1. Physiology of pain
Prof. Vajira Weerasinghe
Professor of Physiology, Faculty of Medicine
University of Peradeniya
www.slideshare.net/vajira54

2. 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

3. 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

4. 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

5. 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

6. 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

7. Dual nature of pain
• Fast pain • Slow pain
– acute – chronic
– pricking type – throbbing type
– well localised – poorly localised
– short duration – long duration
– Thin myelinated nerve – Unmyelinated nerve fibres
fibres are involved (A are involved (c fibres)
delta)

8. 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

9. Pain terminology
International Association for the Study of Pain 2011
• Hype ra lge s ia
– Incre a s e d pa in from a s timulus tha t norma lly provoke s pa in
• Hype ra e s the s ia
– Incre a s e d s e ns itivity to s timula tion, e xcluding the s pe cia l s e ns e s
(incre a s e d cuta ne ous s e ns ibility to the rma l s e ns a tion without pa in )
• P a ra e s the s ia
– An a bnorma l s e ns a tion, whe the r s ponta ne ous or e voke d
• Ana e s the s ia
– A los s of s e ns a tion re s ulting from pha rma cologic de pre s s ion of ne rve
function or from ne urologica l dys function
• Ne ura lgia
– P a in in the dis tribution of a ne rve or ne rve s
• Ana lge s ia
– Abs e nce of pa in in re s pons e to a norma lly pa inful s timulus
• Allodynia
– P a in due to a s timulus tha t doe s not norma lly provoke pa in

10. 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.

11. 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

12. Transduction and perception
• Transduction
– Process of converting noxious stimulus to action
potentials
• Perception
– Central processing of nociceptive impulses in order
to interpret pain

13. 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)

14. 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

15. 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

16. 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

17. afferent fibres
• two types
– Aδ (thin myelinated)
– C (unmyelinated)

18. 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

19. ascending pathway
• crosses the midline
• ascends up as the lateral spinothalamic
tract
Pain
C fibre
lateral
spinothalamic
tract
substantia
gelatinosa

20. se
n
so
r yc
or
te
x
thalamo thalamus
cortical
tracts
lateral
spinothalamic
tract
C fibre

21. 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

22. 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)

23. 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

24. periaqueductal
grey nucleus
midbrain
pons
nucleus raphe
magnus
medulla
spinal cord
substantia gelatinosa

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

26. opioid peptides
∀ β 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

27. • 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

28. • 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

29. • in the subtantia gelatinosa
– enkephalin secreting neuron is involved in
presynaptic inhibition of the pain impulse
transmission by blocking substance P release

30. substantia descending inhibitory tract
gelatinosa
dorsal horn
c fibre input substantia
gelatinosa cell

31. Presynaptic inhibition
enkephalin
substance P

32. Presynaptic inhibition enkephalin
substance P
blocking of
pain impulse
pain impulse

33. • 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

34. se
n
so
r yc
or
te
x
Final pain perception
depends on activity
of the
Ascending
pain impulse
transmitting
C fibre tracts
Descending
pain modulatory
(inhibitory) tracts

35. Intensity theory Specificity theory
Theories
of pain
touch
pain touch pain
There is a single pathway for touch
There are two
and pain
different
Less intensity produces touch pathways for
Increased intensity produces pain touch and pain

36. 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’

37. Gate control theory
pain is felt
+
pain
gate is
opened
When pain fibre is stimulated, gate will be opened & pain is felt

38. 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

40. 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 ?

41. Gate control theory
• But the anatomcal basis for all the connections
of Wall’s original diagram is lacking
?
?

42. 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

43. WDR (wide dynamic range cells)
pain &
mech mech
C fibre A fibre
excitatory
WDR cell inhibitory

44. WDR cells
• have been found in
– Spinal cord
– Trigeminal nucleus
– Brain stem
– Thalamus
– Cortex

45. 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

46. 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

47. referred pain - theories
• convergence theory
– somatic & visceral structures
converge on the same
somatic
dermatome
– generally impulses through +++
visceral pathway is rare ++ +
– centrally brain is programmed second
to receive impulses through visceral
order +
somatic tract only neuron
– therefore even if the visceral
structure is stimulated brain
misinterpret as if impulses are
coming from the somatic
structure

48. referred pain - theories
• facilitatory theory
– somatic & visceral structures
converge on the same
somatic
dermatome
– stimulation of visceral +++
structure facilitates ++ +
transmission through somatic
second
tract order + visceral
neuron

49. 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

50. 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

51. “Pain is a more terrible lord
of mankind than even death
itself”
Dr. Albert Schweitzer (1875-1965)