PHYSIOLOGY OF PAIN PATHWAYS

AND ITS MODULATION

DR HASSAN
 What is Pain???
• The International Association for
the Study of Pain (IASP) defines
pain as "an unpleasant sensory
and emotional experience
associated with actual or
potential tissue damage, or
described in terms of such
damage."
• Derived from Latin -“Poena” meaning
Penalty/punishment from God.
• JCAHO declared pain as fifth vital sign (1999).
• Net effect of a complex interaction of the
ascending and descending nervous systems
involving biochemical, physiologic,
psychological and neocortical processes.
Classification Of Pain:-

Basis Types of pain

Duration Acute
Chronic
Acute on chronic
Cause Cancer
Non cancer
Mechanism Nociceptive (physiological)
Neuropathic (pathological)
• Pain that is caused by noxious stimulation
due to injury, a disease process, or the
abnormal function of muscle or viscera.
• Two types of acute (nociceptive) pain
somatic and visceral.
CLASSIFICATION OF ACUTE PAIN
ACUTE PAIN

SOMATIC VISCERAL (from viscera)

(somasthetic) e.g. angina pectoris, peptic
ulcer, intestinal colic, renal
colic, etc

Superficial (from skin Deep (from muscles/ bones/

& subcutaneous tissue) fascia/ periosteum) e.g.
e.g. superficial fractures/arthritis/fibrositis,
cuts/burns, etc. rupture of muscle belly
 CHRONIC PAIN:-
• Pain that extends 3 or 6 months beyond onset or
beyond the expected period of healing.
• It may be nociceptive, inflammatory,
neuropathic or functional in origin.
• A distinguishing feature is that psychological
mechanisms or environmental factors frequently
play a major role.
 Acute pain Chronic pain

Sudden, short duration Insidious onset

Onset & timing Resolves /disappears when Pain persists despite tissue
tissue heals healing

Not a warning signal of

Warning sign of actual or
Signal damage
potential tissue damage
False alarm

Correlates with amount of Severity not correlated with

Severity
damage damage

CNS CNS intact- acute pain is a CNS may be dysfunctional-

involvement symptoms chronic pain is a disease

Less, but unrelieved pain

Often associate with
Psychological  anxiety and
depression, anger, fear,
effects sleeplessness (improves
social withdrawal etc.
when pain is relieved)
 Neuropathic Pain:-
• Definition:
• Pain that is caused by a lesion or disease of the
somatosensory system (PNS or CNS)
• Peripheral Nerves
• Traumatic brachial plexus injury
• Diabetes Mellitus
• Carpel tunnel syndrome
• Post herpetic neuralgia
• Central Nervous System
• Central post stroke pain
• Neuropathic associated with spinal cord injury
MECHANISM OF NEUROPATHIC PAIN

Nerve Damage/ Persistent Stimulation

Results in

Rewiring Of Pain Circuits Both Anatomically & Biochemically

causing

Spontaneous Nerve Autonomic neuronal Increased Discharge Of

Stimulation stimulation Dorsal Horn Neurons

Finally leading to

NEUROPATHIC PAIN
NOCICEPTIVE VS NEUROPATHIC PAIN
NOCICEPTIVE PAIN NEUROPATHIC PAIN
Well localized Not well localized
Burning
Sharp Shooting
Worse with movement Numbness
Pins and needles
Obvious tissue injury or Tissue injury may not be
illness obvious
Nerve injury
Changes in wiring
Inflammation
Abnormal firing
Loss modulation
Physiological pain * Pathological pain
 REFERRED PAIN
• Pain that is perceived at the site different from
its point of origin but innervated by the same
spinal segment.

• Usually applies to pain that originates from the

viscera.

• Eg. The pain associated with MI commonly is

referred to the left arm, neck & chest.
 REFERRED PAIN

•Convergence Theory:

•This type of referred pain

occurs because both visceral and
somatic afferents often converge
on the same interneurons in the
pain pathways.

so we “refer” the location of

visceral receptor activation to
the somatic source even though
in the case of visceral pain. The convergence of
nociceptor input from the
viscera and the skin.
The perception is incorrect.
 BREAKTHROUGH PAIN:-
• Pain is intermittent, transitory & an increase in pain
occurs at a greater intensity.

• Usually lasts from minutes to hours and can interfere

with functioning.

