Detail pain explained. Definition, Types, Physiological aspect. Total class duration 5 hrs.

1. NEUROBIOLOGY PAIN
BPT class
Dr.Anwesh Pradhan (PT)
MPT (Neurology & Psychosomatic disorders)
Asst. Prof. NIHS, Kolkata

2. PAINPAIN
‘Pain is an unpleasant sensory and emotional
experience associated with actual or potential
tissue damage, or described in terms of such
damage.-- Pain is always subjective. Each
individual learns the application of the word
through experience related to injury in early
life. It is unquestionably a sensation in a part
of the body but is also always unpleasant and
therefore also an emotional experience.’

3. What is Pain?What is Pain?
 “An unpleasant sensory & emotional experience associated with actual
or potential tissue damage, or described in terms of such damage” –
The International Association for the Study of Pain
 Subjective sensation
 Pain Perceptions – based on expectations, past experience, anxiety,
suggestions
◦ Affective – one’s emotional factors that can affect pain experience
◦ Behavioral – how one expresses or controls pain
◦ Cognitive – one’s beliefs (attitudes) about pain
 Physiological response produced by activation of specific types of nerve
fibers
 Experienced because of nociceptors being sensitive to extreme
mechanical, thermal, & chemical energy.
 Composed of a variety of discomforts
 One of the body’s defense mechanism (warns the brain that tissues may
be in jeopardy)
 Acute vs. Chronic –
◦ The total person must be considered. It may be worse at night when the
person is alone. They are more aware of the pain because of no external
diversions.

4. Where Does Pain Come From?Where Does Pain Come From?
Cutaneous Pain – sharp, bright, burning; can have
a fast or slow onset
Deep Somatic Pain – stems from tendons,
muscles, joints, periosteum, & b. vessels
Visceral Pain – originates from internal organs;
diffused @ 1st
& later may be localized (i.e.
appendicitis)
Psychogenic Pain – individual feels pain but cause
is emotional rather than physical

5. Pain SourcesPain Sources
Fast vs. Slow Pain –
◦ Fast – localized; carried through A-delta axons in skin
◦ Slow – aching, throbbing, burning; carried by C fibers
◦ Nociceptive neuron transmits pain info to spinal cord
via unmyelinated C fibers & myelinated A-delta fibers.
 The smaller C fibers carry impulses @ rate of 0.5 to 2.0 m/sec.
 The larger A-delta fibers carry impulses @ rate of 5 to 30 m/sec.
Acute vs. Chronic

6. What is Referred Pain?What is Referred Pain?
 Occurs away from pain site
 Examples: McBurney’s point, Kerr’s sign
 Types of referred pain:
◦ Myofascial Pain – trigger points, small hyperirritable areas within a
m. in which n. impulses bombard CNS & are expressed at referred
pain
 Active – hyperirritable; causes obvious complaint
 Latent – dormant; produces no pain except loss of ROM
◦ Sclerotomic & Dermatomic Pain – deep pain; may originate from
sclerotomic, myotomic, or dermatomic n. irritation/injury
 Sclerotome: area of bone/fascia that is supplied by a single n. root
 Myotome: m. supplied by a single n. root
 Dermatome: area of skin supplied by a single n. root

7. TerminologyTerminology
 Noxious – harmful, injurious
◦ Noxious stimuli – stimuli that
activate nociceptors (pressure,
cold/heat extremes, chemicals)
 Nociceptor – nerve receptors that
transmits pain impulses
 Pain Threshold – level of noxious
stimulus required to alert an
individual of a potential threat to
tissue
 Pain Tolerance – amount of pain a
person is willing or able to tolerate
 Accommodation phenomenon –
adaptation by the sensory
receptors to various stimuli over
an extended period of time (e.g.
superficial hot & cold agents). Less
sensitive to stimuli.
 Hyperesthesia – abnormal
acuteness of sensitivity to touch,
pain, or other sensory stimuli
 Paresthesia – abnormal sensation,
such as burning, pricking, tingling
 Inhibition – depression or arrest
of a function
◦ Inhibitor – an agent that
restrains/retards physiologic, chemical,
or enzymatic action
 Analgesic – a neurologic or
pharmacologic state in which
painful stimuli are no longer painful

