Physiology of painProf. Vajira Weerasinghe

Professor of Physiology, Faculty of Medicine

University of 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

• Hyperalgesia – Increased pain from a stimulus that normally provokes pain

• Hyperaesthesia– Increased sensitivity to stimulation, excluding the special senses (increased

cutaneous sensibility to thermal sensation without pain )• Paraesthesia

– An abnormal sensation, whether spontaneous or evoked• Anaesthesia

– A loss of sensation resulting from pharmacologic depression of nerve function or from neurological dysfunction

• Neuralgia– Pain in the distribution of a nerve or nerves

• Analgesia – Absence of pain in response to a normally painful stimulus

• Allodynia – Pain due to a stimulus that does not normally provoke pain

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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, capsiacin

– 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– A (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 endorphin

• Earliest to discover, present in pituitary

• 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

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)