Pain, Mechanisms, Cellular Substrate, Modulation

1. Pain

2. Significance of Pain
Pain is adaptive
Alerts us to danger
Motivates escape and avoidance learning
Motivates recuperation
Congenital insensitivity to pain
Pain is partly subjective
Influenced by expectations and emotions

3. IASP Definition of Pain
Pain is a sensory and
emotional experience
associated with actual
tissue damage or
described in terms of
such damage
pain is a sensory
experience
associated with
activation of
nociceptors and pain
pathways
pain is an emotional
experience
tissue damage is not
necessary

4. Pain Chronicity
Acute
- Transient / Recurrent
- Reversible
Chronic
- Long lasting/Reversible
- Persistent / Irreversible

5. Types of Pain
Chemical, mechanical pressure, and
extreme heat
All mediated through nociceptors
All go through a common pathway in
the brain
Once activated, nociceptors become
sensitized (hyperalgesic) for the
duration of an injury

6. Pathological Pain - Chronic Pain
Inflammation or nerve damage
Arthritis
Neuropathic pain
Back pain
Migraine
Degenerative diseases (MS)
80% of doctor visits
70 billion in health care costs
and reduced productivity
Current clinical treatments are based on animal research

7. Using Animal Models to Study Pain
Acute pain: gradually incremented stimuli
applied to tail or paw and determine intensity
of stimulation required to elicit a withdrawal
or vocalization response.
Chronic pain: unilateral inflammation of the
paw or joint, nerve ligation, etc. Measure
guarding of limb, hyperreactivity to heat or
mechanical stimulation, or reduced locomotor
activity.
Electrophysiology and histology

8. Justification for animal
models
Pain is a complex biological and
psychological process that must be
investigated in a living organism.
Animal research has led to advances in
understanding pain and its treatment.
Animal rights movement creating barriers to
laboratory animal research on pain.

9. Pain Transmission & Modulation
Research has clarified that the experience of
pain is due to the combined activity of
distinct systems that transmit and modulate
pain.
1) Ascending Pain Transmission: Bottom-up
process of pain transmission provides the
brain with information about tissue damage.
2) Descending Pain Modulation: Top down
process of pain modulation regulates pain
transmission.

10. Ascending Pain
Transmission
Pathway
The ascending neural
pain pathway is only a 3
neuron relay
The major convergence
point is the ventral
posterior lateral nucleus
of the thalamus, which
relays the signal to
limbic and cortical
areas
Ascending Pain Pathway (Purves, 2001).

11. Descending
Pain
Modulation
Pathway
The Descending Pain Pathway –
The Periaqueductal Grey (PAG)
is the major convergence point.
Descending pain pathway (Purves, 2001).

12. Pain Transmission Pathway
Primary afferent nociceptors respond to intense thermal,
mechanical, and chemical stimuli.
Located in all pain sensitive regions of te body.
Activated by chemicals (bradykinin, prostaglandins,
histamine, etc.) released during tissue damage and
inflammation, causing transmission of action potentials.
 Axons of these neurons carry the signal into the cord,
release neurotransmitters that activate pain transmission
neurons in the dorsal horn of the spinal cord.
Pain transmission neurons carry this signal to various
regions of the brain where it is processed and evaluated.
E.g., spinothalamic tract neurons carry the signal from the
spinal cord to specific thalamic nuclei, which have reciprocal
connections with somatosensory cortex - map of body

14. Neural Pathways of Pain
Anatomically related to the cutaneous
senses
Free nerve endings
 The sensitive terminals of pain neurons
are not surrounded by special capsules
or end organs as are the endings of
touch and temperature receptors
 Free nerve endings can be found in all
body tissues from which pain is sensed,
from the skin to the pulp of the teeth.

15. Transduction of
Pain
Tissue Damage and
Chemoreceptors
Substance P, Histamine,
Bradykinin, Serotonin, K+
C Fibers (Type 4) with
chemoreceptors
And the Immune System

16. Two Types of Peripheral
Pain Neurons
A-delta fibers
 Thick, myelinated, fast conducting neurons
 Mediate the feeling of initial fast, sharp, highly
localized pain.
C fibers
 Very thin, unmyelinated, slow-conducting
 Mediate slow, dull, more diffuse, often burning
pain.

