This chapter describes the neurological and neurosynaptic pathways for both acute and chronic pain. It also delineates the psychological differences between acute and chronic pain. Finally, it introduces the concept of the specific type of pain associated with a specific tissue type, which is useful in the diagnosis of pain problems. This chapter is the foundation for understanding all subsequent chapters on pain.

1. Acute versus Chronic Pain
Nelson Hendler, MD, MS
Former Assistant Professor of Neurosurgery
Johns Hopkins University School of Medicine
Past president-American Academy of Pain Management
www.MarylandClinicalDiagnostics.com
Lecture 1

2. Anatomy of a Nerve- I
• Everything in the body works due to nerve input
• Nerves are the signal system of the body
• Think of a nerve as an electrical telephone wire
which transmits information from one place to
another, via electrical impulses
• Just like an electrical wire, nerves have insulation,
called myelin, which can be very thick, or thin.
• The myelin is made by a special cell called a
Schwann cell.
• The myelin wraps around the nerve in layers

3. Anatomy of a Nerve - II
• A nerve has a cell body, which provides the
metabolic energy for the nerve, and receives
information from other nerves.
• The fiber extending from the cell body is an axon
• The axon ends in a “button termineaux” or
terminal button or swelling, where the chemicals
called neurosynaptic transmitters are made
• These neurosynaptic transmitters are what
create the specificity of nerve transmission
• Nerve activity can be modified at the cell
membrane electrically & the synapse chemically

4. Anatomy of a Nerve III
• The center of a axon is called axoplasm, which
transports nutrients to the entire nerve
• The cell wall of the nerve is a lipo-protein
membrane with channels through it, modified by
sodium (Na+), potasium (K+) calcium (Ca++),
magnesium (Mg++) and other cations
• When a nerve discharges, due to stimulation of
the cell body, the channels change, and allow
Na+ into the axon, and K+ goes out
• Then a pump in the axon (Na+/K+ ATPase) moves
the cations back to original position

5. Anatomy of a Nerve IV
• The transient flow of Na+ into the axon, and K+ out
of the axon creates a electron flow along the axon
• This flow moves a signal electrically along the nerve
• This electrical signal reach the end of the nerve and
causes the release of the chemicals- the
neurosynaptic transmitters
• So a sensory nerve receives stimulation, either
mechanical or chemical, and transmits this
information electrically, along the axon, until it
reaches the end where it then converts it to a
chemical message again.

6. Anatomy-Peripheral Receptors
• Meissner's corpuscles are mechanoreceptor, in
the skin, which senses vibration, and light touch
• Pacinian corpuscles in the skin sense pressure
• Free Nerve endings have no myelin-so sensitive
• Afferent Nervous System-carries sensory
messages to the brain- pain is one of these
• There are three major types of pain nerves
• A beta fibers have a moderate amount of myelin
• A delta fibers have some myelin
• C fibers – have no myelin or very little myelin

7. Electrical vs chemical transmission
• Once a peripheral pain receptor is stimulated,
this starts a series of events which allow the
message of pain to reach the cortex of the brain
• This transmission is electrical along the axon and
chemical at the end of the nerve with the
neurosynaptic transmitters
• Without pain information reaching the cortex of
the brain, there is no perception of pain
• Pain relief is directed to preventing the message
of pain from reaching the cortex of the brain

8. Blocking the Pain Message
• Modify the electrical transmission in the axon
using anti-convulsants to stabilize the membrane,
by hyper-polarizing the membrane, or put in
cations, like lithium (Li+), which interfere with
normal cation activity of Na+, K+, Mg++ and Ca++
• Modify the release of neurosynaptic transmitters,
by enhancing those which produce pain relief,
and blocking those which transmit the message
of pain
• Stop cortical reception by electrical stimulation of
the sensory cortex or cutting out the cortex

9. Electrical & Chemical Transmission
• Acute pain is a fast transmission process, i.e. the
time from stimulation ‘til the message reaches
the brain is short
• Chemical transmission of a message at the
synapse is much slower than the electrical
transmission along the axon
• Acute pain is a fast pain pathway, with only 2
synapses. You want fast transmission when your
hand is In a fire. Pain tells you something is wrong
• Chronic pain is a slow pain pathway with many
synapses. It tells you something is still wrong

10. The Value of Spinal Synapses
• Pain information from sensory nerves enters
lamina III and V of the posterior horn of the
spinal cord, and synapse there.
• Wide dynamic range neurons modify this
information, regulating intensity
• Neuronal plasticity allow pain to continue to
exist at a spinal level, even after the source of
the original source of the pain is removed
• Crossing pain fibers in the spinal cord help
localize the location of the pain

