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International Pain School
Neurophysiology of Pain
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The Scream
Edvard Munch 1893
Lecture Objectives
• Basics of the nervous system
• Synaptic function
• Nerve impulses
• Transduction of peripheral painful stimuli
• Central pathways
• Control or modulation of pain signals
• Pathophysiology of pain signaling pathway
Definition of pain
• "Pain is an unpleasant sensory and emotional
experience associated with actual or potential tissue
damage, or described in terms of such damage".
(The International Association for the Study of Pain)
Epidemiology of pain
• Pain is a global health issue (World Health
Organization).
• There is lack of accurate statistics but ~ tens of millions
of people worldwide experience pain every year.
Epidemiology of pain (cont.)
• Post-surgical pain
–About 240 million major surgeries take place annually
worldwide.
–~ 50% of patients report moderate to severe pain.
• Chronic pain
–1.5 billion people worldwide are diagnosed with
chronic pain;
• ~ 20% of Europeans suffer from chronic pain (Breivik et al. 2006).
–3 - 4.5% of the global population suffers from
neuropathic pain.
• The incidence rate increases with age.
Epidemiology of pain (cont.)
• Cancer- & HIV/AIDs - related pain
• 10 million people worldwide who are diagnosed with some form of
cancer each year.
• 1/3 of adults treated for cancer and 2/3 with advanced disease
experience pain.
• "Unrelieved cancer pain is a cause of major worldwide suffering, not
because we don't have the tools necessary to relive pain, but because
most patients don't have access to the essential pain-relieving
medication“. (N. Cherney, European Society for Medical Oncology,
2012).
The Nervous System
• It is important to know the basic structure of the
nervous system.
• This will help in
– understanding the mechanism by which
nociceptive signals are produced.
– know the different regions of the nervous system
involved in processing these signals.
– learn how the different medications and treatment
for pain management work.
Nervous System
Central nervous system (CNS)
•Brain and Spinal Cord
Peripheral Nervous System (PNS)
•Nerve fibers go to all parts of the
body.
•Send signals to the different tissues
and send signals back to the CNS.
Nerve Cells
• The nervous system is made up of nerve cells
which send long processes (axons) to make
contact with other cells.
Dendrites which receive signals
from other nerve cells
Cell Body
Nerve ending that connect to other cells.
Also act of receptors for stimuli
Node of Ranvier
Schwann Cell
Myelin Sheath
Cell nucleus
Nerve Cell-to-Nerve Cell Communication
Nerve cells communicate
with other cells by
releasing a chemical from
the nerve endings –
Neurotransmitters
The Synapse.
Basic Steps in Synaptic Transmission
Synaptic Transmission
Steps in the passage of signal from one
nerve cell to other.
Drugs are used to block the transmission of
signals from one nerve cell to other.
These drugs can effect
1.Ca2+ ion channel to prevent Ca2+ inflow
which is essential for neurotransmitter (NT)
release, e.g., the action of gabapentin.
2. Release of NT.
3. Prevent NT from binding to its receptor so
stop further transmission of the signal.
Electrical impulse
• Signals move along a nerve process (axon) as a wave of
membrane depolarization called the Action Potential.
• The inside of all nerve cells has a negative electrical
potential of around – 60 mV.
• When stimulated this negative electrical
potential becomes positive and then negative again in
milliseconds.
• The action potential moves along the nerve process (axon)
to the nerve ending where it cause release of NT.
Action Potential
•
When there is no stimulation
the membrane potential is at
its Resting Potential.
•
When stimulated, channels in the nerve
membrane open allowing the flow of
sodium ions (Na+) or calcium ions
(Ca2+) into the nerve or cell. This
makes the inside less negative and in
fact positive -the peak of the action
potential (+40 mV).
•
These channels than close and by the
opening of K+ channels the membrane
potential returns to its resting level.
Stopping Action Potentials to Stop
Nociceptive stimuli
• Nociceptive stimuli are those that will create a
sensation of pain after they are processed in the CNS.
• Nociceptive signals can be prevented from reaching
the CNS by blocking the action of the channels that
control the movement of ions across the nerve
membrane.
• A number of anesthetic agents stop Na+ channel from
working and hence stop the generation of actions
potentials and transmission of signals to the CNS.
• E.g. Procaine – local anesthetic agent.