18. Central Pain Pathways: Fast Pain
Fast pain and A-delta fibres




A-delta fibers synapse on cells in the spinal cord that lead to
an area of the thalamus called the ventrobasal complex
ventrobasal complex also receives neurons that mediate
touch
sends its output to the somatosensory cortex
allows us to localize where pain originates

20. Central Pain Pathways: Slow Pain
Slow pain and C fibres
 C fibres synapse on cells in the spinal
cord
 Relays to a midline nucleus in the
thalamus and
 to the limbic system
 responsible for motivational and
emotional aspects of pain
 Those connections are important for
the interpretation of pain.

22. Sensitization of Pain
Transmission
Pain transmission system can be sensitized by
noxious stimuli.
Explains many chronic pain syndromes where pain
perception is distorted
 Allodynia - lowering of pain thresholds to
normally non-noxious stimuli
 Hyperalgesia - lowering of pain thresholds to
noxious stimuli
 Secondary hyperalgesia - spread of pain and
hyperalgesia to uninjured areas
 Spontaneous pain - pain in absence of noxious
stimulation, “pain memory”

23. Multiple Pain
Mechanisms
• Nociception
• Peripheral sensitization
• Central sensitization
• Decreased inhibition/
Structural reorganization

24. Multiple Pain
Symptoms
• Spontaneous Pain
Superficial/Deep
Continuous/Intermittent
• Evoked Pain
Thermal/Mechanical
Allodynia
Hyperalgesia

25. Nociception
Transduction
Conduction
Transmission
Modulation
Noxious
stimulus
“Ouch” Pain
primary sensory neuron
central neuron

26. Nociception – Transduction
Nociceptor Activators
Cold
Heat
Bradykinin
Mechanical
B1/B2
DRASIC/mDEG
H+
CRM1
VR1
ASIC
TRPV3
generator potential
action potentials
COX-2 Insensitive

27. Transmission/Modulation
VGCC
COX-2
Insensitive
GABAA
Adensosine
Opiate
CB1
Glutamate
Activity
AMPA
Sub P
mGluR
NMDA
NK1
Afferent Central
Terminal
Dorsal Horn
Neuron

28. Nociception is not COX2
Sensitive

29. Mechanisms of Neuropathic Pain
Central
sensitization
Non painful information
is processed as painful
Transmission of painful
information is facilitated
Allodynia
Hyperalgesia
Complex Regional Pain
Syndrome
Fibromyalgia

30. Sensitization of pain
transmission
Both peripheral and central mechanisms mediate sensitization
and contribute to the development and maintenance of
pathological pain.
Peripheral: Peptides (bradykinin, histamine, prostaglandin)
released at injury site sensitize peripheral nerve endings of
primary nociceptors
Central: axons from primary nociceptors release peptides
(e.g.,substance P, neurokinin-A, CGRP, CCK) and excitatory
amino acids (e.g., glutamate). Peptides act to amplify
excitatory effects of glutamate, creating a burst of nociceptor
activity causing a long-lasting hyperreactivity of dorsal horn
neurons. Mechanism underlies hyperalgesia.
Central Sensitization, a form of LTP that depends on the
concurrent activation of NMDA receptors (glutamate) and NK-1
tachykinin receptors by neurokinin A and substance P.

31. Neuropathic Pain
Pain caused by damage to nervous system
Involves peripheral and central sensitization
e.g., peripheral nerve cut, crushed, partial
denervation and inflammation
e.g., MVA, diabetes, MS, herpes zoster
Nerve damage causes spontaneous shooting,
stabbing, or burning pain over time. Local pain and
then spreads. Allodynia to touch.
Central sensitization occurs in spinal cord,
brainstem, thalamus, and cortex, where neurons
exhibit spontaneous activity, lowered thresholds,
receptive field expansion. Paralleled by anatomical
reorganization at each level of the pathway. E.g.,
phenotypic switching in cord, somatosensory map

32. Phantom Limb Pain
Pain originating from the absent limb
Pain memories of pre-amputation pain
Animal models of injury prior to
deafferentation increase autonomy behavior
Preemptive analgesia blocks it by blocking
the afferent barrage that leads to central
sensitization
Reorganization of somatosensory cortex
after deafferentation pain
Top down effects

33. Etiological Factors
inflammation/tissue damage/nerve lesions
Pain Mechanism
Pain Syndromes
post-operative/arthritic/back pain/neuropathic