8. Questions to Ask about PainQuestions to Ask about Pain
 P-Q-R-S-T format
 Provocation – How the injury occurred & what activities ↓ ↑ the pain
 Quality - characteristics of pain – Aching (impingement), Burning (n. irritation),
Sharp (acute injury), Radiating within dermatome (pressure on n.)?
 Referral/Radiation –
◦ Referred – site distant to damaged tissue that does not follow the course of a
peripheral n.
◦ Radiating – follows peripheral n.; diffuse
 Severity – How bad is it? Pain scale
 Timing – When does it occur? p.m., a.m., before, during, after activity, all the time
 Pattern: onset & duration
 Area: location
 Intensity: level
 Nature: description

9. PAIN’S VARIABLE FACE

10. PAIN’S VARIABLE FACE
PAIN’S VARIABLE FACE

11. Transmission of PainTransmission of Pain
Types of Nerves
Neurotransmitters

12. Types of NervesTypes of Nerves
Afferent (Ascending) – transmit impulses
from the periphery to the brain
◦ First Order neuron
◦ Second Order neuron
◦ Third Order neuron
Efferent (Descending) – transmit impulses
from the brain to the periphery

13. First Order NeuronsFirst Order Neurons
 Stimulated by sensory receptors
 End in the dorsal horn of the spinal cord
 Types
◦ A-alpha – non-pain impulses
◦ A-beta – non-pain impulses
 Large, myelinated
 Low threshold mechanoreceptor; respond to light touch & low-
intensity mechanical info
◦ A-delta – pain impulses due to mechanical pressure
 Large diameter, thinly myelinated
 Short duration, sharp, fast, bright, localized sensation (prickling, stinging,
burning)
◦ C – pain impulses due to chemicals or mechanical
 Small diameter, unmyelinated
 Delayed onset, diffuse nagging sensation (aching, throbbing)

14. Second Order NeuronsSecond Order Neurons
 Receive impulses from the FON in the dorsal horn
◦ Lamina II, Substantia Gelatinosa (SG) - determines the input sent
to T cells from peripheral nerve
 T Cells (transmission cells): transmission cell that connects sensory n. to
CNS; neurons that organize stimulus input & transmit stimulus to the
brain
◦ Travel along the spinothalmic tract
◦ Pass through Reticular Formation
 Types
◦ Wide range specific
 Receive impulses from A-beta, A-delta, & C
◦ Nociceptive specific
 Receive impulses from A-delta & C
 Ends in thalamus

15. Third Order NeuronsThird Order Neurons
Begins in thalamus
Ends in specific brain centers (cerebral
cortex)
◦ Perceive location, quality, intensity
◦ Allows to feel pain, integrate past experiences
& emotions and determine reaction to
stimulus

16. Descending NeuronsDescending Neurons
 Descending Pain Modulation (Descending Pain Control
Mechanism)
 Transmit impulses from the brain (corticospinal tract in
the cortex) to the spinal cord (lamina)
◦ Periaquaductal Gray Area (PGA) – release enkephalins
◦ Nucleus Raphe Magnus (NRM) – release serotonin
◦ The release of these neurotransmitters inhibit ascending neurons
 Stimulation of the PGA in the midbrain & NRM in the
pons & medulla causes analgesia.
 Endogenous opioid peptides - endorphins & enkephalins