11. Neurochemical and Anatomical Pathway For
Acute Pain-Fast Transmission
(2 synapses)
• Neo-Spino-Thalamic Tract (Acute Pain)
BRAIN
Spinal Cord sends message to the brain
Peripheral Sensory Nerve
(A beta, A delta, C fibers)
carries the message to the
spinal cord
Mechano or
pressure receptor
(Meisner or
Pachinian
corpusule) or
chemoreceptor (C
fiber) in a finger
Synapses (Chemically mediated)
Thalamus
Somato-
Sensory
Cortex
(Pain)
Chemical synapses lends specificity, and a site to manipulate pain perception

12. Neurochemical and Anatomical Pathway For Chronic Pain
(Many areas of the brain are involved and multiple
synapses- so this is slower transmission)
• Palleo-Spino-Thalamic Tract (Chronic Pain)-Slow
BRAIN
Spinal Cord sends message to the brain
Peripheral Sensory Nerve
(A beta, A delta, C fibers)
carries the message to the
spinal cord
Mechano or
pressure receptor
(Meisner or
Pachinian
corpusule) or
chemoreceptor (C
fiber)
Synapses (Chemically mediated)
Reticular
Activating
System
Thalamus
Hypothalamus
Limbic
System
Somato-
Sensory
Cortex (Pain)
Chemical transmission is slower than electrical transmission

13. Other Neurosynaptic transmitters in
the Brain
• Biogenic Amines: dopa, dopamine, nor-
epinephrine, epinephrine, serotonin.
• 35% of neurosynaptic transmitters-GABA
• 10% of neurosynaptic transmitters-Ach
• 2%-5% of all neurosynaptic transmitters in the
brain use biogenic amines
• 95% of biogenic amines transmitters are in the
hypothalamus and limbic system.
• 90% of encephalins are in limbic system

14. Neurochemical and Anatomical
Pathway For Chronic Pain
• Palleo-Spino-Thalamic Tract (Chronic Pain)-slow
BRAIN
Spinal Cord
Peripheral Sensory Nerve
(A beta, A delta, C fibers)
Mechano or
pressure receptor
(Meisner or
Pachinian
corpusule) or
chemoreceptor (C
fiber)
Sleep caused by serotonin
Reticular
Activating
System
Thalamus
Hypothalamus
Limbic
System
Somato-
Sensory
Cortex (Pain)
Encephalin, and 95% of biogenic amines exist in the
same area

15. The Synapse and Neuro-Synaptic
Transmitters (NST)
• Pre-synaptic Synapse Post-synaptic
• MAO and COMT break down NST
• 1)Transmitters are released from nerve A, 2) bind to the receptors, on nerve B, causing nerve
B to fire, and 3) then reuptake occurs to stop the action of the NST.
Post-Synaptic
Receptor Sites
Nerve transmission
of information
Nerve transmission
of information
Neuro-synaptic
transmitter (NST)
1
2
3
1
COMT
MAO
BA

16. How medications works on the synapse
• Pre-synaptic Synapse Post-synaptic
• Increase activity by
1)Cause Release 2) Stop Reuptake 3)Mimic NST
Post-Synaptic
Receptor Sites
Nerve transmission
of information
Nerve transmission
of information
Neuro-synaptic
transmitter
2
3
1
I

17. How medications works on the synapse
• Pre-synaptic Synapse Post-synaptic
• Decrease activity by
1) Stop Release 2) Increase Breakdown 3)Block NST
Post-Synaptic
Receptor Sites
Nerve transmission
of information
Nerve transmission
of information
Neuro-synaptic
transmitter
3
1
COMT
2
2

18. The Axon and Cell Body
• Transmission along a nerve, causing Na+ influx
K+
Na+
Axoplasm
Extracellular fluid
Na+/K+ channelK+ comes out,
Na+ goes in
Pumps Na+ out,
and K+ back in
This entire process generates a current (90uV) across cell membrane

19. Mechanism of Action of Various Drugs
• Medication can work at the synapse, which is very
specific (as an example, there are 20 subtypes of
serotonin receptors)
• Medication can work on the nerve membrane
(more non-specific).
• Medication can inhibit natural transmitters by
blocking release of transmitters or blocking
receptor sites,
• Medication can release transmitters, or block
reuptake pre-synaptically, so the transmitter
remains on a receptor longer

20. Psychological Factors
Acute Pain- impacted by psychological states
Acute Pain –is reduced by enkephlins, ACTH, and
endorphins released at time of stress.
Chronic Pain- less influenced by psychological
states, but causes depression and anxiety
Chronic Pain goes through 4 stages
No psychological change-expecting to get well
Somatic concern and anxiety when not getting well
Depression when realizing that pain is chronic
Adjustment to the deficit

