1) Pain physiology involves transduction, transmission, perception, and modulation of nociceptive signals from the periphery to the brain. 2) Pain signals are transmitted via Aδ and C nerve fibers to the spinal cord and then to the brain. Aδ fibers transmit fast, sharp pain while C fibers transmit slow, dull pain. 3) Central modulation occurs in the spinal cord and brain and can either facilitate or inhibit pain transmission and perception through mechanisms like windup, sensitization, and the release of neurotransmitters.

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