17. NeurotransmittersNeurotransmitters
 Chemical substances that allow nerve impulses to move from one
neuron to another
 Found in synapses
◦ Substance P - thought to be responsible for the transmission of pain-
producing impulses
◦ Acetylcholine – responsible for transmitting motor nerve impulses
◦ Enkephalins – reduces pain perception by bonding to pain receptor sites
◦ Norepinephrine – causes vasoconstriction
◦ 2 types of chemical neurotransmitters that mediate pain
 Endorphins - morphine-like neurohormone; thought to ↑ pain threshold by binding to
receptor sites
 Serotonin - substance that causes local vasodilation & ↑ permeability of capillaries
 Both are generated by noxious stimuli, which activate the inhibition of pain
transmission
 Can be either excitatory or inhibitory

18. Sensory ReceptorsSensory Receptors
Mechanoreceptors – touch, light or deep
pressure
◦ Meissner’s corpuscles (light touch), Pacinian corpuscles
(deep pressure), Merkel’s corpuscles (deep pressure)
Thermoreceptors - heat, cold
◦ Krause’s end bulbs (↓ temp & touch), Ruffini corpuscles
(in the skin) – touch, tension, heat; (in joint capsules &
ligaments – change of position)
Proprioceptors – change in length or tension
◦ Muscle Spindles, Golgi Tendon Organs
Nociceptors – painful stimuli
◦ mechanosensitive
◦ chemosensitive

19. Nerve EndingsNerve Endings
 “A nerve ending is the termination of a nerve fiber in a
peripheral structure.” (Prentice, p. 37)
 Nerve endings may be sensory (receptor) or motor
(effector).
 Nerve endings may be:
◦ Respond to phasic activity - produce an impulse when the stimulus
is ↓ or ↑, but not during sustained stimulus; adapt to a constant
stimulus (Meissner’s corpuscles & Pacinian corpuscles)
◦ Respond to tonic receptors produce impulses as long as the
stimulus is present. (muscle spindles, free n. endings, Krause’s end bulbs)
◦ Superficial – Merkel’s corpuscles/disks, Meissner’s corpuscles
◦ Deep – Pacinian corpuscles,

20. Nerve EndingsNerve Endings
 Merkel’s corpuscles/disks -
◦ Sensitive to touch & vibration
◦ Slow adapting
◦ Superficial location
◦ Most sensitive
 Meissner’s corpuscles –
◦ Sensitive to light touch & vibrations
◦ Rapid adapting
◦ Superficial location
 Pacinian corpuscles -
◦ Sensitive to deep pressure &
vibrations
◦ Rapid adapting
◦ Deep subcutaneous tissue location
 Krause’s end bulbs –
◦ Thermoreceptor
 Ruffini corpuscles/endings
◦ Thermoreceptor
◦ Sensitive to touch & tension
◦ Slow adapting
 Free nerve endings -
◦ Afferent
◦ Detects pain, touch, temperature,
mechanical stimuli

21. NociceptorsNociceptors
 Sensitive to repeated or prolonged stimulation
 Mechanosensitive – excited by stress & tissue damage
 Chemosensitive – excited by the release of chemical
mediators
◦ Bradykinin, Histamine, Prostaglandins, Arachadonic Acid
 Primary Hyperalgesia – due to injury
 Secondary Hyperalgesia – due to spreading of chemical
mediators

22. PAIN RECPTORSPAIN RECPTORS

23. Modulation of PainModulation of Pain
Acute pain response begins with a noxious
stimulus.
◦ IE. A burn or cut externally or internally a muscle
strain or ligament sprain
After trauma chemicals are released in and
around the surrounding tissues.
Immediately after the trauma, primary
hyperalgesia occurs
◦ Lowers the nerve’s threshold to noxious stimuli
and magnifying the pain response

24. Pain fibersPain fibers
A-delta fibers- a type of nerve that transmits
painful information that is often interpreted by
the brain as burning or stinging pain
C-fibers- a type of nerve that transmits painful
information that is often interpreted by the
brain as throbbing or aching

