Physiology of painProf. Vajira Weerasinghe
Professor in Neurophysiology, Faculty of Medicine, University of Peradeniya & Consultant Neurophysiologist, Teaching Hospital, Peradeniya
www.slideshare.net/vajira54
Topics covered in the lecture
1. What is pain? (International definition of pain)
2. Dual nature of pain: fast pain and slow pain
3. What causes pain : pain stimuli
4. Nerve pathways carrying pain signals to the brain
5. Brain areas involved in pain perception
6. Pain modulatory pathways
7. Neurochemicals involved in pain pathways
8. Gate control theory of pain
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
What is pain?• There is an International definition of pain
formulated by the IASP (International Association for the study of pain)
• Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage
IASP – International Association for the Study of Pain 2011
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
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
Dual nature of pain
• Fast pain
– acute
– pricking type
– well localised– short duration
– Thin myelinated nerve fibres are involved (A delta)
• Slow pain
– chronic
– throbbing type
– poorly localised– long duration
– Unmyelinated nerve fibres are involved (c fibres)
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
•Pain due to a stimulus that does not normally provoke pain
•Allodynia
•Pain caused by a lesion or disease of the somatosensory nervous system
•Neuropathic pain
Pain terminologyInternational Association for the Study of Pain 2011
• Hypera lges ia – Increased pa in from a s timulus tha t normally provokes pa in
• Hyperaes thes ia– Increased sens itivity to s timula tion, excluding the specia l senses
(increased cutaneous sens ibility to the rmal sensa tion without pa in )• Paraes thes ia
– An abnormal sensa tion, whether spontaneous or evoked• Anaes thes ia
– A loss of sensa tion resulting from pharmacologic depress ion of nerve function or from neurologica l dys function
• Neura lgia– Pa in in the dis tribution of a ne rve or ne rves
• Ana lges ia – Absence of pa in in response to a normally pa inful s timulus
• Allodynia – Pa in due to a s timulus tha t does not normally provoke pa in
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Pain terminologyInternational Association for the Study of Pain 2011
• Neuropathic Pain – Pain caused by a lesion or disease of the somatosensory nervous
system• Nociceptive pain
– Pain that arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors
• Visceral pain – Pain arising from visceral organs (e.g., heart, lungs, gastrointestinal tract,
liver, gallbladder, kidneys, bladder).• Neuropathy
– A disturbance of function or pathological change in a nerve: in one nerve, mononeuropathy; in several nerves, mononeuropathy multiplex; if diffuse and bilateral, polyneuropathy
• Nociception – The neural process of encoding noxious stimuli
• Noxious stimulus– A stimulus that is damaging or threatens damage to normal tissues.
Pain
• Pain as a sensation– physiologically (nociception)– Nociceptive pain
• Pain as an emotional experience– Psychologically– Psychogenic pain
• Pain caused by damage to nerve– Neuropathic pain
Transduction and perception
• Transduction– Process of converting noxious stimulus to action
potentials
• Perception– Central processing of nociceptive impulses in order
to interpret pain
Stimuli • Physical
– pressure etc
• Electrical
• Thermal– cold, hot
• Chemical– H+, lactic acid, K+, histamine, bradykinin, serotonin, leucotrines,
acetylcholine, proteolytic enzymes, capsaicin
– Prostaglandins (PGE2)• Cannot directly stimulate nociceptors
• Increase the sensitivity of nociceptors for other stimuli (decrease the threshold)
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
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
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
• Then the second order neuron travels through the lateral spinothalamic tracts
afferent fibres
• two types– Aδ (thin myelinated)– C (unmyelinated)
central connections• afferent fibre enters the spinal cord
• synapses in laminae ii,iii– substantia gelatinosa
substantiagelatinosa
Neurotransmitter at the first synapse of the pain pathway is substance P
• Acute pain : glutamate• Chronic pain: substance P• Pain inhibitory neurotransmitters: enkephalin, GABA
Pain
lateralspinothalamic tract
C fibre
substantiagelatinosa
• crosses the midline
• ascends up as the lateral spinothalamic tract
ascending pathway
lateralspinothalamic tract
thalamus
sensory cortex
C fibre
thalamocorticaltracts
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
Pathophysiology of pain
• Pain sensations could arise due to– Inflammation of the nerves (neuritis)– Injury to the nerves and nerve endings with scar
formation (disk prolapse) – Injury to the structures in the spinal cord, thalamus
or cortical areas that process pain information (spinal trauma)
