1. Physiology of pain
Prof. Vajira Weerasinghe
Professor of Physiology, 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

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. definition of pain
• It is a symptom
• Associated signs are crying, sweating,
increased heart rate, blood pressure,
behavioural changes
• It is difficult to describe pain although we know
what it is
• It is difficult to measure pain
– visual analogue scale is used
• It is a complex sensory modality essential for
survival

6. 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

7. Pain terminology
International Association for the Study of Pain 2011
•
•
•
•
•
•
•
•
•
Paresthesia
– An abnormal sensation, whether spontaneous or evoked
Dysesthesia
– An unpleasant abnormal sensation, whether spontaneous or evoked
Hyperalgesia
– Increased pain from a stimulus that normally provokes pain
Allodynia
– Pain due to a stimulus that does not normally provoke pain
Hyperesthesia
– Increased sensitivity to stimulation, excluding the special senses (increased cutaneous
sensibility to thermal sensation without pain )
Hyperalgesia
– Increased pain from a stimulus that normally provokes pain
Causalgia
– A syndrome of sustained burning pain, allodynia, and hyperpathia after a traumatic nerve
lesion, often combined with vasomotor and sudomotor dysfunction and later trophic
changes
Hyperpathia
– a painful syndrome characterized by an abnormally painful reaction to a stimulus, especially
a repetitive stimulus, as well as an increased threshold
Neuralgia
– Pain in the distribution of a nerve or nerves

8. 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
• 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 threshold
– The minimum intensity of a stimulus that is perceived as painful.

9. • Nociceptive pain
• Neuropathic pain
• Psychogenic pain

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

11. Dual nature of pain
fast and slow pain
• fast pain
–
–
–
–
–
–
–
acute
pricking type
well localised
short duration
Aδ fibres are involved
fast conduction 20 m/s
somatic pain
• slow pain
–
–
–
–
–
chronic
throbbing type
poorly localised
long duration
unmyelinated C fibres are
involved
– slow conduction 1-2 m/s
– visceral pain

12. • Physical
Stimuli
– pressure etc
• Electrical
• Thermal
– cold, hot
• Chemical
– H+, lactic acid, K+, histamine, bradykinin, acetylcholine, proteolytic
enzymes
– Prostaglandins
• these increase the sensitivity (decrease the threshold) for other nociceptive
stimuli

13. receptors
•
there are no specialised receptors
•
free nerve endings are sensitive to pain stimuli
•
free nerve endings are distributed everywhere
• both somatic and visceral tissues
• except brain tissue and lung parenchyma
•
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
•
TRPV1 receptor (capsaicin receptor)
– respond to capsaicin, heat, low pH
– stimulation leads to painful, burning sensation

14. central connections
• afferent fibre enters the spinal cord
• synapses in laminae I and II (substantia gelatinosa)
• visceral fibres have more diffused distribution (I,V,X)
– (Large Ab fibres termiate in laminae layers III to V)
substantia
gelatinosa
Neurotransmitter at the first synapse of
the pain pathway is substance P

15. ascending pathway
• crosses the midline
• ascends up as the lateral spinothalamic tract
• pain originating from head and neck region travel through
trigeminal nerve, trigeminal nucleus and supply thalamus
• spontaneous firing of trigeminal pathway may result in
“trigeminal neuralgia”
Pain
C fibre
substantia
gelatinosa
lateral
spinothalamic
tract

16. n
se
r
so
te
or
yc
thalamocortical
tracts
x
thalamus
lateral
spinothalamic
tract
C fibre

18. 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

19. 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)

20. Descending pain modulatory system
• several lines of experimental
evidence show the presence of
descending pain modulatory system
– discovery of morphine receptors
– they were known to be present in the brain
stem areas
– discovery of endogenous opioid
peptides
• eg. Endorphines, enkephalins, dynorphin

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

22. ∀ β endorphin
opioid peptides
• Earliest to discover, present in pituitary
• encephalins - met & leu
• widely distributed
• dynorphin
• Endomorphine 1 & 2
• Pronociceptins
Naloxone is an opioid antagonist. It blocks the actions of opioid
Receptors: mu, kappa, delta, recently discovered ORL1 receptor

23. • 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

24. • 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

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

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

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

28. Presynaptic inhibition
enkephalin
substance P

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

30. • 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

31. • final pain perception depends on activity of the
– ascending pain impulse transmitting tracts
– descending pain modulatory (inhibitory) tracts

32. n
se
r
so
x
te
or
yc
thalamocortical
tracts
thalamus
lateral
spinothalamic
tract
C fibre

33. 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

34. 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’

35. Gate control theory
central control
touch
Aβ fibre
pain
C & Aδ
fibres
transmission
cell

36. Gate control theory
pain is felt
central control
touch
Aβ fibre
pain
C & Aδ
fibres
transmission
cell
+
gate is
opened
when C fibre is stimulated, gate will be opened & pain is felt

37. Gate control theory
central control
touch
Aβ fibre
+
pain
C & Aδ
fibres
-
pain is
not felt
transmission
cell
gate is
closed
when Aβ & C fibres are stimulated together, gate will be closed
& pain is not felt

38. 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 ?