Sensory Systems
• The sensory system that can be divided into two
divisions:
1. A Sensory System that transmits innocuous
stimuli such as touch, pressure, warmth.
2. A System that transmits stimuli that indicate that
tissues have been damaged = nociceptive .
• These two systems have different receptors and
pathways in the PNS & CNS
Skin Receptors
Touch, pressure, vibration, skin stretch
Neuroscience. 2nd edition. Purves D, Augustine GJ, Fitzpatrick D, et al.,
editors. Sunderland (MA): Sinauer Associates; 2001.
Nociceptors
Nociceptors
• Nociceptors are free nerve endings that respond to
stimuli that can cause tissue damage or when tissue
damage has taken place.
• Present in membrane of free nerve endings are
receptors (protein molecules) whose activity changes
in the presence of painful stimuli.
• (Note the use of the same term receptor is used for cell
or organs or molecules that involved in transduction
of a stimuli.)
Transduction
• Transduction is the process of converting the stimuli
into a nerve impulse.
• For this to occur the flow of ions across the nerve
membrane has to change to allow entry of either Na+
or Ca2+ ions to cause depolarization of the
membrane potential.
• This involves a receptor molecule that either directly
or indirectly opens the ion channels.
Chemical agents …
… which can cause the membrane potential at the free nerve
ending (nociceptor) to produce an action potential.
Agents
Source
Effect on nociceptor
Potassium
Damaged cells
Activation
Serotonin
Platelets
Activation
Bardykinin
Plasma kininogen
Activation
Histamine
Mast cells
Activation
Prostaglandins
Arachidonic acid from
damaged cells
Sensitization
Leukotrienes
Arachidonic acid from
damaged cells
Sensitization
Substance P
Primary afferents
Sensitization
from Fields HL. 1987. Pain. New York: McGraw-Hill.
Summary of Transduction Process
at the Periphery
Chemical, Mechanical,
Thermal stimuli
Changes in the receptor
Increase in ion flow
across the membrane
Depolarization of
membrane potential
(Generator potential)
Action potential
TRP Channels
• Many stimuli – mechanical, chemical and thermal –
give rise to painful sensation making transduction a
complex process.
• Recently receptor molecules have been identified Transient Receptor Potential (TRP) channels - that
respond to a number of strong stimuli.
• TRP receptors are also involved in transmitting the
burning sensation of chili pepper.
• In time, drugs that act on these receptors will be
developed to control pain.
Different TRP Channels
Capsasin, the active
ingredient in chili pepper, is
used in patches for relief of
pain.
Menthol and peppermint
gels are used to relieve
muscle pain.
Motor Output and Sensory Input
to Spinal Cord
Sensory nerves have their cell body outside the
spinal cord in the dorsal root ganglia
( = 1st order neurons).
One process goes to the periphery, the other goes
to the spinal cord where it makes synaptic contact
with nerve cells in the spinal cord
( = 2nd order neurons).
The 2nd order neuron sends processes to other
nerve cells in the spinal cord and to the brain.
2nd Order Nerve cells send nerve fibers in the
spinal cord white matter
Silverthorn
Transmission of nociceptive signals from the
periphery to the brain
The spinal cord is more than a
junction area for transmission of
signals to the brain.
There are spinal neural circuits,
which can alter signal
transmission.
nociceptive
stimulus to
brain
nociceptive
stimulus
Silverthorn
A delta (d) and C nerve fibers
• Nerve fibers are classified according to the:
– (1) diameter of the nerve fiber and
– (2) whether myelinated or not.
• Ad and C nerve fiber endings respond to strong
stimuli.
• Ad are myelinated and C are not.
• Action potentials are transmitted 10 times faster in the
Ad (20 m/sec) fibers than in C fibers (2 m/sec).
Ad and C fibers
• Ad fibers respond mainly to mechanical and mechnothermal stimuli.
• C fibers are polymodal, i.e. the nerve ending
responds to several modalities
– thermal, mechanical and chemical
• This polymodal ability is due to the presence of
different receptor molecules in a single nerve ending.
Fast and Slow Pain
C
Ad
• Most people when they are
hit by an object or scrape
their skin, feel a sharp first
pain (epicritic) followed by a
second dull, aching, longer
lasting pain (protopathic).
• The first fast pain is
transmitted by the
myelinated Ad fibers and the
second pain by the
unmyelinated C fibers.
Central Pain Pathways
• Nociceptive signals are sent to the spinal cord and
then to different parts of the brain where sensation of
pain is processed.