– Abnormal activity in the nerve circuits that is perceived as pain (phantom limb pain)
– Nerve invasion, for example by cancer (brachial plexopathy)
Descending pain modulatory system
• several lines of experimental evidence show the presence of descending pain modulatory system– stimulus produced analgesia (Reynolds)
– stimulation of certain areas in the brain stem was known to decrease the neuronal transmission along the spinothalamic tract
– discovery of morphine receptors– they were known to be present in the brain stem
areas
– discovery of endogenous opioid peptides• eg. Endorphines, enkephalins, dynorphin
midbrain
pons
medulla
spinal cord
periaqueductal
grey nucleus
nucleus raphe
magnus
substantia gelatinosa
opioid peptides
• short peptides originally known to be secreted in CNS and later found to be present in GIT etc
opioid peptides∀ β endorphin
• Earliest to discover, present in pituitary • Enkephalins or encephalins - met & leu
• widely distributed• Dynorphin • Endomorphine 1 & 2• Pronociceptins
Receptors: mu, kappa, delta, recently discovered ORL1 receptor
• 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
• 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
• in the subtantia gelatinosa– enkephalin secreting neuron is involved in
presynaptic inhibition of the pain impulse transmission by blocking substance P release
substantiagelatinosa
c fibre input
descending inhibitory tract
dorsal horn
substantia
gelatinosa cell
substance P
enkephalin
Presynaptic inhibition
Presynaptic inhibition
substance P
enkephalin
pain impulse
blocking of pain impulse
• 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 nonopioid peptides are known to be involved
sensory cortex
C fibre
Final pain perception depends on activity of the
Ascending pain impulse transmitting tracts
Descending pain modulatory (inhibitory) tracts
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
touchpain
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’
Gate control theory
When pain fibre is stimulated, gate will be opened & pain is felt
pain
pain is felt
+gate is opened
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
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 ?
Gate control theory
• But the anatomcal basis for all the connections of Wall’s original diagram is lacking
?
?
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
WDR (wide dynamic range cells)
C fibre A fibre
pain &
mech mech
inhibitoryexcitatory
WDR cell
WDR cells
• have been found in– Spinal cord– Trigeminal nucleus– Brain stem– Thalamus– Cortex
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
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
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
++++
+
++
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
++++
+
++
Pain memory
• Memory of pain often overshadows its primary experience in its impact upon pathophysiology and human suffering
• The 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
• hypoxia / pressure / inflating a BP cuff– first affect large A fibres (touch & pressure sense)– then affect Aδ fibres (temperature sense & pricking
pain)– lastly C fibres (burning pain)
local anaesthetics– first relieve burning pain ( C fibres)– then temperature sense & pricking pain (Aδ fibres)– lastly touch& pressure sensation (large A fibres)
Pain arising from abdominal viscera
• Mediated by C fibres
• Mainly due to the sensations of distention, muscular contraction, inflammation, hypoxia but not to cutting, tearing, local irritation, burning
• Typically vague, dull, and nauseating
• These structures are innervated by autonomic nerve fibers
• It is poorly localized and tends to be referred to areas corresponding to the embryonic origin of the affected structure
– stomach, duodenum, liver and pancreas referred to upper abdomen
– small intestines, proximal colon and appendix referred to periumbilical pain– distal colon and GU tract referred to lower abdominal pain
• Peritonitis causes somatic pain
• Diffuse localization of true visceral pain is probably due to the low density of visceral sensory innervation and extensive divergence of the visceral input within the central nervous system
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
Cannabinoid receptor
• Cannabis (marijuvana or ganja) causes pain relief
• Cannabis act on cannabinoid receptors found in pain pathway
• There are endocannabinoids as well
• 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
Summary
• Pain is not just a sensation but is a more complex phenomenon
• Pain can be blocked at many places
• Chemicals play an important role in causing pain as well as in reducing pain
• Neural mechanisms also play a role in pain interaction
• This complex nature of pain perception makes it a very difficult entity to control
“Pain is a more terrible lord of mankind than even death itself”
Dr. Albert Schweitzer (1875-1965)