• Eg. Neuropathic pain

Lower back pain

What are the consequences
of not treating acute pain?
Adverse Effects Of Severe Acute Pain
System Adverse effects
System Adverse effects
Cardiovascular  Heart rate, BP
Psychological Risk of myocardial ischaemia
Anxiety
Insomnia
Psychological Anxiety
Insomnia
Economic Increased in-hospital complications
Economic Prolongedin-hospital
Increased length of stay in the hospital
complications
Increased health
Prolonged length care utilization
of stay and costs
in the hospital
Gastrointestinal Increased
ileus health care utilization and costs

Chronic pain Higher risk of developing chronic pain

e.g. post surgical pain syndrome
 Peripheral Receptor (Nociceptor)
• Nociceptors are free nerve endings that sense
heat, mechanical and chemical tissue damage.
• Characteristic of nociceptors -
• High threshold for activation
• Encode the intensity of stimulation by
increasing their discharge rates in a graded
fashion.
• These receptive endings are widely distributed
in-Skin,Dental pulp,Periosteum,Meninges.
• Types :-
• Mechano nociceptors (pinch and pinprick)
• Silent nociceptors (inflammation)
• Polymodal mechanoheat nociceptors:-
{Most prevalent and respond to excessive
pressure, extremes of temperature (> 42°C and
< 18°C), and alogens (pain-producing
substances)}.
 Types of Fibers involved in Pain
Aβ fibers
Large diameter,
myelinated, fast conduction
velocity
Mechanoreceptors
normally activated by non-
noxious mechanical stimuli
(touch)
Aδ fibers
Medium diameter,
myelinated, intermediate C fibers
conduction velocity Small diameter, unmyelinated, slow
Normally activated by conduction velocity
noxious stimuli (transmit Normally activated by noxious
sharp pain) stimuli
Harrison’s Textbook of Medicine Vol 1, Part II, Chap 11
(responsible for secondary pain,20
normally burning, aching pain)
SOMATIC NOCICEPTORS:-
• Somatic nociceptors include those in skin and
deep tissues (muscle, tendon, fascia and bone)
whereas.
• Deep somatic nociceptors are less sensitive to
noxious stimuli than cutaneous nociceptors but
are easily sensitized by inflammation.

21
 VISCERAL NOCICEPTORS:-
• visceral nociceptors include those in internal organs.
• Visceral organs are generally insensitive tissues that
mostly contain silent nociceptors.
• Most organs such as the intestine are innervated by
polymodal nociceptors that respond to smooth muscle
spasm, ischemia and inflammation.
• These receptors generally don’t respond to cutting
,burning or crushing that occurs during surgery.
•Noxious sensations can often be broken down
into two components(DOUBLE PAIN):-
•A fast (sharp) and a slow (burning) sensation.
• The fast phase is mediated by myelinated
fibers (A).
• The slow and delayed pain is mediated by
unmyelinated fibers (C-fibers).
• This distinction has been used to explain the
phenomenon of double-pain.
• Afferent activity from these neurons enters the
spinal cord between T1 and L2.
• Fibers from the esophagus, larynx, and trachea
travel with the vagus nerve to enter the nucleus
solitarius in the brain stem.
• Fibers from the bladder, prostate, rectum,
cervix and urethra, and genitalia are
transmitted into the spinal cord via
parasympathetic nerves at the level of the S2–
S4 nerve roots.
 • FAST PAIN • SLOW PAIN

• Felt about 0.1 sec after a pain • Usually begins after 1 sec or
stimulus is applied. more and may range from

• It is described as sharp pain, seconds to minutes.

pricking pain, acute & electric • Described as slow, burning,

pain. aching, throbbing, nauseous

• Fast sharp pain is not felt in pain and chronic pain.

most deeper tissues of the • Associated with tissue

body. destruction.
NEUROTRANSMITTERS
• Glutamate - Central
Pain • Substance P - Central
• Brandykinin - Peripheral
Initiators • Prostaglandins – Peripheral
• Aspartate