25. After an injury, A-delta and C fibers carry
noxious stimuli from the periphery to the spinal
cord.
The noxious stimuli activates 10-20% of the A-
delta fibers and 50-80% of the C-fibers.
Triggered by strong mechanical pressure or
intense heat, A-delta fibers produce a fast, bright,
localized pain sensation.
C-fibers are triggered by thermal, mechanical, and
chemical stimuli and generate a more diffuse,
nagging sensation

26. After an injury, such as a sprained ankle, an
athlete feels
◦ Sharp, well-localized, stinging or burning sensation
coming from which fibers??
 A-delta fibers
◦ This initial reaction allows an individual to realise that
trauma has occurred and to recognize the response as
pain
Very quickly, the stinging or burning sensation
becomes an aching or throbbing sensation, which
indicates activation of which fiber
◦ C-fibers
A third type of peripheral afferent nerve fiber
warrants mention. A-beta fibers, respond to light
touch and low intensity mechanical information.
◦ Rubbing and injured area
◦ These interrupt nociception to the dorsal horn

29. The brains limbic system aids in integrating higher
brain function with motivational and emotional
reactions.
◦ Contains afferent nerves from the hypothalamus and
the brain stem.
◦ Receives descending influence from the cortex.
◦ This communication is responsible for the emotional
response to painful experiences.
When an injury occurs, the neural
communication between the limbic system,
thalamus, RF, and cortex produces reactions such
as fear, anxiety, or crying.
In short , the limbic system is responsible for the
body’s affective qualities of reward, punishment,
aversive drives, and fear reactions to pain
AKA: motivational-affective system.

30.  The integration of the cortex is an important component
in both the ascending and descending aspects of pain
modulation.
 Via axons, ascending pain stimuli are transmitted from the
thalamus to the central sulcus in the parietal lobe
(somatosensory cortex), where the pain is discriminated
and localized.
 Because of the proliferation of nerve cells and the cortex’s
functions
◦ Consciousness
◦ Speech
◦ Hearing
◦ Memory
◦ Thought
 It is unlikely that the afferent synapses that occur during
noxious stimulation affect only one efferent neuron.
 Thus, many areas of the cortex can be stimulated during a
painful experience.

31. The notion of central control and descending
inhibition of pain is based on the body’s ability to
use and produce various forms of endogenous
opiates.
◦ Each having a distinct function and a specific receptor
affinity.
The enkephalins are found throughout the central
nervous system, but particularly in the dorsal
horn.
Thus, the aggregation of noxious stimuli may
cause both presynaptic and postsynaptic control
of nociception in the dorsal horn via enkephalin
release

32. Review of the process of PainReview of the process of Pain
TransmissionTransmission
Much decision making in the tx of pain can
be based on the understanding of the
physiological and chemical interaction that
occurs after trauma.
In simple terms, pain transmission appears
to be fairly straightforward.
◦ The acute pain response is initiated when
substances are released form injured tissues,
causing a noxious stimulus to be transmitted via
A-delta and C fiber to the dorsal horn

33. Pain Theory: Historical PerspectivesPain Theory: Historical Perspectives
Theories regarding the cause, nature, and
purpose of pain have been debated since the
dawn of humankind.
Most early theories were based on the
assumptions that pain was related to a form of
punishment.
The word “pain” is derived from the Latin
word “poena” meaning fine, penalty, or
punishment.

34. The ancient Greek believed that pain was
associated with pleasure because the relief of
pain was both pleasurable and emotional.
Aristotle reassessed the theory of pain and
declared that the soul was the center of the
sensory processes and that the pain system was
located in the heart

35. The Romans, coming closer to contemporary
thought, viewed pain as something that
accompanied inflammation.
In the 2nd
century, Galen offered the Romans his
works on the concepts of the nervous system.
◦ However, the views of Aristotle weathered the winds of
time.
In the 4th
century, successors of Aristotle
discovered anatomic proof that the brain was
connected to nervous system
◦ Despite this, Aristotle’s belief prevailed until the 19th
century, when German scientist provided irrefutable
evidence that the brain is involved with sensory and
motor function