• There are a pathways/regions for assessing the:
1. Location, intensity, and quality of the
noxious stimuli
2. unpleasantness and autonomic activation (fightor-flight response, depression, anxiety).
Intensity, Location, and Quality of Pain …
… involve Spinothalamic and Trigeminal Pathways
• The trigeminal pathway brings information from
the face area.
• The spinothalamic pathway brings information
from the rest of the body.
• Both these pathways project to the sensory cortex,
which also receives information on innocuous stimuli
such as touch, pressure and warmth via a separate
pathway.
Trigeminal pathway
Spinothalamic pathway
(Anterolateral Pathway)
2 Pain Transmission Pathways
for location Intensity quality
Neuroscience Purves et al.
Unpleasant Quality and Autonomic Affective
Motivational Pathway for Pain
Spinal cord
Parabrachial nucleus
Amygdala
(involved in fear)
Hypothalamus
(autonomic
responses, e.g
sweating)
Thalamus
Insula
Anterior cingulate gyrus
Frontal lobe
Brain areas involved in processing of
nociceptive signals
Cerebellum
Anterior cingulate gyrus
Midbrain
Frontal cortex
The anterior cingulate and insula cortex are
activated in human subjects …
… in connection with an intense burning sensation
following hand contact with the thermal grill.
Adapted from Craig et al. 1994, 1996. From Principles of Neural Science, Kandell et al.
Control of Pain Perception
• There is difference between the objective and subjective
aspects of injury and pain.
• Despite similar injury, people can differ in how
much pain they feel.
• Depending on the context, pain may not be felt despite injury,
e.g. battlefield injury, during intense sports.
• This suggests that there is a physiological mechanism that
controls the transmission of nociceptive signals to the brain
or modifies the interpretation of pain.
• The pain control system can also explain
the placebo effect.
Pain Modulation
Pathway
Nerve signals are sent form the somatic
sensory cortex and hypothalamus to the
periaqueductal gray matter (PAG).
PAG sends signals to the parabrachial
nucleus, medullary reticular formation,
locus coeruleus, and Raphe neulei.
These in turn can control the in the
transmission of nociceptive signals from
the spinal cord to the brain.
This involves different involves different
neurotransmitters.
Endogenous Opioids
• Internally produced molecules with opioid-like action which
regulate transmission of nociceptive signals.
• Three classes of these molecules have been identified. All
are peptide molecules
1. Enkephalins
2. Endorphins
3. Dynorphins.
• Despite these being powerful, endogenous modifiers of
nociceptive signals, it has been difficult to produce and
administer them in a way than can used in clinical practice.
Location of nerve cells with
endogenous opioid receptors
• Spinal cord, Medulla, Periaqueductal gray matter (PAG)
• In the spinal cord, endogenous opioids can prevent
transmission between 1st order nerve cells (bringing signals
from the periphery) and 2nd order spinal nerve cells that
transmit the signals to the brain.
• Also can prevent the increased synaptic efficiency, which plays
a role in hyperalgesia.
A photograph showing the
presence in the spinal cord gray
matter of endogenous opioids
(bright area).
(Center for Brain Research, Uni Vienna)
Modulation of Pain Signal Transmission in the
Spinal Cord
Connections in the spinal cord
where opiates act.
Pain signals
Spinal cord
gray matters
Block pain signals in
the 2nd order neuron
Neurotransmitters – serotonin
(5-HT) and norephinephrine
(noradrenaline) – in the spinal
cord can block transmission of
pain signals to the brain.
Inflammatory Soup - Hyperalgesia
• Tissue damage results in the
release of a number of
chemicals.
• These increase nociceptors’
response to a stimulus
(=hyperalgesia) & produce
inflammation.
• Hyperalgesia = when the
magnitude of the response to
a nociceptive stimulus is
higher than normal.
Julius-D & Basbaum-AI, Nature 2001;413:203
Clinical Application
• Knowing the molecules involved in the “inflammatory
soup” and how they are synthesized provides
possible targets for pain reduction.
• e.g. prostaglandins are produced by the COX
enzyme. The activity of this enzyme is blocked by
non-steroidal anti-inflammatory drugs (NSAIDs) such
as ibuprofen, diclofenac.
Allodynia
A mechanism for
allodynia
• A condition when normally non-
Nociceptive signals from
the periphery to
spinal cord
painful stimuli cause pain, e.g.,
touch, light pressure, cold.
