GM6052 directed
study
Welcome
To Pain
Materials
Please wait a
moment
Content
Instructions
definitions of pain
Types of pain
Pain Transmission pathwa
y
Analgesic drugs
Exit
Instructions on how to
use this resource
1)
2)
To proceed through this
presentation on pain,
advance to the next slide by
using the left click on the
mouse. The left-click may be
used in two ways.
Simply left-click on any of the
red underlined hyperlinks to
jump to information related to
the word, phrase or image,
alternatively;
Left-click anywhere else on
the slide to advance to the
next slide in the series.
Instructions on how to
use this resource
Hyperlinks you have
already visited in the
session will change
colour to help you see
where you have visited
before and where you
have not.
Instructions on how to
use this resource
All of this resource can be
navigated in this
way, just keep left-clicking on the
slides and eventually you will find
yourself back where you started no matter how many hyperlinks
you click!
If you click anywhere on this slide
now you will be
returned to the slide you originally
clicked the hyperlink on (i.e. the
contents page).
What is pain?
Many definitions..
pain is whatever the experiencing
person says it is, existing when he
says it does (McCaffery, 1980)
Pain is an unpleasant sensory or
emotional experience associated
with actual or potential tissue
damage (International Association
for the study of pain 1986)
Complex warning sign. Difficult to
measure as peoples perception of
pain varies
Perception of Pain?
Perception of pain is
dependent upon:
Cellular damage
Receptor stimulation
Ascending neural pathways
Sensory cortex arousal
Conscious awareness of
stimulation of pain
Types of pain
Acute versus chronic
Nociceptive versus neuropath
ic
Somatic versus visceral
Referred versus non referred
pain
Somatogenic versus
psychogenic
Causes of pain (e.g. cancer,
trauma etc)
Acute v chronic
Acute pain
Chronic pain
Sudden onset
Temporary
(disappears once
stimulus is
removed)
can be somatic,
visceral, referred
Associated anxiety
Physiological
responses to acute
pain include
increased RR, HR,
BP and reduction in
gastric motility
sympathetic
response)
Persistent
usually lasting more
than six months
Cause unknown
may be due to
neural stimulation
or a decrease in
endorphins
Physiological
responses are less
obvious especially
with adaptation.
Psychological
responses may
include depression
See McCance and Heuther (2002) for
more detail on this
Nociceptive v
neuropathic
Nociceptive pains result
from activation of nociceptors
(Pain receptors)
Neuropathic pains result
from direct injury to nerves in
the peripheral nervous
system
Somatic v Visceral
Somatic pain
Superficial: stimulation of receptors
in skin
Deep: stimulation of receptors in
muscles, joints and tendons
Visceral pain
Stimulation of receptors in internal
organs, abdomen and skeleton
Often poorly localised as fewer
receptors located in viscera
Visceral pain can be referred.
Referred pain
Pain experienced at a point distant
to its point of origin
Area of referred pain is supplied by
same spinal segment as actual site
of pain
Brain misinterprets signals as
coming from somatic regions
Knowledge of different types of
referred pain is important in clinical
diagnosis because in many visceral
ailments the only clinical signs is
referred pain.
Good section on referred pain can
be found in Guyton and Hall (2006)
Somatogenic versus
psychogenic
Somatogenic pain is a pain
originating from an actual
physical cause e.g. trauma,
ischaemia etc
Psychogenic pain is pain for
which there is no physical
cause. It is not however
imaginary pain and can be
as intense as somatic pain.
Pain pathway
There are four processes in
the pain pathway
1.
transduction
Noxious stimuli translated into electrical
activity at sensory nerve endings
Transmission
2.
Propagation of impulses along
spinothalamic pathway.
Modulation
3.
Transmission is modified
Perception
4.
Affective / motivational aspect
Each of these processes present a
potential target for analgesic
therapy
Transduction receptors
Pain is detected by
nociceptors (noci = harmful)
Free nerve endings of
sensory neurones
Found in all tissues and
organs (except brain)
Can be classified as either:
Unimodal respond to only
one type of stimulus
Polymodal respond to more
than one type of stimuli.
