Pain is a sensation that occurs when tissue is damaged. It is transmitted by A-delta and C nerve fibers from the periphery to the spinal cord and brain. A-delta fibers allow for fast localization of pain while C fibers transmit slower and induce emotional responses. In the spinal cord, fibers synapse separately and transmit via different tracts. Modulation occurs through gate control theory in the dorsal horn and descending analgesia from the brainstem. This controls pain sensation to allow tissue repair without pain.

1. PainPain

2. What is pain?
Pain is a sensation that you feel when
there is damage to your body
Although this applies to normal
circumstances, pain can be felt when
there is no damage when the mechanism
becomes pathological
Therefore, pain can be described as
nociceptive (in normal situations) or
neuropathic (in pathology)

3. Nociceptive pain
 As mentioned before, this is the pain that is felt
when there is damage to your body and the
pain serves as a mechanism to bring your
attention onto the site of injury
 The response can then be to limit injury by
moving away from the noxious stimulus
 If you couldn’t experience pain, you would not
be aware of any tissue damage and such
individuals die early

4. Nociceptive pain
Brain
1. You stand on a needle
which causes tissue
damage at the point of
impact
2. This information is transmitted to
the brain (the transmission is known
as nociception), where a sensation of
pain is then felt
3. The response is to limit tissue
damage by moving your leg away
from the needle

5. Pain transmission
 Nociceptive pain is sensed and transmitted by two types
of nerve fibres; A-delta and C fibres:
 A-delta fibres are myelinated, with a fast conduction
velocity and a low threshold for activation i.e. the
stimulus doesn’t need to be strong to activate it
 In the skin, A-delta fibres terminate as specialized
receptors
 A-delta fibres can sense mechanical or thermal stimuli
i.e. excessive stretching of the skin or extreme
temperatures

6. Pain transmission
 C fibres are unmyelinated, with a slow conduction velocity and
terminate in the skin as free nerve endings. They have a high
threshold for activation i.e. the stimulus needs to be very strong
to activate it
 C fibres can sense mechanical, thermal and chemical stimuli.
There are two types of C fibres:
 Peptide-rich
 Peptide-poor
 The differences between the two types are related to the type of
neurotransmitter they release (alongside glutamate) in the spinal
cord
 For example, peptide-rich C fibres release glutamate and
substance P in the spinal cord while peptide-poor C fibres release
glutamate and ATP
 Another difference is where the two types synapse in the dorsal
horn of the spinal cord

7. Pain transmission
 Transmission of pain from the periphery to the brain
can be outlined in the following steps:
Step 1:
 Tissue damage occurs – this can be due to excessive
stretch of the skin, extreme temperatures or irritant
chemicals
SkinThe World
Excessive heat
damages tissue

8. Pain transmission
Step 2:
 The thermal stimulus needs to be converted (transduced) into
an electrical signal so that it can be transmitted to the brain
 This tranduction is done by specific membrane channels and
receptors
 For example, heat is sensed by the TRPV1 (capsaicin) receptor,
pH is sensed by the ASIC receptor while receptors for
inflammatory mediators also play a part (bradykinin, TNF etc)
 In this case, the TRPV1 receptor senses the extreme heat and
induces a membrane potential in both the A-delta and C fibres

9. Step 2:
TRPV1
TRPV1
Specialised ending of
A-delta fibres
TRPV1
TRPV1
Free nerve
endings of
C fibres
Impulse towards the brain
Peptide
rich
Peptide
poor

10. Pain transmission
Step 2:
 A-delta fibres are activated first because of their low
threshold and they transmit the impulse as fast as
possible to the brain
 Therefore, A-delta fibres tell you where the pain is
coming from i.e. where the damage is
 C-fibres are activated slower (high threshold) and
transmit slower because they will allow you to actually
feel the pain i.e. generate an emotion (fear, anxiety
etc)
 It is essential that A-delta fibres are activated first
because it is more important to know that there is pain,
and where it’s coming from so that you can produce a
response
 Feeling emotional can come after the danger has been
removed

11. Pain transmission
Step 3:
The impulses travel along the axons of
both A-delta and C fibres towards the
spinal cord
In the spinal cord, they have their own
separate point of synapse

12. Step 3:
1. A-delta fibres enter
the dorsal horn and
synapse in lamina I
2. Neurones from
lamina I cross the
midline via the
anterior white
commissure
3. These neurons enter the contralateral side and go up the
cord in the spinothalamic tract, to the thalamus. In the
thalamus, they synapse in the ventroposterolateral nucleus
Thalamus
Primary somatosensory cortex
4. From the
thalamus, they
travel to the
somatosensory
cortex, where
the location
and intensity of
the pain
become known

