Physiology of painProf. Vajira Weerasinghe Professor of Physiology, Faculty of Medicine, University of Peradeniya & Consultant Neurophysiologist, Teaching Hospital, Peradeniya www.slideshare.net/vajira54

Topics covered in the lectureWhat is pain? (International definition of pain)

Dual nature of pain: fast pain and slow pain

What causes pain : pain stimuli

Nerve pathways carrying pain signals to the brain

Brain areas involved in pain perception

Pain modulatory pathways

Neurochemicals involved in pain pathways

Gate control theory of pain

What is pain?Pain is a difficult word to define

Patients use different words to describe paineg.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 factorsIt is a symptomAssociated signs are crying, sweating, increased heart rate, blood pressure, behavioural changes etc

Measurement of painIt is difficult to describe pain although we know what it isIt is difficult to measure painvisual analogue scale (VAS) is used

Dual nature of pain Fast pain

acutepricking typewell localisedshort duration

Thin myelinated nerve fibres are involved (A delta)

Slow pain

chronicthrobbing typepoorly localisedlong duration

Unmyelinated nerve fibres are involved (c fibres)

Different situations

Pain terminologyInternational Association for the Study of Pain 2011

Hyperalgesia Increased pain from a stimulus that normally provokes painHyperaesthesiaIncreased sensitivity to stimulation, excluding the special senses (increased cutaneous sensibility to thermal sensation without pain )ParaesthesiaAn abnormal sensation, whether spontaneous or evokedAnaesthesiaA loss of sensation resulting from pharmacologic depression of nerve function or from neurological dysfunctionNeuralgiaPain in the distribution of a nerve or nervesAnalgesia Absence of pain in response to a normally painful stimulusAllodynia 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 systemNociceptive painPain that arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptorsVisceral pain Pain arising from visceral organs (e.g., heart, lungs, gastrointestinal tract, liver, gallbladder, kidneys, bladder).NeuropathyA disturbance of function or pathological change in a nerve: in one nerve, mononeuropathy; in several nerves, mononeuropathy multiplex; if diffuse and bilateral, polyneuropathyNociception The neural process of encoding noxious stimuliNoxious stimulusA stimulus that is damaging or threatens damage to normal tissues.

Pain Pain as a sensationphysiologically (nociception)Nociceptive pain

Pain as an emotional experiencePsychologicallyPsychogenic pain

Pain caused by damage to nerveNeuropathic pain

Transduction and perception

TransductionProcess of converting noxious stimulus to action potentials

PerceptionCentral processing of nociceptive impulses in order to interpret pain

Stimuli Physicalpressure etc

Electrical

Thermalcold, hot

ChemicalH+, 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 everywhereboth somatic and visceral tissuesexcept brain tissue and lung parenchyma

Receptors Nociceptors are very slowly adapting type

Different types of nociceptorsSome respond to one stimulusSome 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 pHStimulation leads to painful, burning sensation

Nerve pathways carrying pain signals to the brainPain 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 fibrestwo typesA (thin myelinated)C (unmyelinated)

central connectionsafferent fibre enters the spinal cordsynapses in laminae ii,iiisubstantia gelatinosa Acute pain : glutamate Chronic pain: substance P Pain inhibitory neurotransmitters: enkephalin, GABA

crosses the midlineascends up as the lateral spinothalamic tractascending pathway

Pain perceptionThis occurs at different levelsthalamus is an important centre of pain perceptionlesions of thalamus produces severe type of pain known as thalamic pain Sensory cortex is necessary for the localisation of pain Other areas are also importantreticular formation, limbic areas, hypothalamus and other subcortical areas

Pathophysiology of painPain sensations could arise due toInflammation 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 systemseveral lines of experimental evidence show the presence of descending pain modulatory systemstimulus 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 receptorsthey were known to be present in the brain stem areas

discovery of endogenous opioid peptideseg. Endorphines, enkephalins, dynorphin

midbrainponsmedullaspinal cordperiaqueductalgrey nucleusnucleus raphemagnussubstantia gelatinosa

opioid peptidesshort peptides originally known to be secreted in CNS and later found to be present in GIT etc

opioid peptides endorphinEarliest to discover, present in pituitary encephalins - met & leuwidely distributeddynorphinEndomorphine 1 & 2Pronociceptins

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 Basbaumit involves enkephalin secreting neurons in the reticular formationstarting from the PAG (periaqueductal grey area) of the midbrainending in the NRM (nucleus raphe magnus) of the medullafrom their ending in the substantia gelatinosa of the dorsal horn

in the subtantia gelatinosaenkephalin secreting neuron is involved in presynaptic inhibition of the pain impulse transmission by blocking substance P release

substantiagelatinosac fibre inputdescending inhibitory tractdorsal hornsubstantia gelatinosa cell

substance PenkephalinPresynaptic inhibition

Presynaptic inhibitionsubstance Penkephalinpain impulse

since then various other descending tracts were discoveredall of them share following common featuresinvolved in brain stem reticular areasenkephalins act as neurotransmitters at least in some synapsesmost of these tracts are inhibitorymidbrain nuclei are receiving inputs from various areas in the cortex, subcortical areas, limbic system, hypothalamus etcthe ascending tract gives feedback input to the descending tractsrecently even nonopioid peptides are known to be involved

Final pain perception depends on activity of the

Ascending pain impulse transmitting tracts

Descending pain modulatory (inhibitory) tracts

Theories of painThere is a single pathway for touch and painLess intensity produces touchIncreased intensity produces pain

Gate control theoryThis 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 theoryWhen pain fibre is stimulated, gate will be opened & pain is felt

Gate control theoryWhen pain and touch fibres are stimulated together, gate will be closed & pain is not feltpain is not felt

Gate control theoryThis theory provided basis for various methods of pain reliefMassaging a painful area Applying irritable substances to a painful area (counter-irritation)Transcutaneous Electrical Nerve Stimulation (TENS)Acupuncture ?

Gate control theoryBut the anatomcal basis for all the connections of Walls original diagram is lacking

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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 fibreA fibrepain &mechmechinhibitoryexcitatoryWDR cell

WDR cellshave been found inSpinal cordTrigeminal nucleusBrain stemThalamusCortex

Modifications to the gate control theorythis could be modified in the light of enkephalin activity and WDR cellsinhibitory interneuron may be substantia gelatinosa celldescending control is more importantWDR cells may represent neurons having pain as well as touch input

referred painsometimes 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 armdiaphargmatic pain referred to the shoulder

this paradoxical situation is due to an apparent error in localisation

referred pain - theoriesconvergence theorysomatic & visceral structures converge on the same dermatomegenerally impulses through visceral pathway is rarecentrally brain is programmed to receive impulses through somatic tract onlytherefore even if the visceral structure is stimulated brain misinterpret as if impulses are coming from the somatic structurevisceralsomaticsecond order neuron+++++++

referred pain - theoriesfacilitatory theorysomatic & visceral structures converge on the same dermatomestimulation of visceral structure facilitates transmission through somatic tractvisceralsomaticsecond order neuron+++++++

Pain memory Memory of pain often overshadows its primary experience in its impact upon pathophysiology and human sufferingThe memory of pain can be more damaging than its initial experienceCentral sensitization Increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent inputPeripheral sensitization Increased responsiveness and reduced threshold of nociceptive neurons in the periphery to the stimulation of their receptive fieldsClinical interventions to blunt both the experience and persistence of pain or to lessen its memory are now applied

SummaryPain 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)

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