21. Other Factors Influencing Acute Pain
• Pain tells a person “something is wrong with your
body”
• If the cause of pain is obvious, like your finger in a
fire, you know to withdraw your finger from a fire
• But when a blister forms, this can not only
produce pain, but also fear of the unknown
• Will the skin fall off? How long will the pain last?
• Will the pain spread to my hand? Will this get
infected? Will I lose sensation in the finger?
• Fear of the unknown produces anxiety

22. Psychological Issues of Acute Pain
• The “psychological state” of anxiety worsens the
perception of pain
• When someone is in an accident, with a serious
injury, the anxiety over the loss of the use of an
arm or leg is overwhelming.
• Education about the body, and reducing the
“anxiety about the unknown” can be reduced by
education of the injured person
• Convert “anxiety” into a realistic “fear” by
education about the body,
• Tell the truth. Avoid phony reassurances

23. Modification of Acute Pain
• Assess the type of pain which is present
• See the next slide for an overview method
• The next slide has only suggestions. It is not a
substitute for clinical judgment on the scene
• Tell the patient what you are finding, and what
you think the source of the pain might be
• Educate the patient, with drawings of the body
• Give the patient odds about outcome—”The
medical literature says about 90% of patients
have no residual problems” etc.

24. Mechanism of Pain
• Pain occurs when tissue damage occurs, due to
excessive heat, cold, stretching, pressure, cell
disruption from a cut, or chemical irritation
• Different types of pain are caused by damage to
the bone, blood vessels, skin, muscle or nerve
• Cellular damage causes the release of a series of
inflammatory chemicals
• The chemical irritation creates an electrical
discharge from the sensory nerves which then
leads to a series of neuronal transmissions to the
brain

25. Damage to Different Tissue Feels Differently
• NOTE: Damage to different tissue feels differently
• Pain can be constant or intermittent
• Damage to nerves feels like a burning pain, or
pins and needles
• Damage to bone feels like a deep achy pain
• Damage to muscles feels like a cramp or spasm
• Damage to blood vessels feels like a throbbing,
pounding pain
• Damage to skin feels like a burning, sharp pain
• Each type of pain responds to best a different
type of medication

26. Methods to Assess Pain
Burning Throbbing Sharp Dull Aching Spasm
Constant This
suggest
nerve
irritation –
chemical,
metabolic,
or viral
This suggest
vascular
compression
-look for the
source of
the
compression
This
suggests
entrap-
ment of
sensory
nerves in
skin
Suggest a
compres-
sion,
tumor,
deep
bruise, or
infection-
get bone
scan
Deep achy
pain
suggests
bone
bruise or
fracture
get bone
scan
This suggest
nerve
entrapment,
or
compression
look for the
source of
compression
Intermittent This would
be
associated
with spasm
of muscle
or blood
vessel-
treat those
sources
This suggest
vascular
spasm- use
medications
which
reduce
spasm like
Imitrex
Seen in
visceral
spasm,
such as
Crohn’s
disease-
use anti-
spasmotic
Pain only
with use-
sprain or
strain due
to
damage
to tendon
or
ligament
This
suggests
inflama-
tory
process-
use non-
steroidal
anti-
inflama-
tory drugs
This
suggests
muscle
spasm-use
muscle
relaxants

27. Overview of the Nervous System
Organization
Efferent -motor autonomicAfferent –sensory
Brain
Spinal Cord
Sympathetic Parasympathetic
Alpha Beta Muscaric Nicotinic
Alpha 1 Alpha 2 Beta 1 Beta 2
MusclesSkin

28. Systems Associated with Pain
• Motor Nerves leave the brain to the spinal cord
• They emerge from the spinal cord as nerve roots
• The nerve roots then mix in either the brachial or
lumbar plexus, and emerge as mixed motor
sensory nerve, with specific names such as the
ulnar nerve or sciatic nerve
• As an example, the sciatic nerve has contributions
from the L1-L2, L2-L3, L3-L4,L4-L5, and L5-S1 nerve
roots, which mix in the lumbar plexus, and create
the sciatic nerve, a mixed motor-sensory nerve
• These mixed nerves have motor and sensory fibers

29. Mixed Motor-Sensory Nerve in Cross-section
The motor fibers come
from the brain to the
muscle. The sensory
nerves come from the skin,
muscle and bone, and go
to the brain. The sensory
fibers are the A beta, A
delta and C fibers. The
mixed motor-sensory nerve
arises after the lumbar or
brachial plexus, and is a
named nerve, like the ulnar
nerve, sciatic nerve or tibial
nerve. The sensory nerve
fibers carry messages to
the brain, and the motor
nerve carries message
from the brain to the
muscle.
Motor nerves have thick myelin, and sensory nerve have less myelin. Both types of
nerves are wrapped together in a bundle, which is a mixed motor-sensory nerve. .

