Finals of Kant get Marx 2.0 : a general politics quiz
Lecture Pain 2023 Y2S1.pptx
1. Physiology of pain
Prof. Vajira Weerasinghe
Senior Professor of Physiology, Faculty of Medicine, University of Peradeniya
& Consultant Neurophysiologist, Teaching Hospital, Peradeniya
www.slideshare.net/vajira54
2. Objectives
1. Revised IASP definition of “pain” and different types of pain
2. Nociceptors
3. Stimuli that can excite nociceptors and the role of PGE
4. Ascending pathway
5. Central projections
6. Substance P
7. Descending pain modulatory system
8. Opioid peptides and their actions
9. Gate-control theory of pain
10.Other neurotransmitters
11.“Referred pain”
12.Physiological basis of different methods of pain relief
3. 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
4. What is pain?
• There is an International definition of pain
formulated by the IASP (International
Association for the study of pain)
• Pain is a multidimensional experience
requiring comprehensive and ongoing
assessment and effective management
5. Revised IASP definition 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
6. 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
7. 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
• Pain could be acute or chronic (persistent)
• Multidimensional nature of pain
8. 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
9. 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
10. 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
11. 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
• 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
12. 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 without clear evidence of actual
or threatened tissue damage causing the activation of nociceptors or
evidence for disease or lesion of the somatosensory system causing pain
• eg. Chronic back pain, fibromyalgia, irritable bowel syndrome
13. Transduction and perception
• Transduction
– Process of converting noxious stimulus to action
potentials
• Perception
– Central processing of nociceptive impulses in order
to interpret pain
14. 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)
15. 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
16. 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
• Capsaicin receptor (TRPV1 receptor)
– Respond to capsaicin, heat, low pH
– Stimulation leads to painful, burning sensation
17. 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
19. central connections
• afferent fibre enters the spinal cord
• synapses in laminae ii,iii
– substantia gelatinosa
substantia
gelatinosa
Neurotransmitter at the first synapse of the
pain pathway is substance P
• Acute pain : glutamate (NMDA receptors)
• Chronic pain: substance P (NK1 receptors)
• Pain inhibitory neurotransmitters: enkephalin, GABA
22. 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
23. 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
25. • 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
26. • 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
28. 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
29. Opioid action at the
spinal cord level
substance P
or glutamate
opioids
pain impulse
blocking of
pain impulse
30. Opioid actions
• Act presynaptically or postsynaptically
– Blocks Ca2+ channels and inhibits Ca2+ influx and thereby prevent pain
neurotransmitter release (glutamate, substance P) from presynaptic membrane
– 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
• 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
31. 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
33. • 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
34. C fibre
Final pain perception
depends on activity
of the
Ascending
pain impulse
transmitting
tracts
Descending
pain modulatory
(inhibitory) tracts
35. Theories
of pain
There is a single pathway for touch
and pain
Less intensity produces touch
Increased intensity produces pain
There are two
different
pathways for
touch and pain
Specificity theory
touch pain
Intensity theory
touch
pain
36. 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’
37. Gate control theory
When pain fibre is stimulated, gate will be opened & pain is felt
pain
pain is felt
+
gate is
opened
38. 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
40. 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 ?
41. Gate control theory
• But the anatomcal basis for all the connections
of Wall’s original diagram is lacking
?
?
42. 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
43. WDR (wide dynamic range cells)
C fibre A fibre
pain &
mech mech
inhibitory
excitatory
WDR cell
44. 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
45. • hypoxia / pressure / inflating a BP cuff
– first affect large A fibres (touch & pressure sense)
– then affect A fibres (temperature sense & pricking
pain)
– lastly C fibres (burning pain)
• local anaesthetics
– first relieve burning pain ( C fibres)
– then temperature sense & pricking pain (A fibres)
– lastly touch& pressure sensation (large A fibres)
46. 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
47. 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
++
+
+
+
+
+
48. 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
++
+
+
+
+
+
49. 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
50. Different TRP Channels
Capsasin, the active
ingredient in chili
pepper, is used in
patches for relief of
pain.
Menthol and
peppermint gels are
used to relieve
muscle pain.
51. 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
52. • A condition when normally
non-painful stimuli cause
pain, e.g., touch, light
pressure, cold.
• Involves changes in the
synaptic sensitivity of the
nociceptive neurons in the
spinal cord (central
sensitization).
• Drugs such as ketamine,
block NMDA receptors and
so reduce transmisison of
the nociceptive stimuli.
Allodynia
Nociceptive signals from
the periphery to
spinal cord
NMDA (a receptor for
glutamate) response
increases in the spinal
cord
Nociceptive nerve cells
in the spinal cord now
become responsive to
non-painful stimuli
A mechanism for
allodynia
54. c-fos gene and FOS protein
• Discovery of gene c-fos (a viral oncogene) & its
cellular product, the protein called Fos seem
crucial to the profound central nervous system
changes that occur when an animal (or man)
feels pain
• CNS c-fos expression correlates extremely well
with painful stimulation
• We now have a molecular marker for pain!
55. 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
56. Different methods of pain relief
• Prostaglandin inhibition (Aspirin, NSAIDS)
• Local anaesthetics (Voltage gated Na channel blocking)
• Gate control theory (Blocking first synapse)
• TENS (Gate control theory)
• Opioids (Spinal cord and central descending pathway action)
• Drugs which increase noradrenalin and serotonin (activation of non-opioid
descending pathway)
• Central acting drugs (complex mechanism)
• Psychotherapy (complex mechanism)
• Nerve blocks (Blocking nerve transmission)
• Nerve decompression (Blocking nerve transmission)
• Inhibition of glutamate release by blocking Ca channels (Gabapentin)
• Multidisciplinary management
57. Summary
• Pain is a multidimensional experience requiring
comprehensive and ongoing assessment and effective
management
• Health workers involved in pain management play an
essential role in the prevention, diagnosis and management
of acute and persistent pain
• Pain management options should be modified appropriately
for individual patients according to medical condition,
medicine availability, risk-benefit balance, cost-
effectiveness, culture, mental status, and evidence of
efficacy