Physiology of pain

Objectives
• Classify the types of pain and its characteristics
• Describe the 2 pain pathways , Lateral sensory
discriminative pain pathway and the Medial
Affective motivational pathway
• Discuss Pain sensitization through peripheral
and central mechanisms and mechanisms of
pain inhibition
• Explain neuropathic pain causes and maladaptive
mechanisms
Dr.atef abood 2
 Introduction
• Nociception it is the perception of injurious stimuli,
• Pain perception depends on
– nociceptors and pathways
– The central distribution of nociceptive information involving
multiple areas in the brainstem, thalamus, and forebrain.
• Nociception has many aspects to consider
– discriminative type and nature of pain
– Affective Emotional aspect of pain
– motivational and behavioral aspect of pain
• The obvious importance of pain
– In clinical practice
• a diagnostic
• a focus of treatment
– active area of research

Dr.atef abood 3
 Pain
• As other somatic sensations pain has
• Nociceptors : free nerve endings
• Sensory afferents type Aδ or C
• Sensory pathways
– Lateral discriminative pathway (formely called
neospinothalamic pathway
– Medial affective motivational pathway (formerly
called paleospinothalamic pathway)
• Sensory centers: multiple centers in the thalamus
and cerebral cortex
Dr.atef abood 4
Nociceptors and sensory afferents
• 1. Nociceptors
– Type : structurally, unspecialized free nerve
– endings
– Functionally specialized for transmission of pain

Dr.atef abood 5
 2. Nociceptor afferents
• Aδ afferent are assigned to sharp pricking and extreme
hot stimuli
• C afferents are polymodal pain receptors that respond
to all types of stimuli and produce a diffuse aching pain
sensation
• Pain sensory afferents produce neurotransmitters to
• stimulate post synaptic neuron in the spinal cord which
include substance P, glutamaye, CGRP
• Be released also peripherally and share in exaggeration
of inflammatory response and nociceptor activation

Dr.atef abood 6
Dr.atef abood 7
 Nociceptor activation
• 1.Nociceptors can be activated by
– extreme temperature (thermosensitive nociceptors)
– intense mechanical stimulation (mechanosensitive
pain receptors)
– an array of chemicals through specific receptors
(chemosensitive nociceptors)

Dr.atef abood 8
 Nociceptor activation

• Thermal activation of nociceptors

– A δ and C fibers are activated by thermal stimuli
– These fibers has a specific receptors that respond to
noxiuous stimuli
– TRPV1 Receptors responsive to hot thermal
stimulation which is also responsive to Capsacicin
– TRPV1 receptor activation by extreme hot stimulus
open calcium and sodium channels and causes
depolarization
– Extreme cold is perceived as pain by activation of
cold sensitive nociceptive endings which has another
type of receptor channel called TRPM8 receptors

Dr.atef abood 9
Receptors on nociceptive unmyelinated nerve fibers

Dr.atef abood 11
 Firing of action potential in pain
sensory afferents
• The graded potentials arising at the receptors is transformed into
action potentials in order to be conveyed to synapses in the dorsal
horn of the spinal cord.
• Voltage-gated sodium and potassium channels are critical in this
process.

Clinical
note

Navl.7 is one of channel subtypes generating action potential in nociceptive afferents.

Mutations of the NAV1.7 gene that lead to inability to detect noxious stimulation.
The mutations that lead to hyperexcitability of the channel are associated with pain
exaggeration

Dr.atef abood 12
 Classification of pain

Cutaneous pain Deep pain pain visceral pain

Pain arising from arising from deep Pain arising
the skin and structuires as from viscera
subcutaneous muscle tendons
tissues and bones