• Serotonin
• Endorphins
Pain • Enkephalins
Inhibitors • Dynorphin
• GABA
• Glycine
 THREE NEURONS
DUAL
ASCENDING PATHWAY
 First Order Neuron:-
• Pseudounipolar cell (dorsal root ganglion) ,
divides into central and peripheral branch.
• Impulses are transmitted by Aδ fibre or C fibres.
• Cell bodies located in dorsal root ganglia.
• These impulses are transmitted through the
axons to spinal cord.
• axons of first order neurons may synapse with
interneurons, sympathetic neurons and ventral
motor neurons.
 SECOND ORDER NEURONS
• Second order neurons consist of -
• Nociceptor specific primarily in LAMINA I
• Wide Dynamic Range(WDR) neurons
primarily in LAMINA V
• Nociceptive specific neurons serve only noxious
stimuli, but WDR neurons also receive non
noxious afferent input from Aβ, A∂ and C fibers.
• Cell body in the Spinal Cord or medulla
oblongata.
• Spinal cord grey matter was divided by
REXED into ten lamina.
• The first six lamina, which make up the
dorsal horn, receive all afferent neural
activity, and represent the principal site of
modulation of pain by ascending and
descending neural pathways.
• Lamina II also called the SUBSTANSIA
GELATINOSA ,contains many interneurons
It is believed to be a major site of action for
opioids.
• Lamina V contains WDR neurons ,responds
to both noxious and non noxious sensory
input and receives both visceral and somatic
pain afferents. Thus responsible for referred
pain.
• THIRD ORDER NEURON:-
• located in the thalamus and send
fibers to somatosensory areas 1
and 2 in the postcentral gyrus of
the parietal cortex and the
superior wall of the sylvian
fissure respectively.

• Perception and discrete

localization of pain take place in
this cortical areas.
 SPINOTHALAMIC TRACT
• The axons of most second order neurons cross
the midline close to their level of origin to the
contralateral side before they form the
spinothalamic tract
• They send their fibres to the thalamus ,the
reticular formation, the nucleus raphe Magnus
and the peri aqueductal grey matter.
• The tract can be divided into a lateral and
medial tract.
• The lateral spinothalamic tract projects
mainly to the ventralposterolateral nucleus
of the thalamus and carries discriminative
aspects of the pain such as location ,intensity
and duration and Thermal sensation.
• The medial spinothalamic tract projects to
the medial thalamus and
is responsible for mediating
the autonomic and unpleasant
emotional perception of the
pain, Touch and Pressure.
• Although most neurons from the lateral
thalamic nuclei project to the primary
somatosensory cortex .
• Those from the intralaminar and medial
nuclei project to the anterior cingulate gyrus
and mediate the suffering and emotional
components of pain.
ALTERNATE PAIN PATHWAYS
• Pain fibres ascend diffusely ipsilaterally and
contralaterally, hence some patients continue
to receive pain following ablation of the
contralateral spinothalamic tract.
• The spinoreticular tract is thought to mediate
arousal and autonomic responses to pain.
• The spinomesencephalic tract may be
important inactivating anti-nociceptive
because it has some projection to the
periaqueductal grey matter.
• The spinohypothalamic and spinotelencephalic
tract activates the hypothalamus and evoke
emotional behavior.

• The spinocervical tract ascends uncrossed to

the lateral cervical nucleus which relays the
fibres to the contralateral thalamus. This tract
is likely a major alternative pathway for pain.
 MECHANISMS OF PAIN
• Pain sensation involves a series of complex
interactions between peripheral nerves & CNS.

• Pain sensation is modulated by excitatory and

inhibitory NTs released in response to stimuli.

• Sensation of pain is composed of :--

-Transduction;-Transmission;

-Modulation;-Perception
•MODULATION OF PAIN
• Modulation of pain occurs
• - peripherally at the nociceptors ,
- spinal cord
-supraspinal structure.
• This modulation can either inhibits or facilitates
pain.
• The major site of modulation is dorsal horn of
spinal cord.
PERIPHERAL MODULATION
• Nociceptors and their neurons display
sensitization following repeated stimulation.
• It occurs by two mechanisms:
• PRIMARY HYPERALGESIA (exaggerated
response to pain at site of injury)
SECONDARY HYPERALGESIA (response to
pain outside the site of injury)
 PRIMARY HYPERALGESIA
• Sensitization of nociceptors commonly occurs
with injury and following application of heat.
• Primary hyperalgesia is mediated by the
releaseof alogens from damaged tissues:-
1) Bradykinin- macrophages
2) Histamine- platelets and mast cells
3) Serotonin
4) Prostaglandin
 Peripheral Sensitization
Reduced Transduction Threshold