Transduction
-Receptor activation
When cellular damage occurs,
tissues release chemicals that
stimulate nociceptors
Bradykinin
Histamine
Serotonin
Acetylcholine
Potassium ions
Prostaglandins (PGE2, PGI2)
Substance P
The activity and sensitivity of
nociceptors is profoundly altered by
such mediators (enhances receptor
response to noxious stimuli).
See article by Kelly et al ( 2001) for
interesting information on this aspect
Transduction
TRAUMA
Mechanical
Thermal
chemical
Overall effect is
increased nociceptor
activation
noc
r
o
t
p
ice
Mediators
Bradykinin Histamine
Serotonin Acetylcholine
Potassium ions
Prostaglandins (PGE2,
PGI2)
Substance P
Types of stimuli
Receptors respond to injury
Thermal excessive heat or
cold
Mechanical tearing, crushing,
stretching etc
Chemical
Inflammatory mediators
Lactic acid
ischemia
Transduction - A delta
fibres and C fibres
Nociceptors respond to noxious
stimuli and covert energy at the site
of the stimulus into neural impulses
Nociceptors are terminal endings of
primary afferent fibres. These can be
classed into two main types
myelinated A-delta fibres
or
non-myelinated C fibres
When the threshold level of the
stimulus is reached, then
depolarisation occurs along these
fibres in the form of action potentials
Transduction - A delta
fibres and C fibres
A-Delta fibres
C- fibres
myelinated
unmyelinated
fast ( first) pain -conduct Slow (second) pain
at 5-35m/sec
conduct at 0.5-2.0m/sec
Associated with Sharp,
brief, prinking pain
Associated with
dull,burning, aching,
prolonged pain
Well localised
More diffuse
Elicited by mechanical
or thermal stimuli
Elicited mainly by
chemical stimuli or
persisting mechanical
or thermal stimuli
Transmission
A-delta and C ( primary) fibres
enter the spinal cord via the
dorsal root
They synapse with secondary
neurones in the grey matter of
the dorsal horn
Marginal zone ( lamina I)
Substantia gelatinosa ( lamina II)
Lamina V
Evidence to suggest that:
A-delta fibres synapse in lamina I, II
and V
C-fibres in lamina I and II
Transmission by
primary A-delta and Cfibres
a
Grey
matter of
Dorsal
horn
Secondary neuron
in
m
I A-Delta or
la
II
III
C fibre
IV
V
Pain Transmission
Pathway
Both A delta and C nociceptor fibres
synapse in the dorsal horn of the spinal
cord
Evidence suggests that
neurotransmitters released at this point
include substance P, glutamate,
calcitonin gene-related peptide
(CGRP).
Secondary neurones cross the cord
and ascend through the antero-lateral
spinothalamic tract to the thalamus
where they synapse with tertiary
neurones
These tertiary neurones ascend from
the thalamus to somatosensory cortex.
Pain Transmission
Pathway
Some neurones ascend directly to
the thalamus allowing rapid
analysis
The spinothalamic tract also
sends collaterals to reticular
formation, hypothalamus and
other limbic structures (associated
more with C-fibres and slow pain)
This more indirect pathway
mediates arousal and emotional
reactions to pain. It is also
responsible for somatic and
autonomic motor reflexes.
Somatosensory cortex
Somatosensory cortex is involved
in the localisation and
identification of pain.
Check out these web sites which
demonstrate the homunculus and
sensory perception.
http://www.cs.uta.fi/~jh/homuncul
us.html
http://faculty.washington.edu/chu
dler/flash/hom.html
Perception
Transduction, transmission,
modulation interact to create
subjective emotional
experience of pain.
Modulation of Pain
Evidence that pain is inhibited by
select neural pathways
In dorsal horn
Interneurones in the substantia
gelatinosa can regulate the
conduction of ascending afferent
input
Such interneurons can exert an
inhibitory effect on synapses
between primary and secondary
neurones
These neurones release opioid
peptides (enkephalin, -endorphins
and dynorphins) which act on the
pre-synaptic terminals of nociceptor
fibres to prevent the release of
substance P / glutamate
interneuron
Pain
transmission
blocked by
release of
opiates
opioid
opioid
recepto
t
n
re ay
e
Af thw
pa
Primary
neurone
To thalamus
Secondar
y neuron
Interneuron
(releases
endogenous
opiates
e.g.endorphins)
Primary
neuron
(nociceptor)
Modulation of Pain
Action of opioids
Pre-synaptic terminals of neurones
involved in pain transmission are
opioid receptors
When these receptors are activated
by opioid peptides or other agonists
the release of Neurotransmitters
(Sub P, glutamate etc) is decreased.