Fast pain Slow pain

Dr.atef abood 13
 Cutanous pain
• Types of cutaneous pain
– fast localized sharp pain sensation
– diffuse long lasting dulling pain sensation
Fast pain Slow pain
afferents Aδ C
Onset 0.01 second 1 second
course Acute Chronic
Character sharp, pricking, and slow burning, aching,
electric pain. throbbing , nauseous
pain,
stimulus Usually cut with a More diffuse injuries
knife, electric shock
sever burn
site In the skin not in deep Both cutaneous, deep
structures or abood
Dr.atef viscera and visceral 14
In the left diagram the post synaptic cells or the secondary order neuron is of two types NS type
synapse only with Nociceptive afferents Adelta and C. while WDR neurons synapse with painful
(Adelta and C fibers and non nociceptive afferent (Abeta)
In the right diagram are the neurotransmitter released from nociceptive afferents including
glutamate, substance P, and CGRP with their receptors on the post synaptic membrane.
Dr.atef abood 16
 PAIN PROCESSING IN THE SPINAL CORD

• The pain afferents or first order neuron enters

the spinal cord gray matter in the superfial layers
lamina I and II or substantia gelatinosa of Rolandi
and lamina V
• A. Synaptic targets
– nociceptive-specific (NS) cells,
• synapse only with Aδ and C fibers
• encode only for painful stimuli
– Wide dynamic range (WDR) neurons,
• receive synaptic input from all types of sensory fibers
• encode for a range of stimuli, both painful and nonpainful.

Dr.atef abood 17
 Neurotransmitters
• The synapse in the posterior horn is
excitatory.
• The neurotransmitters released by the
afferent nociceptive fibers are
– glutamate, which acts mainly on (AMPA) and
(NMDA) receptors
– substance P, which acts on the NK1 receptor; and
– CGRP, which also has an excitatory effect via the
CGRP receptor.

Dr.atef abood 18
Central Pain Pathways
 Lateral sensory discriminative pain pathway)

• It is also called neospinothalamic pathway in the Aδ

afferent
• Responsible for acute fast sharp pain
• encodes for the location, intensity, and quality of pain
• It relays in lamina I, II and V in the dorsal horn gray
matter
• The second order neuron ascends after crossing
immediately to opposite side as lateral spinothalamic
tract to the VPL nucleus of the thalamus
• Third order neuron arsie from the thalamus to the
somatosensory cortexto sensory cortex,

Dr.atef abood 20
 (Medial affective-motivational pathways)

• Paleospinothalamic Pathway for Transmitting

Slow- Chronic Pain.
• transmits pain mainly from the slow-chronic
type C pain afferents.
• The slow-chronic paleospinothalamic pathway
terminates widely in the brain stem, in various
sites

Dr.atef abood 21
 Importance of projections of medial
affective pain pathways
• To the reticular formation produces motor responses to
pain and stimulate release of monoamines (Serotonin, NE
and opioids) acts as substrate for wakefulness and sleep.
• To the PAG area of midbrain: to stimulate brain analgesic
system
• To the limbic system: to produce emotional components of
pain
• To the hypothalamus : autonomic and endocrinal responses
to pain
• All these projections can perceive pain sensations.
• Lesions above the midbrain does not abolish most of pain
sufferings

Dr.atef abood 22
 Thalamic relay of medial affective pathway

• ascend to the intralaminar nuclei and

ventrolateral nuclei of the thalamus where
these structures act as a higher center for
perception of slow pain.

Dr.atef abood 23
Medial affective pain pathway

Dr.atef abood 24
Role of spinohypothalamic and spinolimbic pathways in pain
affection

Hypothalamus Limbic system

Release of cortisol
and stimulation of Emotional aspects
autonomic centers like fear and
anxiety

Visceral and
endocrine
function
Medial pain pathway

Dr.atef abood 25
 Cortical pain matrix

Active during actual pain

perception and if pain is
imajined and if watching
other suffer pain

Dr.atef abood 26
 Affective motivational Discriminative pain
pain
Localization Poor localization Locality, intensity and
modality discrimination
Conscious perception thalamus , Somatosensory cortex
of pain hypothalamu , RF

Pain reactions Emotional feeling, Avoidance behavior

Central pain autonomic and
endocrine responses
pathways

Pathway Extensive branches and Little branching and

synapses few synapses
Relay in Brain stem and 90% 10%
subcortical centers

Thalamus Intralaminar and VPL and VPM

ventrolateral
Cortical complex Cingulate cortex an Somatosensory cortex
(medial system) insular (lateral system)
Dr.atef abood 27
cortex
 VISCERAL PAIN
• Characters of visceral pain
• It is the slow diffuse type of pain which is aching or colicky and
transmitted in C afferents
• Viscera has a scarce pain receptors
• Sharp localized cut produce no or little pain
• Parenchyma of most organs are pain insensitive
• Elicited by diffuse stimulation like ischemis or overstretch
• It is usually referred
• Causes of visceral pain
– Ischemia
– Spasm
– Overstretch
– Chemical irritations

