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To Pain
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Content

Instructions
definitions of pain
Types of pain
Pain Transmission pathwa
y
Analgesic drugs
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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