36. Specificity Theory of PainSpecificity Theory of Pain
ModulationModulation
Modern concepts of pain theory continue to
advance from the ideas of Aristotle.
◦ However, controversy still exists as to which
theories are correct.
The theories accepted at the turn of the
century were the specificity theory and the
pattern theory, two completely different and
seemingly contradictory views

37. The specificity theory suggests that there is a
direct pathway from peripheral pain receptors to
the brain.
◦ The pain receptors are located in the skin and are
purported to carry pain impulses via a continuous fiber
directly to the brain’s pain center
◦ The pathway includes the peripheral nerves, the lateral
STT (spinothalamic tract) in the spinal cord and the
hypothalamus (the brain’s pain center)
◦ This theory was examined and refuted using clinical,
psychological, and physiological evidence by Melzack and
Wall in 1965.
 They discussed clinical evidence describing pain sensations in
severe burn patients, amputee patients, and patients with
degenerative nerve disease.

38. These syndromes do not occur in a fixed, direct
linear system
Rather in the quality and quantity of the perceived
pain are directly related to a psychological variable
and sensory input.
This theory had been previously addressed by
Pavlov, who inflicted dogs with a painful stimulus,
then immediately gave them food.
The dogs eventually responded to the stimulus as
a signal for food and showed no responses to the
pain

39.  The psychological aspect of pain perception was later
addressed by Beecher, who studied 215 soldiers seriously
wounded in the Battle of Anzio, finding that only 27%
requested pain-relieving medication (Morphine).
 When the soldiers were asked if they were experiencing
pain, almost 60% indicated that they suffered no pain or
only slight pain, and only 24% rated the pain as bad.
 This was most surprising because 48% of the soldiers had
received penetrating abdominal wounds.
 Beecher also noted that none of the men were suffering
from shock or were insensitive to pain because inept
intravenous insertions resulted in complaints of acute pain.

41.  The conclusion was drawn that the pain experienced by
these men was blocked by emotional factors.
 The physical injuries that these men had received was an
escape from the life-threatening environment of battle to
the safety of a hospital, or even release form the war.
 This relationship suggests that it is possible for the central
nervous system to intervene between the stimulus and the
sensation in the presence of certain psychological
variables.
 No physiological evidence has been found to suggest that
certain nerve cells are more important for pain perception
and response than others; therefore, the specificity theory
can be discounted.

42. Peripheral and Central Pathways for PainPeripheral and Central Pathways for Pain
Ascending TractsAscending Tracts Descending TractsDescending Tracts
Cortex
Midbrain
Medulla
Spinal Cord
Thalamus
Pons

43. PRIMARY AFFERENTSPRIMARY AFFERENTS
Initial input – bradykinin, histamine,
prostaglandin E2, cyclic adenosine
monophosphate, thermal factors and pH.
Ionic channels – sodium and calcium
mediated; multiple subtypes– differentially
stimulated.

44. PRIMARY AFFERENTSPRIMARY AFFERENTS

45. TRANSMISIONTRANSMISION

46. PRIMARY AFFERENTSPRIMARY AFFERENTS
Peripheral Messaging
◦ Sodium channels(v1.8, 1.9) release glutamate in the dorsal
horn  AMPA & NMDA Glutamate also activates kianate
receptors - positive feedback loop  more glutamate.
◦ Calcium mediated channels (thermal/pH ,C fiber type) 
substance P.  NMDA  positive peripheral nocioceptor
recruitment.
◦ Calcium mediated channels calcitonin gene – related
peptide (CGRP) as well as nitric oxide (NO). Leads to
vasodilatation, endothelial permeability & tissue swelling.

47. SENTIZATION KEY POINTSSENTIZATION KEY POINTS
All afferents become sensitized with repeated
stimulation- “windup” in seconds.
Within seconds to minutes “sensitization”:
◦ Mild pain stimuli hyperalgesia
◦ Innocuous stimuli pain: allodynia
◦ Injured C-fibers may fire spontaneously
◦ A-beta fibers may send pain messages.
◦ involves “second messengers” (DRG
mitochondria)

48. Pain Control TheoriesPain Control Theories
Gate Control Theory
Central Biasing Theory
Endogenous Opiates Theory

49. Gate Control TheoryGate Control Theory
Melzack & Wall, 1965
Substantia Gelatinosa (SG) in dorsal horn of
spinal cord acts as a ‘gate’ – only allows one
type of impulses to connect with the SON
Transmission Cell (T-cell) – distal end of the
SON
If A-beta neurons are stimulated – SG is
activated which closes the gate to A-delta & C
neurons
If A-delta & C neurons are stimulated – SG is
blocked which closes the gate to A-beta
neurons

50. Gate Control TheoryGate Control Theory
 Gate - located in the dorsal horn of the spinal cord
 Smaller, slower n. carry pain impulses
 Larger, faster n. fibers carry other sensations
 Impulses from faster fibers arriving @ gate 1st
inhibit
pain impulses (acupuncture/pressure, cold, heat, chem. skin irritation).
BrainBrain
PainPain
Heat, Cold,Heat, Cold,
MechanicalMechanical
GateGate ((TT
cells/ SG)cells/ SG)

51. Central Biasing TheoryCentral Biasing Theory
Descending neurons are activated by:
stimulation of A-delta & C neurons,
cognitive processes, anxiety, depression,
previous experiences, expectations
Cause release of enkephalins (PAG) and
serotonin (NRM)
Enkephalin interneuron in area of the SG
blocks A-delta & C neurons

52. Endogenous Opiates TheoryEndogenous Opiates Theory
 Least understood of all the theories
 Stimulation of A-delta & C fibers causes release of B-
endorphins from the PAG & NRM
Or
 ACTH/B-lipotropin is released from the anterior pituitary
in response to pain – broken down into B-endorphins and
corticosteroids
 Mechanism of action – similar to enkephalins to block
ascending nerve impulses
 Examples: TENS (low freq. & long pulse duration)

53. Goals in Managing PainGoals in Managing Pain
Reduce pain!
Control acute pain!
Protect the patient from further injury
while encouraging progressive exercise

54. Other ways to control painOther ways to control pain
Encourage central biasing – motivation,
relaxation, positive thinking
Minimize tissue damage
Maintain communication w/ the athlete
If possible, allow exercise
Medications

55. PAIN GATE THEORYPAIN GATE THEORY
Melzack & Wall 1965
proposed a balance of input by large A-
beta & A-delta excitatory/excitatory and
small C fibers excitatory/inhibitory fibers.

56. GATE THEORYGATE THEORY

57. PAIN GATE THEORYPAIN GATE THEORY
A-delta thinly myelinated fibers provide
rapid response with positive input to
stimulating and inhibiting areas in the dorsal
horn.
C fibers provide slower response with
postive stimulation to activation areas and
negative input to inhibiting areas in the
dorsal horn.
A-beta are recruited after repeated
stimulation.

58. SPINAL AFFERENTSSPINAL AFFERENTS
Doral Horn
◦ Glutamate  AMPA and NMDA and activated kianate
receptors providing a positive feedback loop to release
even more glutamate and subsequently lowers
threshold and recruits.
◦ Calcium mediated channels (thermal/pH ,C fiber type)
releases substance P. Substance P + NMDA serves as
positive recruitment in the tract of Lissaeur (ipsilateral)
and (ipsilateral and contralateral) spinothalamic tracts.
◦ GABA is main inhibitory transmitter; also ran - glycine

59. REQUIRED MEMORIZATIONREQUIRED MEMORIZATION

61. Second MessengersSecond Messengers

62. NEUROMEDIATORS IN THENEUROMEDIATORS IN THE
DORSAL HORNDORSAL HORN

63. WINDUP/SENSITIZATIONWINDUP/SENSITIZATION
NEURAL PLASTICITYNEURAL PLASTICITY
The region of hypersensitivity progressively
enlarges beyond the initial area of injury
Actual neural growth in the Tract of Lissauer
above and below the initial dermatome
representing the initial area of injury
protein called Fos - inducible transcription
factor (ITF) that controls mammalian gene
expression. Central nervous system c-fos
expression correlates well with painful
stimulation..

64. C-FosC-Fos
C-fos is a proto-oncogene - promotes
intracellular changes including cellular
restructuring & protein proliferation.
Noxious peripheral stimulation not only
causes Fos to appear in the spinal cord, but
also the ITFs -Jun and Krox and many others.
Apoptosis of GABAergic inhibitory neurons is
major feature – one week.

65. SPINOTHALAMIC TRACTSSPINOTHALAMIC TRACTS
neospinothalamic tract for acute pain  to midbrain, -VPL thalmus  postcentral gyrus
paleospinothalamic tract for dull and burning pain to the reticular formation, limbic system &
midbrain VM thalmus  anterior cingulate gyrus
Ascending Pathways

66. Cortical RepresentationCortical Representation

67. Cortical RepresentationCortical Representation

68. Midbrain structures
The peri-aqueductal grey matter (PAG)
deep layers of the superior colliculus
red nucleus
pre-tectal nuclei
nucleus of Darkschewitsch
interstitial nucleus of Cajal
intercolliculus nucleus,
nucleus cuneiformis
Edinger-Westphal nucleus

69. MODULATIONMODULATION
sites of descending modulation-
◦ PAG, PVG synapse in rostroventral medulla
via reticulospinal tract - includes the 5-HT
producing raphae magnus to laminae I, II and V.
◦ Cortex (parietal areas 1,2 &3) and diencephalon
via corticospinal tract

70. MODULATIONMODULATION
Descending ModulationDescending Modulation

71. Descending ModulationDescending Modulation
Descending modulation greatly changes
concentration and activity of NMDA
receptors
Descending modulation affects apoptosis
of GABAergic inhibitory
interneurons/dysinhibition
Descending modulation is through
dynorphins and change in opioid receptor
number/activity may contribute to opioid
tolerance/pain sensitivity

72. ENDOGENOUS OPIATESENDOGENOUS OPIATES
high concentration in the spinal dorsal horn
and medulla - also hypothalamus and
peripherally.
Three classes:
 ß-endorphins- basal hypothalamus
-Proopiomelanocortin is the precursor for ß-
END, ACTH, and MSH
◦ Enkephalins - dorsal horn, rahpe magnus, and
the globus pallidus - spinal action
◦ Dynorphins - hypothalamus, PAG, reticular
formation, and DH

73. Various Opiate ReceptorsVarious Opiate Receptors
Receptor Primary
Ligand
Other
µ Pro ENK A heroin
κ Pro ENK B - DYN, pentazocine
δ Pro ENK A
-
ENK
ε β-Endorphin
Each has subtypes & local metabolism / sensitivity may vary

74. SUMMARYSUMMARY
At the peripheral receptor and every
synapse, thereafter the transmission of
the pain message is subject to significant
modulation.
The brain itself filters, selects, and
modulates inputs through up & down-
regulation, multichannel neural as well as
hormonal feedback.
Outcome may permanent and may/may
not be beneficial to the individual.

75. SUMMARYSUMMARY
The complexity of the feedback system limits
conclusions from simple analysis.
In the evaluation of treatment modalities, it is
usual for empirical fact to be supported,
rather than revealed by physiologic studies.
Since most neural circuitry involves complex
feedback loops and modulation with multiple
neurotransmitters – multi– modality
treatment is likely to be the most beneficial.

76. Sources:
 Melzack R, Wall PD. Pain mechanisms: A new
theory. Science 1965;150:971–9.
 International Association for the Study of Pain
http://www.iasp-pain.org/terms-p.html
 Molecular Biology of Pain: Should Clinicians Care?
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