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

41. 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 can be stimulated by pain stimuli but
inhibited by touch stimuli

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

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

44. 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

45. 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

46. 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

47. 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

48. • 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)

49. Pain arising from abdominal
viscera
•
Mediated by C fibres
•
Mainly due to the sensations of distention, muscular contraction, inflammation, hypoxia but not
to cutting, tearing, local irritation, burning
•
Typically vague, dull, and nauseating
•
These structures are innervated by autonomic nerve fibers
•
It is poorly localized and tends to be referred to areas corresponding to the embryonic origin of
the affected structure
–
–
–
stomach, duodenum, liver and pancreas referred to upper abdomen
small intestines, proximal colon and appendix referred to periumbilical pain
distal colon and GU tract referred to lower abdominal pain
•
Peritonitis causes somatic pain
•
Diffuse localization of true visceral pain is probably due to the low density of visceral sensory
innervation and extensive divergence of the visceral input within the central nervous system

50. Capsaicin and vanniloid receptors
•
Active compound in chilies is capsaicin
•
Capsaicin chemically is one of the vanilloids
•
Capsaicin receptor is called TRPV1
–
•
(Transient receptor potential vanilloid type 1)
This receptor is also stimulated by
– heat greater than 43°C
– low pH
•
This receptor is sensitised by prostaglandins and bradykinins
•
Upon prolonged exposure to capsaicin TRPV1 activity decreases
– this phenomenon is called desensitization
– Extracellular calcium ions are required for this phenomenon
– This causes the paradoxical analgesic effect of capsaicin

51. Cannabinoid receptor
• Cannabis (marijuvana or ganja) causes pain relief
• Cannabis act on cannabinoid receptors found in pain
pathway
• There are endocannabinoids as well
• Cannabinoid receptor-related processes are involved
in cognition, memory, anxiety, control of appetite,
emesis, motor behavior, sensory, autonomic and
neuroendocrine responses, immune responses and
inflammatory effects

52. Neurotransmitters in the CNS
• Excitatory
– Substance P
– Glutamate (NMDA receptor)
– Neurokinin A and B
– calcitonin gene-related peptide
– vasoactive intestinal polypeptide
– Somatostatin
– bombesin

53. Neurotransmitters in the CNS
• Inhibitory
– GABA
– Noradrenalin
– Serotonin
– Enkephalins

54. Glutamate
•
•
•
•
•
•
•
The NMDA receptor mediates a host of spinal responses to severe painful
stimulation
Normally, the receptor is inactive as it is blocked by a Mg ion
C fibre stimulation removes this Mg ion and activates the receptor
there is a dramatic and long-lasting central response, with some populations
of spinal neurones becoming more and more sensitive to stimulation
Activation causes production of c-fos & spinal production of prostanoids and
nitric oxide
drugs that antagonise the effect of glutamate at the NMDA receptor tend to
induce side effects in higher functions too
but the combination of low dose NMDA antagonists with opioids may be
supra-additive with fewer side effects.

55. GABA
•
•
•
•
GABA is widespread in the brain and spinal cord
inhibitory effects
Interneurones in laminae I, II and III are GABA-rich
mediate gate control in the dorsal horn by synapsing
on neurones that contain substance P

56. c-fos gene and FOS protein
• Discovery of gene c-fos (a viral oncogene) & its
cellular product, the protein called Fos seem
crucial to the profound central nervous system
changes that occur when an animal (or man)
feels pain
• CNS c-fos expression correlates extremely well
with painful stimulation
• We now have a molecular marker for pain!

57. Pain memory
•
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
•
Preemptive analgesia
– Pre-emptive analgesia is a treatment that is initiated before the surgical procedure in order
to reduce sensitization
– Many studies have demonstrated that analgesic intervention before a noxious stimulus or
injury is more effective at averting central sensitization than the same analgesic
intervention given after the stimulus