34. Inflammatory and Neuropathic Pain
Chemical mediators are released from damaged tissue and
inflammatory cells. Some inflammatory mediators directly activate
nociceptors, while others act together to sensitize the pain pathway.
Neuropathic pain

35. Peripheral Sensitization
Reduced Transduction Threshold
Innocuous/Noxious
stimulus
Primary hyperalgesia
Primary heat allodynia
Inflammation
primary sensory neuron
central neuron

36. Peripheral Sensitization
Macrophage
Na
ive
Skin
Mast
cell
6h 12h
PG
VR1
PGS
Cox-2
EP/IP
H+
Ca2+
IL1β, IL6
TNFα
AA
Tissue
damage
COX-2
Sensitive
PKC
PKA
(SNS/SNS2)
Primary sensory neuron
peripheral terminal
There are prostanoid and non-prostanoid sensitizers

37. Central Sensitization
Increased Pain Responsiveness
Noxious
stimulus
Secondary hyperalgesia
Tactile allodynia
Irritants
primary sensory neuron
Tissue damage
Inflammation
central neuron

38. Central Sensitization –
Central Pain Hypersensitivity
Aβ fibre mechanoreceptor
innocuous
stimulus
innocuous
stimulus
Weak
synapse
Increased
synaptic
strength
non-painful
sensation
painful
sensation
Brush-Evoked Mechanical Allodynia

39. Relevance to human pain
Cutaneous Hyperalgesia - e.g, burn pain -
primary hyperalgesia at site of burn,
secondary hyperalgesia in surrounding skin.
allodynia - touch sensitivity
Primary hyperalgesia linked to prolonged
changes in excitability of peripheral
nociceptors and central neurons.
Secondary hyperalgesia due to sensitization
of dorsal horn neurons and expansion of
their receptive fields

40. Central Sensitization - Acute
Phase
src
NMDA
Activity
Glutamate
Sub P
Central Terminal
AMPA
mGluR
NK1
Tyr
S/T
pERK
PKC
S/T
Ca2+
PKA
IP3
COX-2
Insensitive

41. tR
NA
Na
ïve
1H
r
2H
rs
4H
rs
6H
rs
12
Hr
s
24
Hr
s
48
Hr
s
COX-2 Induction in the
Spinal Cord - Inflammation
COX-2
β-actin

42. 7
d
h
11
72
24
11
h
12
0
10
h
Sh
am
Cox-2 is not induced in the
Spinal Cord by Peripheral
Nerve Injury
Cox2
β−Actin
88
97
5
2
Cox2 band
intensity

43. Central Sensitization Late
Phase (Inflammation)
Primary sensory neuron
central terminal
+
EP
+
EP/IP
Nociceptive dorsal
horn neuron
+
PGE2
COX-2
Glycine receptor
Inhibitory
interneuron
–
EP
COX-2
Sensitive

44. There are COX-2 sensitive peripheral and
central components of inflammatory pain
Cox-2 inhibitors can only act when COX-2
is induced - time lag for induction
There are non-prostanoid contributors to
inflammatory pain - ceiling effect
Peripheral nerve injury may not be sensitive
to COX-2 inhibitors

45. Etiology
A
B
C
Mechanism
1
2
3
Symptom
α
β
γ

46. Etiology
A
B
C
Mechanism
1
2
3
Symptom
α
β
γ

47. Need to differentiate Analgesic
and Anti-hypersensitivity drugs
Temporal and Intensity characteristics
of pain do not reflect mechanisms and may
not be useful predictors of analgesic action
Pain Mechanisms and Drug Mechanisms
may provide the most useful input for
determining Indication and Efficacy

48. Need mechanism sensitive/specific
outcome measures in addition
to global pain scores
Need clinical trials that validate
mechanistic hypotheses
Need to consider labeling claims in light
of action of a drug with specific
pain mechanism(s) as well as empirical
clinical data on efficacy
Are there global analgesics?

49. Descending Pain Modulation
The brain and higher psychological
processes can alter the activity of the pain
transmission system. The brain can amplify
or inhibit incoming pain signals through
descending modulatory pathways.

50. Gate control theory
•Ronald Melzack and Patrick Wall (1965, 1982) For pain to be experienced, input from
•peripheral pain neurons must pass through a gate located at the point where
•they enters the spinal cord and lower brain stem.

