Pain physiology

1. Pain Physiology
R.Srihari

2. Topics for discussion
• Definitions
• Physiology of pain
• Pain pathway
• Important terminologies

3. Definition
• Pain:
– An unpleasant sensory or emotional experience
associated with actual or potential tissue damage
or described in terms of such damage
• Nociception:
– neural response related to potentially tissue
damaging stimuli

4. Terminologies for pain
• dysthesia – experience of abnormal noxious
sensation
– paraesthesia - abnormal nonpainful sensation;
– hyperpathia- exaggerated pain response to
noxious or nonoxious stimuli)
• allodynia - perception of nonoxious stimuli as
painful

5. • Hyperalgesia: increased pain response to
painful stimuli
• Hypoalgesia: decreased sensitivity to noxious
stimuli
• Hyperesthesia and Hypoesthesia :increase or
decrease, respectively, in sensitivity to
nonnoxious stimuli

6. Physiology of Pain
• Pain transmission:
– A good way to understand physiology of pain is to
follow nociceptive signal pathways from the
periphery to the brain,
– with emphasis on integration and modulation of
nociceptive signal at different steps in the CNS

7. • Transmission of pain occurs by :
– Transduction
– Transmission
– Perception
– Modulation
• For understanding, it can be divided into
peripheral transmission and central
transmission

9. • Peripheral Transmission:
– Peripheral transmission of pain consists
production of electrical signals at the pain nerve
endings (Transduction) followed by propagation of
those signals through the peripheral nervous
system (Transmission)
• Central Transmission:
– Includes transmission and perception whereby
signals are transmitted from spinal cord to the
brain

10. • Transduction:
– Primary sensory structure that accomplishes
transduction –nociceptor (free nerve endings sensing
heat, mechanical and chemical tissue damage)
– Several types are described:
• Mechanoceptors – sense pinch and pin prick
• Silent nociceptors- sense pain only during inflammation
• Polymodal mechanothermal receptors- most prevalent and
respond to excess pressure, temperature and algogens

11. • Transmission:
– Pain impulses transmitted by 2 fibre systems
– The presence of 2 pain pathways-explains
existence of 2 components of pain: Fast pain(Ad)
and Slow pain (C )
– Ultimately synapse in spinal cord with second
order neurons which send impulse to CNS

12. • Perception:
– From thalamus to somatosensory areas of
cerebral cortex( in the post central gyrus) and
superior wall of the sylvian fissure
– Fibres are also projected to limbic system- anterior
cingulate gyrus and insula

13. • Modulation:
– Occurs at different sites:
• Nociceptor
• Spinal cord
• Supraspinal structures
– This modulation can either inhibit or facilitate pain

14. • Peripheral Modulation:
– Nociceptors and their neurons display sensitization
following repeated stimulation
– Sensitization of nociceptors result in
• decrease in threshold
• Increase in frequency response
• Decrease in response latency
• Spontaneous firing even after cessation of stimulus
– Primary hyperalgesia mediated by algogens like
histamine, bradykinin, PGE2 and leukotrienes from
damaged tissues

15. • Secondary hyperalgesia or neurogenic inflammation-
longterm tissue hypersensitivity beyond area of
original injury  within the CNS
– Repeated recruitment of C-fibres following an injury will cause change
in response properties of membranes of secondary neurons
– Over a period – can cause increase in perceived pain even if intensity
of stimulation remains constant
– This spinal sensitization can persist for minutes, but can also present
for hours or even days
– The prolonged activation of NMDA receptors will induce transcription
of rapidly expressed genes (c-fos, c-jun), resulting in sensitization of
nociceptors
– This neuronal plasticity of the secondary neuron will result in reduced
recruitment threshold of secondary neurons in the spinal cord
hyperalgesia and allodynia that persist even after healing of injury

16. • Central Sensitization: refers to phenomenon where
second neuron membrane permeability changes and
responds at higher frequency when recruited by nociceptive
and non-nociceptive primary input
– This can facilitate or inhibit pain. The mechanisms of
facilitation are as follows:
• Windup and sensitization of second order neurons
• Receptive field expansion
• Hyper excitability of flexion responses
– Neurochemical mediators of central sensitization
• sP , CGRP, VIP, Cholecystokinin, angiotensin, galantin, L-
aspartate and L-glutamate