Primary hyperalgesia
Primary heat allodynia
Innocuous/Noxious
stimulus

Inflammation

primary sensory neuron central neuron

 Prostaglandins:-
• Prostaglandins are produced following tissue damage
by the action of phospholipase A2 on phospholipids
released from cell membranes to form arachidonic
acid.
• The cyclooxygenase (COX) pathway then converts
the latter into endoperoxides, which in turn are
transformed into prostacyclin and prostaglandin E2
(PGE2).
• PGE2 directly activates free nerve endings, whereas
prostacyclin potentiates the edema from bradykinin.
• Pharmacological agents such as acetylsalicylic
acid (ASA, or aspirin), acetaminophen, and
nonsteroidal antiinflammatory drugs
(NSAIDs) produce analgesia by inhibition of
COX.
• Analgesic effect of corticosteroids
• likely the result of inhibition of prostaglandin
production through blockade of phospholipase
A2 activation.
SECONDARY HYPERALGESIA
(Neurogenic inflammation)
• It is manifested by the “triple response’’ of a red
flush at the site of injury(flare), local tissue edema,
and sensitization to noxious stimuli.
• Secondary hyperalgesia is primarily due to release
of substance P (and probably CGRP) from
collateral axons of the primary afferent neuron.
 Substance P
• Substance P is an peptide that is synthesized and
released by first order neurons both peripherally
and in the dorsal horn.
• It degranulates histamine and 5-HT, vasodilates
blood vessels, causes tissue edema, and induces
the formation of leukotrienes.
• The compound capsaicin, degranulates and
depletes substance P. When applied topically,
capsaicin diminishes neurogenic inflammation
and appears to be useful for some patients with
postherpetic neuralgia.
Tissue injury causes
release of chemicals.

They sensitize or
activate receptors.

Neurons release
substance P, which
stimulates mast cells
and blood vessels.

Histamine released
from mast cells and
bradykinin released
from blood vessels add
to pain stimulus.
What are the Modulators
Of peripheral Sensitisation?
 Central Sensitization

Increased Pain Responsiveness

Secondary hyperalgesia
Tactile allodynia
Noxious
stimulus

Irritants primary sensory neuron central neuron

Tissue damage
Inflammation
 CENTRAL MODULATION
FACILITATION

• Three mechanisms are responsible for central

sensitization in the spinal cord:-
(1) Wind up and sensitization of second order
neurons. WDR neurons increase their frequency of
discharge with same repeated stimuli and exhibit
prolonged discharge even after afferent C fiber input
has stopped.
(2) Receptor Field Expansion Dorsal horn
neurons increase their receptive fields
such that adjacent neurons become
responsive to stimuli to which they were
previously unresponsive .

(3) Hyperexcitability of flexion reflexes

 • Neurochemical Mediators Of Central
Sensitization:-

• Substance P
• Vasoactive Intestinal Peptide (VIP)
• Cholecystokinin (CCK)
• Angiotensin
• L-glutamate
• L-aspartate
•Mechanism Of Action:-
•These substances trigger changes in
membrane excitability by interacting with G
protein–coupled membrane receptors on
neurons, activating intracellular second
messengers, which in turn phosphorylate
substrate proteins.
•A common pathway is an increase in
intracellular calcium concentration.
• Glutamate and aspartate receptors play an
important role in wind up via activation of
NMDA and non NMDA receptor mechanism.

• These amino acids are believed to be largely

responsible for the induction and
maintenance of central sensitization.
• The spreading flare of pain, allodynia, and hyperalgesia is
explained by activated NMDA receptors in the dorsal horn which
increases calcium conductance, leading to activation of protein
kinases and to activation of the enzyme nitric oxide synthase,
leading to nitric oxide synthesis. These actions also depend on
activation of secondary messenger systems
• Both prostaglandins and nitric oxide
facilitate the release of excitatory amino
acids in the spinal cord.

