Physiology of pain was discussed covering several key topics: 1. Pain was defined by the IASP as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. 2. Pain pathways involve nociceptors transmitting signals via Aδ and C fibers to the spinal cord and brain areas involved in perception. 3. Descending pain modulatory pathways originate in the brainstem and midbrain and can inhibit pain transmission via neurotransmitters like enkephalins. 4. The gate control theory proposes that activity in large diameter fibers can close the "gate" and inhibit pain transmission in the spinal cord. Modifications to this theory incorporate concepts like wide dynamic range neurons and endogenous opioids.

1. Physiology of pain
Prof. Vajira Weerasinghe
Professor in Neurophysiology, Faculty of Medicine, University of Peradeniya &
Consultant Neurophysiologist, Teaching Hospital, 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
• McGill Pain Questionnaire

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
– acute
– pricking type
– well localised
– short duration
– Thin myelinated nerve
fibres are involved (A
delta)
– Somatic
• Slow pain
– chronic
– throbbing type
– poorly localised
– long duration
– Unmyelinated nerve fibres
are involved (c fibres)
– Visceral

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 (pain pathways)
•Neuropathic pain

9. 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

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, capsaicin
– 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
• Cross over to the other side
• 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. Pain
lateral
spinothalamic
tract
C fibre
substantia
gelatinosa
• crosses the midline
• ascends up as the lateral spinothalamic
tract
ascending pathway

20. lateral
spinothalamic
tract
thalamus
sensorycortex
C fibre
thalamo
cortical
tracts

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. midbrain
pons
medulla
spinal cord
periaqueductal
grey nucleus
nucleus raphe
magnus
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
• Enkephalins or 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
gelatinosa
c fibre input
descending inhibitory tract
dorsal horn
substantia
gelatinosa cell

31. substance P
enkephalin
Presynaptic inhibition

32. Presynaptic inhibition
substance P
enkephalin
pain impulse
blocking of
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. sensorycortex
C fibre
Final pain perception
depends on activity
of the
Ascending
pain impulse
transmitting
tracts
Descending
pain modulatory
(inhibitory) tracts

35. Theories
of pain
There is a single pathway for touch
and pain
Less intensity produces touch
Increased intensity produces pain
There are two
different
pathways for
touch and pain
Specificity theory
touch pain
Intensity theory
touch
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
When pain fibre is stimulated, gate will be opened & pain is felt
pain
pain is felt
+
gate is
opened

38. Gate control theory
When pain and touch fibres are stimulated together, gate will be
closed & pain is not felt
pain is
not felt
touch
pain
+ -
gate is
closed

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)
C fibre A fibre
pain &
mech mech
inhibitory
excitatory
WDR cell

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
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
visceral
somatic
second
order
neuron
++
++
+
+
+

48. referred pain - theories
• facilitatory theory
– somatic & visceral structures
converge on the same
dermatome
– stimulation of visceral
structure facilitates
transmission through somatic
tract
visceral
somatic
second
order
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. • hypoxia / pressure / inflating a BP cuff
– first affect large A fibres (touch & pressure sense)
– then affect Aδ fibres (temperature sense & pricking
pain)
– lastly C fibres (burning pain)
local anaesthetics
– first relieve burning pain ( C fibres)
– then temperature sense & pricking pain (Aδ fibres)
– lastly touch& pressure sensation (large A fibres)

51. 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

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