Achieved in two ways:
Inhibit Neurotransmitter release by
activation of potassium channels on
pre-synaptic terminal (mu () and
kappa () receptors)
Inhibit Neurotransmitter release by
inhibiting voltage dependent calcium
channels (delta () receptors)
Modulation of Pain
Interneurons in the
Substantia gelatinosa cells
respond to the activity of :
Descending pathways
Endogenous analgesic
pathway. Norepinephrine,
serotonin and opioids are
involved in brainstem inhibitory
pathways that modulate pain
in the spinal cord.
Afferent fibres entering the
cord (gate control theory)
Touch receptors v pain
receptors
Modulation of Pain
descending pathways
The periaqueductal grey matter (PAG)
in the midbrain has a role in
analgesia and is rich is opioid
receptors
PAG receives impulses from many
brain regions inc. hypothalamus,
cortex and thalamus. Stimuli include
stress, exercise, acupuncture.
Main neuronal pathway activated by
PAG stimulation extends first to
nucleus raphe magnus (NRM) in
the medulla and then to dorsal horn
interneurones. Enkephalins are
released at these synapses and
inhibit nociceptor NT release
Pain modulation descending
pathway
MIDBRAIN
Periaqueductal grey
matter
Medial lemniscus
Red nucleus
Corticospinal tract
MEDULLA
Nucleus Raphe
magnus
Medial lemniscus
Corticospinal tract
To thalamus
interneuron
SPINAL CORD
Spinothalamic
tract
nociceptor
Gate control theory
Stimulation of large touch sensory
fibres ( type A beta fibres) can depress
transmission of pain signals from the
same body area.
Thought that A beta fibres stimulate
endorphin releasing inteneurons in
dorsal horn
Thus pain pathway gate is closed by
touch.
Research into this theory continues
May be basis of tens and acupuncture
along with psychogenic excitation of
central analgesia system
Schematic diagram of gate
control theory of pain
mechanism
Large
Abeta
fibre
impulses
Central nervous system
pain modulation may
increase or decrease pain
Closes
pain gate
Substanti
a
gelatinosa
in spinal
cord
Pain
transmissio
n
Opens
pain
gate
Small
Adelta / C
fibres
Actions
and
response
s
Analgesic drugs
As mentioned previously the
aim of analgesic drugs is to
inhibit the processes of pain
transmission. Drug types
considered in this
presentation include opioids,
NSAIDS, paracetamol, local
anaesthetics, amitriptyline
and anticonvulsants.
Can you identify where each
group act on the pain
pathway?
Opioid drugs
The term opioid is used to describe a
group of drugs that are opium- like
Act on opioid receptors (mainly ) as
agonists
Opioids excite neurones in
periacqueductal grey matter and thus
activate the descending analgesia
pathway.
Also act directly on pre-synaptic
terminal of nociceptor neurons in
dorsal horn and inhibit pain impulse
transmission
Bind to other receptors affecting
chemoreceptor trigger zone,
respiratory centre and bowel.
Side effects of Opiates
Respiratory Depression
Bradycardia / Hypotension
Effect on oculomotor nucleus mediated by
parasympathetic nervous system
Nausea
Depresses cardiovascular centre in medulla
Pupillary constriction
Opioids bind to receptors which cause reduced
sensitivity of central chemoreceptors in
medulla to pCO2
Acts on chemoreceptor trigger zone in medulla
Constipation
Decreases motility of gut
Euphoria
Acts on receptors in reticular formation / limbic
system
Opioid agonist and antagonists
agonist drug
e.g.