Dr.atef abood 28
 Referred Pain
• the complaint of pain at a site other than its actual source
or site of origin
• Clinical example
– is anginal pain (pain arising from ischemic heart muscle)
referred to the upper chest wall, with radiation into the left arm
and hand.
– Gallbladder pain referred to the scapular region,
– esophageal pain referred to the chest wall,
– ureteral pain (e.g., from passing a kidney stone) referred to the
lower abdominal wall,
– bladder pain referred to the perineum, and the
– pain from an inflamed appendix referred to the anterior
abdominal wall around the umbilicus

Dr.atef abood 29
 Mechanisms of referred pain
• Convergence projection theory
• It supposes that the somatic and visceral structures
have sensory afferent that converge on the same
second order neuron in the same dorsal horn of the
spinal cord
• When the pain signal reaches the brain it reaches
through one single neuron
• The brain has to decide which is the signal somatic or
visceral
• As the brain is accustomed to receive pain afferents
from somatic structures It will project to the somatic
structure as the site pain.

Dr.atef abood 30
Dr.atef abood 31
Dr.atef abood 32
Dr.atef abood 33
Examples of pain arising from a visceral disorder
referred to a cutaneous region
Dr.atef abood 35
Transmission of visceral
pain in the dorsal
column-medial
leminiscus sytem

Dr.atef abood 36
 Pain and Temperature Pathways from the Face
The cell body lies in the trigeminal
ganglia and the central branches
enter the brain stem and ascend as
trigeminal tract where it synapses
with the second order neuron in
the spinal nucleus of the trigeminal
complex.
From the spinal nucleus the second
order neuron arises and crosses to
the opposite side to ascend as
trigemniothalamic pathway to relay
in the ventroposteromedial nucleus
of the thalamus from there a third
order neuron arise to the face area
in the somatosensory cortex

Dr.atef abood 37
PAIN MODULATION

Dr.atef abood 38
 Nociceptive modulation by
descending modulation system
• This system is modulatory either inhibitory or facilitatory.
• According to the situation, the system decides inhibits or
facilitate
• If the situation require behavioral response that is
essential, facilitation occur
• Conditions that drive pain inhibition
– Stress
– All conditions that threaten survival
• Conditions that favor facilitation
– Inflammation
– Internally originated pain
– Absence of stressful conditions

Dr.atef abood 39
Ascending and descending nociceptive pathways

• Ascending pathway in the

medial affective pathway
(Red) (paleospinothalamic)
• Descending modulatory
pathway (blue)
• Mutual supply between the
ascending and descending
pathways occur so that both
pathways affect each other
in multiple relay sites as
shown in the figure

Dr.atef abood 40
 B. Descending influences from the
brainstem
• The key center for pain modulation is
the periaqueductal gray area in the
midbrain
• It receives collateral from ascending
nociceptive pathways as well as
descending information from higher
centers (cortical centers, amygdala
and hypothalamus)
• It integrates these information and
act as a saliency filter and decides if
the situation require facilitation or
inhibition
Dr.atef abood 41
 B. Descending influences from the
brainstem
• The descending inhibitory pathways arises from
• the PAG (release encephalin) and the reticular formation,
which includes the locus coeruleus (NE) and the raphe
nuclei (Serotonin), rostral ventromedial medulla (NE)
• The target for these descending pathways is the dorsal
horn gray matter in substantia Gelatinosa of Rolandi
• Neurotransmitters utilized in these systems include
Serotonin, NE and encephalin and glutamate and others.

• NB: the cortical pain matrix exert influence on the

descending brainstem systems as well as on the thalamus,
which gates the information to the cortex.