• Involves changes in the synaptic
sensitivity of the nociceptive
neurons in the spinal cord (central
sensitization).
NMDA (a receptor for
glutamate) response
increases in the spinal
cord
• Drugs such as ketamine, block
NMDA receptors and so reduce
transmisison of the nociceptive
stimuli.
Nociceptive nerve cells
in the spinal cord now
become responsive to
non-painful stimuli
Gate Control Theory of Pain
• Mother says to child, “Come I will rub the area which
is painful and this will make it feel better.”
• After stubbing a toe, we instinctively rub the area; this
reduces the sensation of pain.
• Ronald Melzack and Patrick Wall in 1962 provided an
possible explanation for this effect.
Gate Theory
Rubbing the area that hurts
stimulates receptors of innocuous
stimuli like touch, pressure and
vibration.
These mechano-receptors send
signals along the Ab nerve fibers
that (1) stimulate spinal nerves
(inhibitory inter-neurons) that in
turn inhibit signaling in the 2nd
order neurons (projection neuron)
and (2) directly inhibit the 2nd
order neuron to reduce or stop
pain signal from being sent to the
brain
(1)
http://wikidoc.org/images/f/fe/Gate_control_A_firing.png
(2)
The Gate Control theory has
been superseded by newer
ones but is still used for the
sake of demonstration.
Clinical Application
Transcutaneous Nerve
Stimulation (TENS) is based
on the Gate Control Theory.
Nerves of the innocuous
sensory system are
stimulated and they in turn,
inhibit transmission of
nociceptive stimuli in the
spinal cord.
Abnormalities of Pain System
Phantom Pain
• Patients with amputation
often have burning or tingling pain in the body
part removed.
• One possible cause is that nerve fibers at the stump are
stimulated and the brain interprets the signals as
originating in the amputated portion.
• The other is the rearrangement within the
cortical areas so that area say for the hand now responds
to signals from other parts of the body but still interprets
them as coming for the amputated hand.
Somatosensory Cortex Organization
Cortical Reorganization
Brain surface of an owl
monkey.
The area of the hand
representation for each of the
5 hand digits (1 to 5)
After digit 3 was amputated,
its area has been taken over
by digits 2 and 4.
Neuroscience. 2nd edition. Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Fig 25.14
Referred Pain
• Often originates from a visceral organ.
• May be felt in a part of the body remote from the site
of the pathology.
• The mechanisms may be spinal convergence of
visceral and somatic afferent fibers on spinothalamic
neurons.
• Common manifestations: cutaneous and deep
hyperalgesia, tenderness, muscular contractions.
Pain sensation referred from
visceral organs … … to another part of the body
surface
Purves et al.
This talk was originally prepared by:
Nilesh Patel, PhD
University of Nairobi, Nairobi, Kenya
International Pain School
Talks in the International Pain School include the following:
Physiology and pathophysiology of pain
Nilesh Patel, PhD, Kenya
Assessment of pain & taking a pain history
Yohannes Woubished, M.D, Addis Ababa,
Ethiopia
Clinical pharmacology of analgesics
and non-pharmacological treatments
Ramani Vijayan, M.D. Kuala Lumpur, Malaysia
Postoperative – low technology treatment methods
Dominique Fletcher, M.D, Garches & Xavier
Lassalle, RN, MSF, Paris, France
Postoperative– high treatment technology methods
Narinder Rawal, M.D. PhD, FRCA(Hon),
Orebro, Sweden
Cancer pain– low technology treatment methods
Barbara Kleinmann, MD, Freiburg, Germany
Cancer pain– high technology treatment methods
Jamie Laubisch MD, Justin Baker MD, Doralina
Anghelescu MD, Memphis, USA
Palliative Care
Jamie Laubisch MD, Justin Baker MD,
Memphis, USA
Neuropathic pain - low technology treatment methods
Maija Haanpää, MD, Helsinki & Aki Hietaharju,
Tampere, Finland
Neuropathic pain – high technology treatment methods
Maija Haanpää, M.D., Helsinki & Aki Hietaharju,
M.D., Tampere, Finland
Psychological aspects of managing pain
Etleva Gjoni, Germany
Special Management Challenges
Debra Gordon, RN, DNP, FAAN, Seattle, USA
International Pain School
The project is supported by these organizations: