This document provides an overview of neurophysiology topics including nerve conduction, membrane potential, action potentials, neuromuscular junction function, neurotransmitters, sensory and motor pathways, reflexes, control of movement by various brain regions like motor cortex, basal ganglia, cerebellum, and physiology of pain. It discusses concepts like electrophysiology, synapses, nerve fiber types, propagation of action potentials, factors contributing to resting membrane potential, sodium-potassium pump, action potential generation and propagation, different neurotransmitters, ascending pain pathways, descending pain modulation, and gate control theory of pain.

1. MD Dental - Neurophysiology
• Electrophysiology
• Synapse
• NMJ
• Neurotransmitters
• Sensory functions
• Motor system
• Physiology of Pain
Prof. Vajira Weerasinghe
Senior Professor of Physiology
Faculty of Medicine, Peradeniya &
Consultant Neurophysiologist,
Teaching Hospital, Peradeniya
www.slideshare.net/vajira54
vajira54@gmail.com

2. Nerve conduction
• Electrochemical basis
• concentration gradient, membrane permeability
ionic channels
• Resting membrane potential (RMP)
• K+ efflux, Na/K pump
• Leaky channels
• Action potential (AP)
• depolarisation, repolarisation
• Voltage-gated channels
• Propagation of AP
• Local current flow

3. Membrane potential
– A potential difference exists across all cell membranes
– This is called resting membrane potential (RMP)
– Inside is negative with respect to the outside
– This is measured using microelectrodes and an a
oscilloscope
– This is about -70 to -90 mV

4. Factors contributing to RMP
• One of the main factors is K+ efflux (Nernst Potential: -
94mV)
• Contribution of Na influx is little (Nernst Potential:
+61mV)
• Na/K pump causes more negativity inside the
membrane
• Negatively charged protein remaining inside due to
impermeability contributes to the negativity
• Net result: -70 mV inside

5. Na/K pump
• Active transport system for Na-K exchange using
energy
• It is an electrogenic pump since 3 Na influx coupled
with 2 K efflux
• Net effect of causing negative charge inside the
membrane
3 Na+
2 K+
ATP ADP

6. -70
+35
RMP
Hyperpolarisation
Slow depolarisation
Threshold -55

7. • At rest: the activation gate is closed
• At threshold level: activation gate opens
– Na influx will occur
– Na permeability increases to 500 fold
• when reaching +35, inactivation gate closes
– Na influx stops
• Inactivation gate will not reopen until resting membrane potential is reached
outside
inside
outside
inside
-70 Threshold level +35
Na+ Na+
outside
inside
Na+
m gate
h gate

8. – At rest: K channel is closed
– At +35
• K channel open up slowly
• This slow activation causes K efflux
– After reaching the resting still slow K channels may
remain open: causing further hyperpolarisation
outside
inside
outside
inside
-70 At +35
K+ K+
n gate

9. Propagation of AP
• When one area is depolarised
• A potential difference exists between that site
and the adjacent membrane
• A local current flow is initiated
• Local circuit is completed by extra cellular fluid

11. Type Diameter
(uM)
Velocity
(m/s)
A 10-20 60-120
A 5-15 40-80
A 2-8 10-50
A 1-5 6-30
B 1-4 1-4
C 0.5-2 0.5-2
Myelinated
Unmyelinated
faster
slower

12. Different types and functions
• A alpha
• Motor pathways
• Alpha motor neuron
• Proprioceptive
• A beta
• Proprioceptive
• Mechanoreceptive
• A gamma
• Gamma motor neuron (muscle spindle)
• A delta
• Fast pain
• Temperature
• B
• Autonomic preganglionic
• C
• Slow pain
• Temperature
• Autonomic postganglionic

13. Synapse
• A gap between two neurons
• More commonly chemical
• Rarely they could be electrical (with gap
junctions)

15. NMJ function
• Pre-synaptic membrane
• Ca channels
• Acetycholine release
• Postsynaptic membrane
• Acetylcholine receptors
• Ligand-gated channels
• Synaptic cleft
• cholinesterase

16. Neuromuscular blocking agents
• Non-depolarising type (competitive)
– Act by competing with Ach for the Ach receptors
– Binds to Ach receptors and blocks
– Prevent Ach from attaching to its receptors
– No depolarisation
– Prolonged action (30 min)
– Ach can compete & the effect overcomes by an excess Ach
– Anticholinesterases can reverse the action
– eg.
• Curare
• Tubocurarine
• Gallamine
• Atracurium

17. Neuromuscular blocking agents
• Depolarising type (non-competitive)
– Act like Ach, but resistant to AchE action
– Bind to motor end plate and once depolarises
– Persistent depolarisation leads to a block
• Due to inactivation of Na channels
– Two phases
• Phase I block (postjunctional membrane become unresponsive to ACh released by
motor neurons)
• Phase II block (a desensitized state where the membrane becomes repolarized, but
insensitive to ACh due to receptor desensitization)
– Ach cannot compete
– Quick action (30 sec), short duration (10 min)
– Action terminated due to rapid hydrolysis of succinylcholine by cholinesterase in
the plasma & liver
– Anticholinesterases cannot reverse the action
– eg.
• Succinylcholine
– Side effect: hyperkalaemia
– Metabolized by plasma pseudocholinesterase

18. Botulinum toxin
• Most potent neurotoxin known
• Produced by bacterium Clostridium botulinum
• Causes severe diarrhoeal disease called botulism
• Action:
– enters into the presynaptic terminal
– cleaves proteins (syntaxin, synaptobrevin) necessary for Ach vesicle
release with Ca2+
• Chemical extract is useful for reducing muscle spasms, muscle
spasticity and even removing wrinkles (in plastic surgery)

20. Type Neurotransmitter
Amines Serotonin (5HT), Dopamine, Norepinephrine, Acetylcholine, Histamine
Amino acids Gamma-aminobutyric acid (GABA), Glycine, Glutamate, Aspartate
Opioids Beta-endorphin, Enkephalins, Dynorphin, Nociceptin, Kyotorphin
Neurokinins Substance P, Neurokinin A, B
Endocannabinoids Endocannabinoids (Anandamide, 2AG)
Mixed types Nitric oxide and Carbon monoxide (CO)
ATP, ADP
CART (cocaine and amphetamine regulated transcript)
Neuropeptide Y
Orexin
Other Angiogensin, Calcitonin, Glucagon, Insulin, Leptin, Atrial natriuretic factor,
Estrogens, Androgens, Progestins, Thyroid hormones, Cortisol. Hypothalamic
releasing hormones, Corticotrophin-releasing hormone (CRH), Gonadotropin
releasing hormone (GnRH), Luteinizing hormone releasing hormone (LHRH),
Somatostatin, Thyrotropin releasing hormone (TRH), Growth hormone releasing
hormone (GHRH), Pituitary peptides, Corticotrophin (ACTH), Growth
hormone (GH), Lipotrophin, Alpha-melanocyte-stimulating hormone(alpha-MSH),
Oxytocin, Vasopressin, Thyroid stimulating hormone (TSH), Prolactin,
Gut hormones Cholecystokinin (CCK), Gastrin, Motilin, Pacreatic polypeptide, Secr
etin, Vasoactive intestinalpeptide (VIP), Bombesin, Bradykinin, Carnosine,
Calcitonin G related peptide, Delta sleep factor, Galanin, Focretin, Melanocyte
concentration hormone

21. Neuromodulators
• Neurotransmitters transmit an impulse from one
neuron to another
• Neuromodulator modulate regions or circuits of the
brain
• They affect a group of neurons, causing a modulation
of that group
• Neuromodulators alter neuronal activity by amplifying
or dampening synaptic activity
– Eg. dopamine, serotonin, acetylcholine, histamine,
glutamate
• Volume neurotransmission

23. Dorsal column pathway Spinothalamic pathway
• touch: fine degree
• highly localised touch
sensations
• vibratory sensations
• sensations signalling
movement
• position sense
• pressure: fine degree
• Pain
• Thermal sensations
• Crude touch &
pressure
• crude localising
sensations
• tickle & itch
• sexual sensations

24. Dorsal column nuclei
(cuneate & gracile nucleus)
Dorsal column
Medial lemniscus
thalamus
thalamocortical tracts
internal capsule
1st
order
neuron
2nd
order
neuron
3rd
order
neuron

25. Spinothalamic
tracts
thalamus
thalamocortical tracts
internal capsule
1st
order
neuron
2nd
order
neuron
3rd
order
neuron

27. What is a reflex?
Stimulus
Effector organ
Response
Central
connections
Efferent nerve
Afferent nerve
Receptor
Higher centre
control

28. Ia afferent nerve
 motor neuron
one
synapse
muscle
stretch
muscle
contraction
Stretch reflex

29. Medulla
internal capsule
Upper
motor
neuron
Lower
motor
neuron
anterior horn cell

30. Complex nature of Cortical
Control of Movement
8.30

31. idea
•premotor area
•supplementary
motor area
(SMA)
•Prefrontal
cortex (PFC)
Primary
motor cortex
movement
basal ganglia
cerebellum cerebellum
plan execute
memory, emotions

32. Lower motor neuron lesion
• muscle weakness
• flaccid paralysis
• muscle wasting (disuse atrophy)
• reduced muscle tone (hypotonia)
• reflexes: reduced or absent (hyporeflexia or areflexia)
• spontaneous muscle contractions (fasciculations)
• plantar reflex: flexor
• superficial abdominal reflexes: present
• eg. Bell’s palsy

34. Upper motor neuron lesion
• muscle weakness
• spastic paralysis
• increased muscle tone (hypertonia)
• reflexes: exaggerated (hyperreflexia)
• Babinski sign: positive
• superficial abdominal reflexes: absent
• muscle wasting is very rare
• clonus can be seen:
– rhythmical series of contractions in response to sudden stretch
• clasp knife effect can be seen
– passive stretch causing initial increased resistance which is released
later
• eg. Stroke

35. cerebellum
• centre of motor coordination
• cerebellar disorders cause
–incoordination or ataxia

36. Functions of cerebellum
• planning of movements
• timing & sequencing of movements
• particularly during rapid movments such as
during walking, running
• from the peripheral feedback & motor cortical
impulses, cerebellum calculates when does a
movement should begin and stop

37. Motor Cortex
Thalamus
Cerebellum
Muscles
brain
stem
nuclei
proprioceptive
tactile
feedback

38. features of cerebellar disorders
• ataxia
– incoordination of movements
– ataxic gait
• broad based gait
• leaning towards side of the lesion
• dysmetria
– cannot plan movements
• past pointing & overshoot
• decomposition of movements
• intentional tremor

39. features of cerebellar disorders
• dysdiadochokinesis
– unable to perform rapidly alternating movements
• dysarthria
– slurring of speech
• nystagmus
– oscillatory movements of the eye

40. features of cerebellar disorders
• hypotonia
– reduction in tone
• due to excitatory influence on gamma motor neurons by cerebellum
(through vestibulospinal tracts)
• Present in pure cerebellar diseases
• Spinocerebellar ataxia
• Cerebellar features with increased muscle tone
• decreased reflexes
• head tremor
• head tilt
• Rebound
• Increased range of movement with lack of normal recoil to original
position

41. Basal ganglia
• These are a set of deep nuclei located in and
around the basal part of the brain that are
involved in motor control, action selection, and
some forms of learning
• Caudate nucleus
• Putamen
• Globus pallidus
– (internal and external)
• Subthalamic nuclei
• Substantia nigra

42. 42

43. Basal ganglia
• Interconnecting circuitry through these
nuclei
• These circuits start from the cortex and
ends in the cortex
• These circuits are very complex
• Their effect is excitatory or inhibitory on
motor functions (depending on the
neurotransmitter involved)
• They also have a role in cognitive
functions

44. Basal ganlgia
• Some of these circuits are excitatory
and some inhibitory
• This depends on the neurotransmitter
involved.
• Inhibitory: dopamine and GABA
• Excitatory: Ach
• Others: glutamate (from cortical
projections) enkephalin etc

45. Functions of Basal Ganglia
• Motor control
• Learning
• Sensorimotor integration
• Reward
• Cognition
• Performs purposeful movement
• Suppresses unwanted movements

46. Parkinson’s Disease (PD)
• due to destruction of dopamine secreting pathways
from substantia nigra to caudate and putamen.
– also called “paralysis agitans” or “shaking palsy”
– first described by Dr. James Parkinson in 1817.
• In the west, it affects 1% of individuals after 60 yrs
Classical Clinical features:
• Tremor, resting
• Rigidity of all the muscles
• Akinesia (bradykinesia): very slow movements
• Postural instability

47. – expressionless face
– flexed posture
– soft, rapid, indistinct speech
– slow to start walking
– rapid, small steps, tendency to run
– reduced arm swinging
– impaired balance on turning
– resting tremor (3-5 Hz) (pill-rolling tremor)
• diminishes on action
– cogwheel rigidity
– lead pipe rigidity
– impaired fine movements
– impaired repetitive movements
47

48. POSTURAL MECHANISMS

49. Dynamic vs static nature of motor
control
• Static stability
– is dependent on the position of the centre of gravity
with respect to the base of support
• whereas dynamic stability
– is dependent more on the moment of inertia of the
body
For normal postural control three inputs are required
Vision
Proprioception (joint position sense)
Vestibular Mechanism (balance mechanisms)

51. Summary of control of motor system
• 1. Cerebral cortex: As a whole is essential for sending analytical command
signal for execution
• Frontal: corticospinal pathways
• Premotor and SMA: sequencing and modulation of all voluntary movements
• Prefrontal cortex (PFC): planning and initiation
• Parietal cortical areas: guidance of movement
• Visual, auditory and somatosensoy association areas: conscious guidance of
movement
• Proprioceptive: unconscious guidance of movement
• 2. Subcortical centres
– Basal ganglia: maintenance of tone and posture
– Cerebellum: coordination
• 3. Brainstem centres
• Major relay station through pontine and medullary nuclei, vestibular: stretch reflex,
posture, repetitive movements
• 4. Spinal cord
• Final common pathway
• Motor unit
• Spinal cord reflexes (stretch reflex, withdrawal reflex)
51

52. Physiology of Pain
Prof. Vajira Weerasinghe

53. Objectives
• Definition of “pain” and different types of pain
• Nociceptors
• Stimuli that can excite nociceptors and explain the role of PGE
• Ascending pathway
• Central projections
• Substance P, Glutamate
• Descending pain modulatory system
• Opioid peptides and their actions
• Non-opioid analgesics
• Gate-control theory of pain
• Other neurotransmitters
• “Referred pain”
• Physiological basis of different methods of pain relief

54. What is pain?
• Pain is a difficult word to define
• Patients use different words to
describe pain
• eg.
• Aching, Pins and needles, Annoying, Pricking, Biting, Hurting,
Radiating, Blunt, Intermittent, Burning, Sore, Miserable, Splitting,
Cutting, Nagging, Stabbing, Crawling, Stinging, Crushing, Tender,
Dragging, Numbness, Throbbing, Dull, Overwhelming, Tingling,
Electric-shock like, Penetrating, Tiring, Excruciating, Piercing,
Unbearable
• Different words in Sinhala or in Tamil
• Pain Questionnaires

55. Multidimensional nature of pain
• Definition of pain
•An unpleasant sensory and emotional
experience associated with, or
resembling that associated with, actual
or potential tissue damage
(2020 Revised IASP definition)
IASP (International Association for the study of pain)
• Revised IASP definition addresses a person’s ability to
describe the experience to qualify as pain
• There are 6 key notes given with the international IASP
definition

56. Key notes
1. Pain is always a personal experience that is influenced to
varying degrees by biological, psychological, and social
factors
2. Pain and nociception are different phenomena. Pain
cannot be inferred solely from activity in sensory neurons
3. Through their life experiences, individuals learn the
concept of pain
4. A person’s report of an experience as pain should be
respected
5. Although pain usually serves an adaptive role, it may
have adverse effects on function and social and
psychological well-being
6. Verbal description is only one of several behaviors to
express pain; inability to communicate does not negate
the possibility that a human or a nonhuman animal
experiences pain

57. What is pain?
• Pain is
– subjective
– protective
– and it is modified by developmental, behavioural, personality and cultural
factors
• It is a symptom
• Associated signs are crying, sweating, increased heart rate,
blood pressure, behavioural changes etc
• Multidimensional nature of pain

58. Measurement of pain
• It is difficult to describe pain although we know
what it is
• It is difficult to measure pain
– visual analogue scale (VAS) is used

59. Dual nature of pain
• Fast pain
– acute
– pricking type
– well localised
– short duration
– Thin myelinated nerve
fibres are involved (A
delta)
– Somatic
• Slow pain
– chronic
– throbbing type
– poorly localised
– long duration
– Unmyelinated nerve fibres
are involved (c fibres)
– Visceral

60. Different situations
• No stimuli, but pain is felt
“Phantom limb pain”
eg. in amputated limb
• Stimuli present, but no pain felt
eg. soldier in battle field, sportsman in
arena
“Stress induced analgesia” (SIA)
• Pain due to a stimulus that does not
normally provoke pain
Allodynia
• Pain caused by a lesion or disease of the somatosensory
nervous system (pain pathways)
Neuropathic pain

61. Pain terminology
International Association for the Study of Pain
• Hyperaesthesia
– Increased sensitivity to stimulation, excluding the special senses (increased
cutaneous sensibility to thermal sensation without pain )
• Allodynia
– Pain due to a stimulus that does not normally provoke pain
– seen in patients with lesions of the nervous system where touch, light pressure,
or moderate cold or warmth evoke pain when applied to apparently normal skin.
• Hyperalgesia
– Increased pain from a stimulus that normally provokes pain
• Neuralgia
– Pain in the distribution of a nerve or nerves
• Analgesia
– Absence of pain in response to a normally painful stimulus
• Anaesthesia
– A loss of sensation resulting from pharmacologic depression of nerve function or
from neurological dysfunction
• Paraesthesia
– An abnormal sensation, whether spontaneous or evoked

62. Peripheral & central sensitization
Peripheral sensitization
• Increased responsiveness and reduced threshold of nociceptive neurons in
the periphery to the stimulation of their receptive fields
Central sensitization
• Increased responsiveness of nociceptive neurons in the central nervous
system to their normal or subthreshold afferent input.
• This may include increased responsiveness due to dysfunction of
endogenous pain control systems. Peripheral neurons are functioning
normally; changes in function occur in central neurons only.

63. Pain terminology
International Association for the Study of Pain
• Nociceptive pain
– Pain that arises from actual or threatened damage to non-neural tissue
and is due to the activation of nociceptors
• eg. Burns, fractures, injury
• Neuropathic Pain
– Pain caused by a lesion or disease of the somatosensory nervous
system
• eg. Sciatica, neuropathy
• Nociplastic pain
– Pain that arises from altered nociception despite no clear evidence of
actual or threatened tissue damage causing the activation of peripheral
nociceptors or evidence for disease or lesion of the somatosensory
system causing the pain.
– eg. Chronic back pain, fibromyalgia, irritable bowel syndrome
– Patients can have a combination of nociceptive and nociplastic pain

64. Processing of nociceptive impulse
• Transduction
– Process of converting noxious stimulus to action
potentials
• Transmission
– Ascending pathway
• Modulation
– Descending pathaway
• Perception
– Central processing of nociceptive impulses in order
to interpret pain

65. Stimuli
• Physical
– pressure etc
• Electrical
• Thermal
– cold, hot
• Chemical
– H+, lactic acid, K+, histamine, bradykinin, serotonin, acetylcholine,
proteolytic enzymes, cytokines, leucotrienes, capsaicin
– Prostaglandins (PGE2)
• Cannot directly stimulate nociceptors
• Increase the sensitivity of nociceptors for other stimuli (decrease the
threshold)

66. Receptors
 There are no specialised receptors
 Pain receptors are called nociceptors
 A sensory receptor that is capable of transducing and
encoding noxious stimuli (actually or potentially tissue
damaging stimuli)
 Nociceptors are free nerve endings
 Free nerve endings are distributed everywhere
 both somatic and visceral tissues
 except brain tissue and lung parenchyma

67. Receptors
• Nociceptors are very slowly adapting type
• Different types of nociceptors
– Some respond to one stimulus
– Some respond to many stimuli (polymodal)
– Some may not respond to the standard stimuli (silent nociceptors)
• they respond only when inflammatory substances are present
• Nociceptive transduction involve several ion channels including
voltage gated Na channels, transient receptor potential
channels (TRPV1), acid sensing ion channels (ASIC)
• Capsaicin receptor (TRPV1 receptor)
– Respond to capsaicin, heat, low pH
– Stimulation leads to painful, burning sensation

68. Nerve pathways carrying pain signals to
the brain
• Pain signals enter the spinal cord
• First synapse is present in the dorsal horn of
the spinal cord
• Cross over to the other side
• Then the second order neuron travels through
the lateral spinothalamic tracts

69. central connections
• Afferent signal enters via A delta and C fibres into the spinal
cord
• Synapses in laminae ii,iii
– substantia gelatinosa
substantia
gelatinosa
Neurotransmitters at the first synapse of
the pain pathway
• Glutamate
• Substance P
• CGRP (Calcitonin gene-related peptide)
• Opioids

70. Pain
lateral
spinothalamic
tract
C fibre
substantia
gelatinosa
• crosses the midline
• ascends up as the lateral spinothalamic
tract
ascending pathway

71. lateral
spinothalamic
tract
thalamus
C fibre
thalamo
cortical
tracts

72. Pain perception
• This occurs at different levels
– thalamus is an important centre of
pain perception
• lesions of thalamus produces severe
type of pain known as ‘thalamic pain’
– Sensory cortex is necessary for the
localisation of pain
– Other areas are also important
• reticular formation, limbic areas,
hypothalamus and other subcortical
areas

73. Descending pain modulatory system
• several lines of experimental evidence show the
presence of descending pain modulatory system
– Electrical stimulus produced analgesia (Reynolds)
– stimulation of certain areas in the brain stem was known to
decrease the neuronal transmission along the
spinothalamic tract
– Chemical stimulus produced analgesia
– Discovery of morphine receptors
– they were known to be present in the brain stem areas
– discovery of endogenous opioid peptides
• eg. Endorphines, enkephalins, dynorphin

74. midbrain
pons
medulla
spinal cord
periaqueductal
grey nucleus
nucleus raphe
magnus
substantia gelatinosa

75. • descending tracts involving opioid peptides as
neurotransmitter were discovered
• these were known to modify (inhibit) pain
impulse transmission at the first synapse at the
substantia gelatinosa

76. • first tract was discovered in 1981 by Fields and
Basbaum
– it involves enkephalin secreting neurons in the
reticular formation
– starting from the PAG (periaqueductal grey area) of
the midbrain
– ending in the NRM (nucleus raphe magnus) of the
medulla
– from their ending in the substantia gelatinosa of the
dorsal horn

77. substantia
gelatinosa
c fibre input
descending inhibitory tract
dorsal horn
substantia
gelatinosa cell

78. opioid peptides
•  endorphin
• Enkephalins or encephalins - met & leu
• Dynorphin
• Receptors: mu, kappa, delta
• Morphine, fentanyl, pethidine, codeine are opioid
drugs
• Naloxone is opioid receptor antagonist
• Opium (derived from poppy plant) is a naturally
occurring substance
• “Heroin” contain naturally occurring opiates and are
highly addictive

79. Opioid action at the
spinal cord level
substance P
or glutamate
opioids
pain impulse
blocking of
pain impulse

80. Opioid actions
• Act presynaptically or postsynaptically
– Presynaptic action: Blocks Ca2+ channels and inhibits Ca2+ influx and thereby
prevent pain neurotransmitter release (glutamate, substance P) from presynaptic
membrane
– Postsynaptic action: Open up K+ channels and causes K+ efflux and resulting in
hyperpolarisation of the membrane and prevents pain neurotransmitter activity
– Inhibits cAMP activity and alters pain neurotransmitter activity
– Inhibition of serotonin reuptake and through GABA inhibition increased release of
serotonin (activate serotoninergic descending mechanisms)
– Binds to NMDA receptor and inhibit glutamate action
• Act at the spinal cord level or brainstem reticular formation level
• Activates descending pathways
• Opioid and non-opioid mechanisms are activated
• Non-opioid mechanisms use noradrenergic or serotoninergic
pathways
• Also inhibit GABA mediated inhibition of descending pathway
activity

81. Opioid actions
• Basis of respiratory depression when morphine is given is due
to inhibition of pre- Botzinger complex (BOTC) (which is the
respiratory rhythm pattern generator present in the medulla
which controls inspiratory centre) by opioids through mu
receptor
• Activate chemoreceptor trigger zone and may cause vomiting
• Opioid system is involved in pain modulation, stress, appetite
regulation, learning, memory, motor activity, immune function
• Opioids/opiates addiction (eg. due to heroin) is due to their
action through mesolimbic reward pathway (involving VTA and
nucleus accumbens) and increasing dopamine levels in the
brain which causes feeling of pleasure and euphoria
• Subsequent increased compulsion leads to tolerance and
dependence

83. • since then various other descending tracts were
discovered
• all of them share following common features
– involved in brain stem reticular areas
– enkephalins act as neurotransmitters at least in some
synapses
– most of these tracts are inhibitory
– midbrain nuclei are receiving inputs from various areas in
the cortex, subcortical areas, limbic system, hypothalamus
etc
– the ascending tract gives feedback input to the descending
tracts
– recently even non-opioid peptides (serotonin and
noradrenaline) are involved

84. Non-opioid analgesics
• NSAIDs
– Selective cox 2 inhibitors
– Disrupt production of PG (mediator of pain)
– Side effects limit their use
• Paracetamol
– Both central and peripheral action
– Central action through serotoninergic pathways
– Peripheral action may be by PG inhibition (COX3 inhibition)
– Influences cannabinoid pathways

85. C fibre
Final pain perception
depends on activity
of the
Ascending
pain impulse
transmitting
tracts
Descending
pain modulatory
(inhibitory) tracts

86. Gate control theory
• This explains how pain can be relieved very quickly by
a neural mechanism
• First described by P.D. Wall & Melzack (1965)
• “There is an interaction between pain fibres and touch
fibre input at the spinal cord level in the form of a
‘gating mechanism’

87. Gate control theory
When pain fibre is stimulated, gate will be opened & pain is felt
pain
pain is felt
+
gate is
opened

88. Gate control theory
When pain and touch fibres are stimulated together, gate will be
closed & pain is not felt
pain is
not felt
touch
pain
+ -
gate is
closed
Animation

90. Gate control theory
• This theory provided basis for
various methods of pain relief
– Massaging a painful area
– Applying irritable substances to a
painful area (counter-irritation)
– Transcutaneous Electrical Nerve
Stimulation (TENS)
– Acupuncture ?

91. Gate control theory
• But the anatomcal basis for all the connections
of Wall’s original diagram is lacking
?
?

92. WDR (wide dynamic range cells)
• It is known that some of the second order neurons of the pain
pathway behave as wide dynamic range neurons
• They are responsive to several somatosensory modalities
(thermal, chemical and mechanical)
• They can be stimulated by pain but inhibited by touch stimuli
• They have been found in the spinal cord, trigeminal nucleus,
brain stem, thalamus, cortex

93. WDR (wide dynamic range cells)
C fibre A fibre
pain &
mech mech
inhibitory
excitatory
WDR cell

94. Modifications to the gate control theory
• this could be modified in the
light of enkephalin activity
and WDR cells
• inhibitory interneuron may be
substantia gelatinosa cell
• descending control is more
important
• WDR cells may represent
neurons having pain as well
as touch input

95. referred pain
• sometimes pain arising from viscera are not felt
at the site of origin but referred to a distant site.
– eg.
• cardiac pain referred to the left arm
• diaphargmatic pain referred to the shoulder
– this paradoxical situation is due to an apparent error
in localisation

96. referred pain - theories
• convergence theory
– somatic & visceral structures
converge on the same
dermatome
– generally impulses through
visceral pathway is rare
– centrally brain is programmed
to receive impulses through
somatic tract only
– therefore even if the visceral
structure is stimulated brain
misinterpret as if impulses are
coming from the somatic
structure
visceral
somatic
second
order
neuron
++
+
+
+
+
+

97. referred pain - theories
• facilitatory theory
– somatic & visceral structures
converge on the same
dermatome
– stimulation of visceral
structure facilitates
transmission through somatic
tract
visceral
somatic
second
order
neuron
++
+
+
+
+
+

98. Capsaicin and vanniloid receptors
• Active compound in chilies is capsaicin
• Capsaicin chemically is one of the vanilloids
• Capsaicin receptor is called TRPV1
– (Transient receptor potential vanilloid type 1)
• This receptor is also stimulated by
– heat greater than 43°C
– low pH
• This receptor is sensitised by prostaglandins and bradykinins
• Upon prolonged exposure to capsaicin TRPV1 activity decreases
– this phenomenon is called desensitization
– Extracellular calcium ions are required for this phenomenon
– This causes the paradoxical analgesic effect of capsaicin

99. Cannabinoid receptor
• Cannabis (marijuvana or ganja) causes pain relief
• Cannabis act on cannabinoid receptors CB1 found in pain pathway
(presynaptic receptors)
• There are endocannabinoids as well (2-arachidonoyl glycerol (2-AG) and
anandamide)
• Secreted from the postsynaptic terminal, act on the presynaptic terminal,
receptors present on the pre-synaptic terminal
• This is a form of retrograde signalling
• Via G protein coupled activity blocks Ca++ entry or increase K efflux
• Inhibit pain neurotransmitter release
• Cannabinoid receptor-related processes are involved in cognition, memory,
anxiety, control of appetite, emesis, motor behavior, sensory, autonomic and
neuroendocrine responses, immune responses and inflammatory effects
apart from modulating pain

100. Neurotransmitters in the CNS
• Excitatory
Substance P (neurokinin receptors)
Glutamate (NMDA receptor)
Calcitonin gene-related peptide (CGRP)
• Inhibitory
GABA
Noradrenalin
Serotonin
Enkephalins
Endocannabinoids

101. Pain memory
• Memory of pain can be more damaging than its initial experience
• Central sensitization
 Increased responsiveness of nociceptive neurons in the central nervous system to their
normal or subthreshold afferent input.
• Peripheral sensitization
 Increased responsiveness and reduced threshold of nociceptive neurons in the periphery to
the stimulation of their receptive fields
• Clinical interventions to blunt both the experience and persistence of pain or to
lessen its memory are now applied
• Preemptive analgesia
 Pre-emptive analgesia is a treatment that is initiated before the surgical procedure in order
to reduce sensitization
 Many studies have demonstrated that analgesic intervention before a noxious stimulus or
injury is more effective at averting central sensitization than the same analgesic
intervention given after the stimulus

102. Methods of pain relief
• Prostaglandin inhibition: NSAIDs
• Blockage of voltage gated NA+ channels: Lignocaine (local
anesthetics)
• Gate control theory: TENS
• Descending inhibitory control: Opioids
• Central acting drugs: Non-opioids, serotoninergic and
noradrenergic drugs, antiepileptics, antidepressants
• Anti-inflammatory drugs: steroids, NSAIDs
• Others: capsaicin (desensitisation effect)
• Complex mechanism: Psychotherapy
• Multidisciplinary management

103. Dental Pain
• Pulp & dentine are sensitive to pain
• Nerve supply to pulp
• Innervation mainly from maxillary and mandibular
nerves
• Muscle nerve may also be involved
• Autonomic fibres also may be involved

104. Pulpal Pain
• Stimulated by
• Thermal
– heat may act via crown, causes throbbing type of pain
• Osmotic
• Electical
– Mechanism of Pulp tester (stimulus may spread to other
tissues)
• chemical & Pharmacological
– Sensitive to ZnO, serotonin
– But insensitive to direct application of histamine,
bradykinin, substance P

105. Dentinal Pain/sensitivity
• Amelodentinal junction is very sensitive
• Cervical dentine can also be highly
sensitive

106. Dental Pain
• Nerve supply of the dentine
• is limited to the crowns
• numerous under cusps
• Extend only a short distance (0.1 mm) in dentinal tubules
• Nerves in dentine do not degenerate when the
main axon is cut
• May suggest these nerve fibres are autonomic
• Nerve fibres lie close to odontoblastic processes
• But nerve fibres do not reach the amelodentinal
junction
• Root dentine is not well innervated

107. • There are different theories accounting for
dentinal sensitivity
• Neural theory
• Odotoblastic transduction theory
• Hydrodynamic theory

108. Hydrodynamic theory
• This is now fully accepted
• Dentinal stimuli causes an outward or inward flow
of dentinal tubular contents
• This disturbance is transmitted to the pulp
• Resulting mechanical disturbance excite pulpal
pain fibres
• Activation of these fibres may be proportional to
the rate of dentinal fluid displacement

109. • Cell bodies are located in the trigeminal
ganglion
• First synapse is in the medullary dorsal
horn
– Synapses with nociceptive specific and WDR
cells
– May synapse in sensory nucleus too
• Goes to the thalamus
• Then to the sensory cortex (oral area)

110. • Pulpal innervation is capable of
regenerating and reinnervating dentinal
tubules
• Even during reimplantation reinnervation
can take place