Dr.atef abood 42
Origin of descending modulatoy
system

Dr.atef abood 43
Descending brain
modulation system

• PAG area releases

encephalin into the
raphe magnus nucleus
• The raphe magnus
nucleus releases
serotonin into the
dorsal horn
• Serotonin excites
enkephalinergic
inhibitory interneuron
in the SGR
Dr.atef abood 44
 Dorsal horn processing of descending pain
analgesic system
• The descending
serotonergic neuron
excites inhibitory
interneuron
• The inhibitory
interneuron releases
encephalin.
• The encephalin binds
opioid receptors
• It causes presynaptic and
post synaptic inhibition of
nociceptive neurons
Dr.atef abood 45
 Critical thinking

• Descending pain modulation system acts as a

filter for priority.
• Apply this concept for a soldier in a battle and for
a man struck by a car?

• What does the brain modulation do in both

situations?

Dr.atef abood 46
 STRESS-INDUCED ANALGESIA
• Soldiers wounded in battle often feel no pain
until the battle is over; this is an example of
stress-induced analgesia.
• It is related to release of:
– Endogenous opioids
– endogenous cannabinoids
• endogenous cannabinoids may contribute to stress-induced
analgesia by acting on CB1 and CB2receptors
• activation of CB1 receptors produces euphoria
• Binding of an agonist to CB2 receptors on microglia reduces
the inflammatory response and has an analgesic effect.

Dr.atef abood 47
 C. Endogenous opioid system

• Opioid derivatives like morphine are used as a powerful analgesic

• Opioid receptors are discovered at all levels of the pain system:
– Pain matrix, in medial cortex
– in the descending brainstem systems
– the posterior horn of the spinal cord.
• Opioid receptors are physiologically activated by enkephalins,
endorphins, and dynorphins.
• These opioid peptides act as neurotransmitters or
neuromodulators and can produce potent analgesic effects.
• Opioid receptors respond to exogenous agonists and so used
pharmacologically
• Opioid receptors are present on peripheral nerves helps use of
opioid antagonist locally on peripheral nerves

Dr.atef abood 48
Opioid receptors activation

• Activation of Opioid receptors

results in the
• Presynaptic
– inhibition of voltage-gated
Ca2+ channels on the
presynaptic terminals so
decrease release of
neurotransmitter
• Post synaptic
– increase the opening of
– K+ channels, K+ efflux
cuases hyperpolarization
and decrease response to
neurotransmitter
Dr.atef abood 49
 Gate control theory of pain

• Involves influencing the

balance between the
nociceptive input (through
Aδ and C fibers) and the
input through Aβ fibers,
which encode for touch
• Example
– Rubbing your skin after
injury
– Acupuncture

Dr.atef abood 50
 Gate control theory of pain: mechanism
• Aβ mechanosensitive afferents
excite inhibitory interneuron
result in inhibition of
postsynaptic dorsal horn
neuron
• Afferent C fibers inhibit the
inhibitory interneuron and
excite the post synaptic second
order neuron
• The gate for nociception is
inhibited when the inhibitory
input is higher than the
excitatory input.
Dr.atef abood 51
 Treatment of Pain by Electrical
Stimulation
• Stimulating electrodes are placed on selected
areas of the skin or implanted over the spinal
cord, stimulate the dorsal sensory columns.
• In some patients, electrodes have been placed
– in intralaminar nuclei of the thalamus or
– in the periventricular or
– periaqueductal area of the diencephalon.
• The patient can then personally control the
degree of stimulation.
• Dramatic relief has been reported

Dr.atef abood 52
Pain sensitization (hyperalgesia)

Dr.atef abood 53
 Peripheral sensitization(primary
hyperalgesia)
• Definition
– It is the exaggerated pain sensation at the area of
tissue damage
– It is called nociceptor sensitization
• Lowering the activation threshold
– The inflammatory mediators augment the sensitivity
of nociceptors by direct and indirect pathways to
facilitate opening of the ion channels on nociceptors.
– The inflammatory mediators include variety of
substances (see figure).