• Thus, COX inhibitors such as ASA and

NSAIDs also appear to have important
analgesic actions in the spinal cord.
•What are the Modulators
Of Central Sensitisation?
 INHIBITION
• SEGMENTAL INHIBITION
• Activation of large afferent fibers inhibits
WDR neuron and spinothalamic tract activity.
• Moreover, activation of noxious stimuli in
noncontiguous parts of the body inhibits WDR
neurons at other levels; ie, pain in one part of
the body inhibits pain in other parts.
• These two observations support a gate theory
for pain processing in the spinal cord.
 Gate Theory of Pain
• Melzack & Wall (1965).
• The gate = spinal cord interneurons that
release opioids.
• The synaptic junctions between the peripheral
nociceptor fiber and the dorsal horn cells in
the spinal cord are the sites of considerable
plasticity.
• A “GATE” can stop pain signals arriving at
the spinal cord from being passed to the brain.
The Gate-Control Theory ofPain

Figure 10-12a
The Gate-Control Theory of Pain

Figure 10-12b
The Gate-Control Theory of Pain

ACUPUNCTURE
AND TENS

Figure 10-12c
• The introduction of the gate control theory in
1965 [Melzack &Wall 1965] has acted as a
catalyst for the global proliferation of the
different techniques for pain alleviation based
on afferent stimulation, such as
transcutaneous electric nerve stimulation
[TENS] and ACUPUNTURE.
 Mechanisms Of Action Of TENS
• Afferent activity set up by TENS inhibits
nociceptive transmission in the spinal cord
through pre as well as post synaptic inhibitory
mechanisms. Not only the spinal cord but also
the thalamic regions may be involved.

• TENS stimulation may activate mechanisms at

both spinal segment and supraspinal centres.
Mechanism Of Action Of ACUPUNTURE
• Acupuncture is a mode of peripheral stimulation
based on the activation of peripheral receptors,
sensory nerve fibers or both.
• While a needle can mechanically stimulate nerve
fibers of many types, the pain relieving effect of
acupuncture has been attributed to the
activation of Aδ and possibly C fibers.
SUPRA SPINAL INHIBITION
• Several supraspinal structures send fibers down
the spinal cord to inhibit pain in the dorsal horn.
• Important site of origin for these pathways include
the periaqueductal grey, reticular formation and
nucleus raphe Magnus(NRM)
• Stimulation of the periaqueductal gray area in
midbrain produces widespread analgesia in
humans. Axons from these tracts act
presynaptically on primary afferent neurons and
postsynaptically on second-order neurons (or
interneurons).
• These pathways mediate their
antinociceptive action via α2-adrenergic,
serotonergic, and opiate (μ,∂ and k)
receptor mechanisms.
• The role of monoamines in pain inhibition
explains the analgesic action of
antidepressants that block reuptake of
catecholamines and serotonins.
COGNITIVE MODULATION
• Cognitive modulation of pain involves the
patients ability to relate a painful experience
to another event.
• Example if a patient in pain concentrate on
separate and unrelated images it is possible to
decrease the effects of painful sensation.
PSYCOLOGICAL MODULATION

• Relaxation – systematic relaxation of the

large muscle groups.
• Hypnosis – effective analgesic, state of
inner absorption and focused attention.
Reduces pain by distraction, altered pain
perception, increased pain threshold.
NON-PHARMACOLOGICAL MODULATION

• Massage reduces pain, including release of muscle

tension, improved circulation, increased joint
mobility, and decreased anxiety.
• Physical modalities
• Cold for acute injuries in first 48 hours, to
decrease bleeding or hematoma formation,
edema, and chronic back pain.
• Heat works well for relief of muscle aches and
abdominal cramping.
 Neurostimulation
Neurostimulation uses a small implanted
system to send precisely controlled mild
electrical impulses to the nervous system
–Typically the dorsal horn in the Spinal
Cord
SCS
The patient feels the Neurostimulation as a
pleasant tingling sensation, also known as
“paraesthesias”
Neurostimulation is divided into subcategories
based upon the type of nerve that is being
stimulated.
Spinal cord stimulation (SCS) involves PNS
stimulation of the dorsal column of the
spinal cord,
Peripheral nerve stimulation (PNS)
involves stimulation of a specific nerve
branch.
SCS is the most effective technique for
chronic pain management.
 Intracerebral Stimulation
• Method of Deep Brain Stimulation.
• Used for intractable cancer pain , intractable
neuropathic pain .
• for nociceptive pain electrodes are implanted into the
periaqueductal and periventricular gray areas.
• For neuropathic pain the electrodes are placed into
specific sensory thalamic nuclei.
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