13. Step 3: C fibres (both peptide-rich
and peptide-poor) enter
the dorsal horn and
immediately travel in
Lissauer’s tract to 1-2
spinal segments above the
level of entry
For example, if C
fibres enter at L4,
they would ascend up
Lissauer’s tract and
synapse in L2

14. Step 3:
1. C fibres ascend up
Lissauer’s tract
2. Peptide-rich C fibres synapse in
lamina I
3. The majority of these
peptide-rich C fibres
cross the mid-line and
ascend in the
dorsolateral funiculus, as
the spinoparabrachial
tract
Pons
4. They synapse in the
lateral parabrachial
nucleus, in the pons
Hypothalamus
Amygdala
5. From the pons, they go to the
hypothalamus and the amygdala.
This tract is responsible for the
emotional response to pain

15. Step 3:
1. C fibres ascend up
Lissauer’s tract
2. Peptide-poor C fibres synapse on
interneurons in lamina II
3. The interneurons
travel down to lamina V
4. From lamina V, the
fibres cross the mid-line
and ascend up the
spinoreticular tract
Medulla
Nucleus raphe Locus coeruleus Thalamus
5. Fibres synapse in the
reticular formation of the
medulla, nucleus raphe and
the locus coeruleus
6. Finally, these fibres synapse in the
intralaminar nuclei of the thalamus and the
cingulate cortex. All these connections
activate the descending analgesic pathways
Anterior
cingulate
cortex

16. Summary of pathways
Type
of
fibre
Synapse
in the
dorsal
horn
Tract Connections Function
A-delta Lamina I Spinothalamic
Ventroposterolateral nucleus
in the thalamus
Localisation of stimulus
Peptide-
rich C
fibre
Lamina I Spinoparabrachial
Lateral parabrachial nucleus
in the pons
Emotional aspects
Peptide-
poor C
fibre
Lamina II ->
Lamina V
Spinoreticular
Reticular formation, locus
coeruleus, nucleus raphe,
intralaminar nuclei in the
thalamus, anterior cingulate
cortex
Emotional aspects and
descending analgesic
activation

17. Pain modulation
 Once pain has been sensed and the
danger averted, pain sensation needs to
be depressed
 This is so that tissue repair can carry on
without having to feel pain
 Pain modulation occurs at two main
sites:
1. In the periphery i.e. gate control
2. From the brain/brainstem i.e. descending analgesic
pathways

18. Gate control
 This is a theory that A-beta fibres (which carry
sensations other than pain) can control the
transmission of pain in the dorsal horn
 When the activity of A-beta fibres are high,
they stop the transmission of pain (as well as
transmitting their own stimulus) – the ‘gate is
closed’
 When the activity of C fibres are higher than A-
beta, they ‘open the gate’ and allow pain
transmission to occur

19. Gate control
A-beta fibres synapsing in lamina V
Pain projection
neurone
Interneuron in lamina III.
This interneuron inhibits
the projection neurone,
when A-beta is active
C fibres synapsing in lamina I and II
C fibres act on
inhibitory
interneurons
This interneuron acts to inhibit the
interneuron in lamina III, which has an
inhibitory block on the projection
neurone

20. Pain projection
neurone
‘Opening the gate’
1. Activity in the C
fibres is higher than
activity in A-beta
fibres
2. This activates the
interneuron in lamina II.
This interneuron inhibits
the interneuron in lamina
III
3. The
block on
the pain
projection
neurone is
removed
Glu
Glu
Glu
GABA or Gly

21. ‘Closing the gate’
Pain projection
neurone
1. Activity in the A-
beta fibres is higher
than C fibres
2. This activates the
interneuron in lamina
III. This interneuron
inhibits the projection
neurone
Glu
GABA or Gly
Glu
Glu
GABA or Gly

22. Descending analgesia
 Activated by the spinoreticular tract, as it
synapses at the locus coeruleus, nucleus raphe
and the thalamus
 The locus coeruleus inhibits nociceptive fibres
with Noradrenaline
 Nucleus raphe inhibits nociceptive fibres by
using 5-HT and the opioid, Enkephalin
 The thalamus and amygdala activate the
periaquductal grey, which activates both the
locus coeruleus and the nucleus raphe

23. Descending analgesia
Periaqueductal
grey
(midbrain)
ThalamusAmygala
Nucleus rapheLocus coeruleus
Dorsal horn of the spinal cord
5-HT and EnkephalinNoradrenaline