17. – These substances trigger changes in membrane excitability by
interacting with G-protein coupled receptors
– Activating intracellular second messengers
– Phorsphorylate substance proteins
– Leading to increased intracellular calcium concentration
– Stimulate Nitric oxide synthase and production of NO
– NO diffuses action of neuron and by action on guanylyl cyclase,
NO stimulates formation of cGMP in neighbouring neurons
– Depending on the expression cGMP- controlled ion channels in
target neurons, NO may be excitatory or inhibitory- most cases
implicated in development of hyperalgesia and allodynia

18. • Inhibitory mechanisms can be either Spinal or
Supraspinal
– Segmental inhibition –consists of activation of large
afferent fibres of inhibitory WDR neurons and
spinothalamic activity
– Glycine and GABA –inhibitory neurotransmitters
– Segmental inhibtion mediated by GABA receptor
activity increases K+ conductance across cell
membrane

19. – Supraspinal inhibition – occurs whereby several
supraspinal structures send fibres down the spinal cord to
inhibit pain at the level of the dorsal horn
• Includes –Periaqueductal Gray, Nucleus Raphe Magnus and
Reticular formation
– Axons from these structures act pre-synaptically on the
primary afferent neurons and post synaptically on the
second order neurons(interneurones)
– These axons utilise monoamines (NA and Serotonin) as
neurotransmitters and terminate on nociceptive neurons
in spinal cord + spinal inhibitory interneurones (store and
release opioids)
– Noradrenaline mediates action via alpha 2 receptors
– Endogeneous opioids via enkephalins and B-endorphins–
mainly act presynaptically whereas opiates act
postsynaptically

20. – Cognitive Modulation:
• Involves patient’s ability to relate a painful experience
to another event

21. Pain Pathway

25. Important terminologies
• Physical characteristics of nerve fibres:
Ab Ad C
Diameter 6-12 microns
Myelinated
1-5 microns
Myelinated
0.2-1 microns
Unmyelinated
Conduction 33–75 m/s 3–30 m/s 0.5-2.0 m/s
Role Light touch
Proprioception
Temperature
Nociception
(mechanical,thermal)
Nociception
(mechanical,
thermal, chemical)

26. • Ab fibres:
– Besides conduction of non-nociceptive signal, stimulation
of Ab fibres will recruit inhibitory interneurones in the
substantia gelatinosa of dorsal horn  inhibition
nociceptive input at same spinal segment (innocuous
stimulus)
• Ad fibres:
– Responsible for the first pain sensation, rapid pinprick,
sharp and transient sensation
• C fibres:
– Represent 3 quarters of the sensory afferent input and are
mostly recruited by nociceptive stimulation
– Responsible for dull aching pain

27. • First and Second pain:
– Conduction velocity between Ad and C fibres can be
appreciated when isolating sensation of 1st and 2nd
pain
– Following brief nociceptive stimulation- Ad fibres will
transmit brief and acute pin-prick like sensation,
perceived to be precisely located at he point of
stimulation  results in nociceptive withdrawal reflex
– Following this activity, C fibres will transmit their
information with long delay (100ms to 1 s) depending
on stimulus location

29. • Secondary neurons : can be classified as
– Nociceptive specific neurons:
• Respond only to nociceptive stimulation
• Can be divided into 2 subclasses depending on their recruitment
by Ad alone or combination of Ad and C fibres
– Wide dynamic range neurons:
• Respond gradually to stimuli from innocuous to nociceptive
• Their capacity to respond to both nociceptive and innocous stimuli
is related to the fact that they have received input from Ad, C and
Ab fibres
• Receptive field is dynamic
• Changes in receptive field, membrane permeability to ion
exchange and discharge frequency of these neurons all suggest
substantial role in chronicity of pain

30. • Temporal Summation:
– Good illustration of importance of signal conduction in Ad
and C fibres
– Here, pain perception is compared with repeated
stimulations at same intensity but different rates
– High frequency of stimulation will produce temporal
summation of C-fibre activity as a result of relatively slow
conductance of these fibres
– Resulting in increased perceived intensity of second pain

31. • Spatial Summation:
– Stimulation of a large territory will recruit more
nociceptors than when a small area is stimulated
– Results in more intense pain perception
– However increasing surface area that is stimulated
recruits both excitatory and inhibitory
mechanisms

32. Thank You