosa cell

Presynaptic inhibition

enkephalin

substance P

Presynaptic inhibition

enkephalin
substance P
blocking of
pain impulse

pain impulse

since then various other descending tracts


were discovered
all of them share following common features
involved in brain stem reticular areas
enkephalins act as neurotransmitters at least in
some synapses
most of these tracts are inhibitory
midbrain nuclei are receiving inputs from various
areas in the cortex, subcortical areas, limbic
system, hypothalamus etc
the ascending tract gives feedback input to the
descending tracts
recently even nonopioid peptides are known to be
involved

yc
or
ns
se
x
te
or

Final pain perception


depends on activity
of the

C fibre

Ascending
pain impulse
transmitting
tracts
Descending
pain modulatory
(inhibitory) tracts

Theories
of pain

Intensity theory

touch
pain

There is a single pathway for touch


and pain
Less intensity produces touch
Increased intensity produces pain

Specificity theory

touch pain

There are two


different
pathways for
touch and pain

Gate control theory


This explains how pain can be relieved very quickly by
a neural mechanism
First described by P.D. Wall & Melzack (1965)
There is an interaction between pain fibres and touch
fibre input at the spinal cord level in the form of a
gating mechanism

Gate control theory


pain is felt

pain

+
gate is
opened

When pain fibre is stimulated, gate will be opened & pain is felt

Gate control theory


pain is
not felt

touch

+
pain

gate is
closed

When pain and touch fibres are stimulated together, gate will be
closed & pain is not felt

Gate control theory


This theory provided basis for
various methods of pain relief
Massaging a painful area
Applying irritable substances to a
painful area (counter-irritation)
Transcutaneous Electrical Nerve
Stimulation (TENS)
Acupuncture ?

Gate control theory


But the anatomcal basis for all the connections
of Walls original diagram is lacking

?
?

WDR (wide dynamic range cells)


It is known that some of the second order neurons of
the pain pathway behave as wide dynamic range
neurons
They are responsive to several somatosensory
modalities (thermal, chemical and mechanical)
They can be stimulated by pain but inhibited by touch
stimuli

WDR (wide dynamic range cells)


pain &
mech

C fibre

mech

A fibre

excitatory

WDR cell

inhibitory

WDR cells
have been found in
Spinal cord
Trigeminal nucleus
Brain stem
Thalamus
Cortex

Modifications to the gate control theory


this could be modified in the
light of enkephalin activity
and WDR cells
inhibitory interneuron may be
substantia gelatinosa cell
descending control is more
important
WDR cells may represent
neurons having pain as well
as touch input

referred pain
sometimes pain arising from viscera are not felt
at the site of origin but referred to a distant site.
eg.
cardiac pain referred to the left arm
diaphargmatic pain referred to the shoulder

this paradoxical situation is due to an apparent error


in localisation

referred pain - theories


convergence theory
somatic & visceral structures
converge on the same
dermatome
generally impulses through
visceral pathway is rare
centrally brain is programmed
to receive impulses through
somatic tract only
therefore even if the visceral
structure is stimulated brain
misinterpret as if impulses are
coming from the somatic
structure

somatic
+ ++
++ +
second
order
neuron

visceral

referred pain - theories


facilitatory theory
somatic & visceral structures
converge on the same
dermatome
stimulation of visceral
structure facilitates
transmission through somatic
tract

somatic
+ ++
++ +
second
order
neuron

visceral

Pain memory
Memory of pain often overshadows its primary experience in its
impact upon pathophysiology and human suffering
The memory of pain can be more damaging than its initial experience
Central sensitization
Increased responsiveness of nociceptive neurons in the central nervous system
to their normal or subthreshold afferent input

Peripheral sensitization
Increased responsiveness and reduced threshold of nociceptive neurons in the
periphery to the stimulation of their receptive fields

Clinical interventions to blunt both the experience and persistence of


pain or to lessen its memory are now applied

Summary
Pain is not just a sensation but is a more complex
phenomenon
Pain can be blocked at many places
Chemicals play an important role in causing pain as
well as in reducing pain
Neural mechanisms also play a role in pain interaction
This complex nature of pain perception makes it a
very difficult entity to control

Pain is a more terrible lord


of mankind than even death
itself
Dr. Albert Schweitzer (1875-1965)