30. Types of Sensory Nerve Fibers
• The sensory fibers are sparsely myelinated, or
unmyelinated
• The sensory fibers are the A beta, A delta and
C fibers
• C fibers are unmyelinated unlike most
other fibers in the nervous system.[1]
This lack
of myelination is the cause of their
slow conduction velocity, which is on the
order of no more than 2 m/s.[1]
C fibers are on
average 0.2-1.5 μm in diameter.[1]
Purves, Dale; et.al (2004). Neuroscience. Massachusetts: Sinauer Associates, Inc

31. C Fiber Activity
• C fibers are considered polymodal because
they can react to various stimuli. They react to
stimuli that are thermal, or mechanical, or
chemical in nature. C fibers respond to all
kinds of physiological changes in the body. For
example, they can respond to hypoxia,
hypoglycemia, hypo-osmolarity, the presence
of muscle metabolic products, and even light
or sensitive touch. C fiber receptors include
the following functions
Purves, Dale; et.al (2004). Neuroscience. Massachusetts: Sinauer Associates, Inc

32. Functions of C-Fibers
• C fiber nociceptors
– responsible for the second, burning pain
• C fiber warming specific receptors
– responsible for warmth
• ultra-slow histamine-selective C fibers
– responsible for itch
• tactile C fibers
– sensual touch
• C mechano- and metabo- receptors in muscles or joints
– responsible for muscle exercise, burn and cramps

33. A -delta Fiber Activity
• Because of their higher conduction velocity,
Aδ fibers are responsible for the sensation of
a quick shallow pain that is specific on one
area, termed as first pain. They respond to a
weaker intensity of stimulus. C fibers respond
to stimuli which have stronger intensities and
are the ones to account for the slow, but
deeper pain, and spread out over an
unspecific area
Purves, Dale; et.al (2004). Neuroscience. Massachusetts: Sinauer Associates, Inc

34. Spinal Connections
• C fibers synapse to “second-order
projection neurons” in the spinal cord at
the upper laminae of the dorsal horn in
the substantia gelatinosa. The second-
order projection neurons are of the wide
dynamic range (WDR) type, which
receive input from both nociceptive
terminals as well as myelinated A-type
fibers.
• Baron, Ralph (2006). "Mechanisms of Disease: neuropathic pain—a clinical
perspective". Nature Clinical Practice Neurology 2.

35. Spinal Synapses
• After repeated stimulation, WDR (wide
dynamic range) neurons, in the substania
gelatenosa, experience a general increase in
excitability
• C fibers cause central sensitization of the
dorsal horn in the spinal cord in response to
their hyperactivity.
• Sensitized C fibers release glutamate
• Glutamate interacts with the
postsynaptic NMDA receptors, which creates
the sensitization of the dorsal horn.

36. Various lamina of the dorsal horn
I-V are sensory laminae.
Synapses occur here.
Various nuclei, which are a
collection of cell bodies,
which give rise to axons

37. Pain Connections After the Spine
• The second-order neurons ascend to
the brain stem and thalamus in
the ventrolateral, or anterolateral, quadrant
of the contralateral half of the spinal cord,
forming the spinothalamic tract. The
spinothalamic tract is the main pathway
associated with pain and temperature
perception, which immediately crosses the
spinal cord laterally. This crossover feature is
clinically important because it allows for
identification of the location of injury.
• Purves, Dale; et.al (2004). Neuroscience. Massachusetts: Sinauer Associates, Inc

38. Pathway of chronic pain-Spine to Brain
• Central sensitization of the dorsal horn neurons that is
evoked from C fiber activity is responsible for temporal
summation of “second pain” (TSSP). This event is called
‘windup.’Windup is associated with chronic pain and
central sensitization. Functional MRIs show common areas
activated by the TSSP responses which include
contralateral thalamus, anterior and posterior insula, mid-
anterior cingulate cortex, and supplemental motor
areas. TSSP events are also associated with other regions of
the brain that process functions such as somatosensory
processing, pain perception and modulation, cognition, and
pre-motor activity in the cortex.
(1)Staud,Roland;et.al(2007)."BrainactivityrelatedtotemporalsummationofC-fiberevokedpain".Pain(1-2ed.)129(1–2):130–142.

39. Activity in the Brain
• Pain transmission reaches a variety of cells of
the lamina 1 of the cortex of the brain
• There are different cell types in this layer
• These varying neurons are responsible for the
different feelings we perceive in our body
• They can be classified by their responses to
ranges of stimuli
• The brain uses the integration of these signals
to maintain regulation of the body, by positive
or negative feedback, like a thermostat