51. Descending Pain
ControlAmygdala
Cingulate Cortex &
Emotional states
Periaqueductal Gray



Opioid Receptors
Projects to Raphe Nuclei
Raphe Nuclei



Project down to dorsal horn
and Spinal 5 Nucleus
Serotonin (5-HT)
Inhibits Ascending Systems
 Substance P release by
Primary Afferents
Locus Coeruleus

Norepinephrine
Stress-Induced Analgesia

52. Descending
Pain
Modulation
Pathway
The Descending Pain Pathway –
The Periaqueductal Grey is the
major convergence point.
Descending pain pathway (Purves, 2001).

53. Pain-inhibiting System
•Periaqueductal gray (PAG)
–PAG neurons have excitatory connections with
inhibitory interneurons in the spinal cord
–These inhibitory interneurons prevent ascending
neurons to relay pain messages to the brain
–Stimulation produced analgesia
•Endorphins or endogenous opioids
-Receptors for exogenous opioids
-Microinjection of opioids - PAG, intrathecal
-Endogenous opioids - POMC-endorphins,
enkephalins, dynorphin
–The spinal cord inhibitory interneurons release
endorphins
–Endorphins are inhibitory neurotransmiters
–Opiate epidurals inhibit ascending pain signal

54. No perception of pain
To thalamus
Opiate
receptor
Periagueductal
gray matter
Reticular
formation
Noxious
stimulus
Endogenous opiate
Transmission
of pain
impulses to
brain blocked
Substance P
Afferent pain fiber
Nociceptor

55. Inhibition of ascending pain pathways
Important anatomical connections between descending brain
regions and the dorsal horn of the spinal cord.
There are a number of opioids that exist naturally in the brain that
can reduce pain.
Electrical stimulation or pharmacological administration in the
PAG produces profound analgesia.

56. Descending Regulation
Endorphins exert multiple effects that include suppressing the release
of glutamate from presynaptic terminals and inhibiting neurons by
hyperpolaring their postsynaptic membranes.

57. Targets of Pain
Therapies
Pharmacotherapy
Non-opioid analgesics
Opioid analgesics
Nerve Blocks
Adjuvant analgesics (neuropathic,
musculoskeletal)
Electrical Stimulation
Transcutaneous electrical nerve
stimulation (TENS)
Percutaneous electrical nerve
stimulation (PENS)
Alternative methods
Gottschalk et al., 2001
Acupuncture
Physical Therapy
Chiropractics
Surgery

58. Nonopioid neurotransmitters
involved in pain modulation
Serotonin (5-HT), Norepinephrine (NE)
5-HT containing neurons in rostral ventral
medulla (RVM) and NE containing neurons in
the pons send projections to the spinal cord
which modulate pain transmission
Neurochemical lesions of these systems
attenuates morphine analgesia, intrathecal
injections of 5-ht and NE induce analgesia
Antidepressant drugs increase 5-HT and NE,
used in arthritis, migraine, herpes zoster pain

59. Descending Inhibition and
Facilitation
Cells in brainstem nuclei can inhibit and
facilitate pain transmission (Fields, 1992)
Off Cells - inhibit transmission and firing rate
increased by opioids
On Cells - enhance transmission, show
increased firing rates before withdrawal
responses and associated with enhanced
pain during opioid abstinence
Conclude: pain modulation is bi-directional

60. Influence on pathological
pain?
A decrease in tonic descending inhibition
contributes to chronic pain.
Increased on-cell activity may generate pain
in the absence of pain.
Activity of these cells may mediate the
effects of psychological states on pain
perception, e.g., anxiety and attention which
increase pain in animals and humans

61. Activation of Pain Inhibitory
Systems
Intense sensory stimulation counterirritation - rubbing, acupuncture,
vibration, TENS, Gate Control Theory
Stressful or Frightening Stimuli - potentially
threatening stimuli and cues that predict their
occurrence.
 Cat exposure
 Context conditioning
CS (place)-->US (shock)
CR (analgesia) UR (analgesia)

62. Memorial Processes
Shock induced hypoalgesia
 Distractor study in animals
 Distractor study in humans
Scopolamine study
Placebo analgesia - a form of conditioned
analgesia

63. Afferent Regulation