Dr.atef abood 54
Peripheral sensitization(primary
hyperalgesia)

Dr.atef abood 55
Dr.atef abood 56
Sensitization of peripheral receptors
(primary hyperalgesia)
• Mechanism
– Bradykinin and nerve growth factors, released
during tissue damage Sensitize peripheral
nociceptors indirectly
– Substance P released from nerve endings activates
mast cells to releases histamine
– CGRP released from nerve endings causes VD
– Silent nociceptors are recruited
– Activation threshold is lowered and nociceptors
are facilitated

Dr.atef abood 57
 Applications
• The mechanism of action of inflammatory
mediators is ac active area of research for new
analgesics.
– NSAIDs (nonsteroidal anti-inflammatory drugs),
act by inhibiting cyclooxygenase (COX), and so the
biosynthesis of prostaglandins.
– Anti-NGF antibodies prevent and reverse the
behavioral signs of hyperalgesia in animal models
– TNF-α neutralizing antibodies are significantly
effective in the treatment of rheumatoid arthritis.

Dr.atef abood 58
 Central sensitization

• Definition
– Progressive increase of the excitability of second order neurons
in the dorsal horn which may also occur in more central pain
pathways after long period nociceptive stimulation
• Causes
– Subthreshold activity in nociceptor afferent become able to
generate action potential in the second order neuron
(hyperalgesia)
– Low threshold mechanosensitive afferents could activate
nociceptive second order neuron which is already receiving
subthreshold stimulation from peripheral nociceptors
– Non nocuous stimulus . In this case brushing hair could elicit
pain. The induction of pain by a normally innocuous stimulus is
called allodynia

Dr.atef abood 59
Mechanism of central sensitization or wind up

Dr.atef abood 60
 Wind up mechanism of central
sensitization
• Wind-up is an amplification system within the
spinal cord to respond to the cumulative
nociceptive input from C fibers.
• Frequent stimulation of WDR neurons by C
afferents produces sustained depolarization, this
opens NMDA receptor by removal of magnesium
block. The increase intracellular calcium produces
change in receptor channels in the WDR neuron
through increasing sodium and blocking
potassium channels. In this case the response at
the WDR afferents are facilitated

Dr.atef abood 61
 Mechanism of central sensitization
(Cont.)

• Reduction in the level of GABAergic or glycinergic

inhibition in spinal cord circuits which increases
excitability of projection neurons in the dorsal
horn (second order neuron).
• Microglia and astrocytes produce cytokines which
activates COX2 which increases prostaglandin in
central pathway to contribute to central
sensitization

Dr.atef abood 62
 Importance of sensitization
• It is a protective alarming mechanism
• If persists after causative agent disappears it
becomes maladaptive and produces chronic
pain.

Dr.atef abood 63
 Chronic pain

Chronic Chronic
nociceptive pain neuropathic pain

Chronic activation of Persistent pain

nociceptors in after healing of a
inflammation somatosensory
-Osteoarthritis lesion
-Peptic ulcer Post herpetic pain
-Rheumatoid
arthritis

Dr.atef abood 64
Characteristics of neuropathic pain
• Spontaneous
• pain without any apparent stimulus
• hyperalgesia : Sever pain in response to minor stimuli
• allodynia (painful reaction to innocuous stimuli).
• Summation repeated applications of a low-intensity
noxious stimulus lead to a worsening pain experience.
• Paresthesias, spontaneous tingling sensation
• Dysesthesias, painful experiences characterized by
burning, electrical sensations, or shooting pain, in the
absence of an external stimulus

Dr.atef abood 65
 Mechanism of neuropathic pain

• Maladaptive peripheral sensitization

– Changes in the nature of the receptors on Aδ and
C afferents
– Expression of more sodium channels
– Overexpression of TRPV1 leads to burning feeling

Dr.atef abood 66
 Mechanism of chronic neuropathic pain

• Maladaptive central sensitization

• Changes occur in the postsynaptic membrane of WDR neurons
during central sensitization becomes long term and permanent
• LTP like condition: NMDA dependent mechanism
– Sustained depolarization of the post synaptic neurons by low frequency stimulation of AMBa
kainite receptor remove the mg block and activate NMDA glutamate receptors which
increases intracellular calcium that act as a signal to increase glutamate receptors.
– Increases number of glutamate receptors
– The overexpression of (Na+ channels) and reduction of (K+ channels)
– produces a lowered threshold and facilitated synaptic transmission.

Dr.atef abood 67