diamorphine
mimics
action
of
endogenou
s opioid
endogenous
opioid
binds to
receptor
receptor
antagonists
such
as naloxone
bind to
receptors
and block
action
of
endogenous
and
exogenous
opioids
produces reaction
in cell
antagonist produces
no reaction in cell
NSAIDS
All nociceptors can be sensitised by
prostaglandins. i.e. prostaglandins
greatly enhance the receptor response
to noxious stimuli
NSAIDs act by suppressing cyclooxygenase, an enzyme involved in
synthesis of prostaglandins
This blocks inflammatory process (antiinflammatory) and reduces sensitivity
of nociceptors (analgesic)
A good website giving more detail on
this is as follows:
http://www.elfstrom.com/arthritis/nsaids
/actions.html
Action of cyclooxygenase
Constitutive
pathway
(stable conc)
Induced
pathway
phospholipid
phospholipid
Arachidonic acid
COX 1
enzyme
Prostaglandins
associated with
normal body
functions
e.g. prostaglandin
E2 (for kidney
function),
prostaglandin I2
(for stomach
protection)
Arachidonic acid
COX-2
enzyme
Inflammatory
prostaglandins
NSAIDS: mode of
action
NSAIDS block both COX-1
and COX-2
This accounts for most of the
side effects of NSAIDS
Different types of NSAIDS
have different specificities for
COX-1 and COX-2
This contributes to
differences in side effects
between the NSAIDS.
Side effects of
NSAIDs
Linked to inhibition of
prostaglandins
Gastric problems prostaglandins
have a role in protecting gastric
mucosa and also regulate blood
flow to gastric mucosa ( inhibition of
COX-1)
Renal failure prostaglandins
influence renal blood flow (inhibition
of prostaglandin reduces glomerular
filtration as well as causing sodium
retention)
Aspirin anti-coagulant as inhibits
platelet aggregation (inhibition of
COX-1)
Paracetamol
Mechanism not certain may be
weak inhibitor of the synthesis of
prostaglandins or act on
descending analgesic pathway.
Read this article to find out more
you can access it online!!!
Graham,GG and Scott, KF (2005).
Mechanism of action of
paracetamol American Journal of
Therapeutics Jan-Feb;12(1):4655/.
Anaesthetics
Local : block
neurotransmission by
blocking sodium transport
General: affect ion channels
to prevent impulse
transmission
Local anaesthetics
Epidurals administered to
epidural space
Spinal anaethesia
Administered in intrathecal
(subarachnoid) space
Refer to a text book to see
where these spaces are
located in the meninges
Local Anaesthetics
nervous impulses
depend on Na+ ions
entering axons of
neurons via Na+
gates
Na
Na+
nervou
s
impuls
e
axon of
pain
neuron
Na+ gates
local anaesthetics
block Na+ gates so
nervous impulse are
not transmitted
Side Effects of Local
Anaesthetics
Epidurals / spinal
anaethesias
Sympathetic block hypotension
Urine retention
Motor block
Amitriptyline
Acts to Increase levels of
norepinephrine and serotonin
Norepinephrine and
Serotonin act on
endogenous descending
analgesic pathway
Reduces / blocks impulses
along pain pathway
Useful in neuropathic pain
Anti-convulsants
Mechanism of action unclear
Decreases electrical activity
along pain pathway
Useful in some types of
neuropathic pain
References
Gilman S and Newman SW (2002) Manter and Gatzs
Essentials of clinical neuroanatomy and neurophysiology
(10th Ed). FA Davis.
Graham,GG and Scott, KF (2005). Mechanism of action of
paracetamol American Journal of Therapeutics JanFeb;12(1):pp46-55.
Guyton,A.C. and Hall,J.E. (2006) Textbook of Medical
Physiology. Philadelphia, Elsevier
Kelly, D.J. (2001) Preemptive analgesia I: physiological
pathways and pharmacological modalities. Canadian
Journal of Anaesthesia. Vol 48:10, pp1000-1010
McCance,K.L. and Heuther,S.E. (2002). Pathophysiology:
The Biological basis for Disease in Adult and Children.
St.Louis, Mosby.
Rang et al (2003) Pharmacology. Edinburgh. Churchill
Livingstone
Web sites
http://www.cs.uta.fi/~jh/homunculus.html
http://faculty.washington.edu/chudler/flash/hom.html
http://www.elfstrom.com/arthritis/nsaids/actions.html
http://www.painresearch.utah.edu/crc/CRCpage/defi
nit.html
END OF
SESSION
We hope that this has been a useful
resource in preparing for the pain
seminar
