Physiology of pain

Prof. Vajira Weerasinghe

Professor of Physiology, Faculty of Medicine

University of Peradeniya & Consultant Neurophysiologist, Teaching Hospital, Peradeniya www.slideshare.net/vajira54

Topics covered in the lecture1. 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

definition of pain

• It is a symptom• Associated signs are crying, sweating, increased

heart rate, blood pressure, behavioural changes• It is difficult to describe pain although we know what

it is• It is difficult to measure pain

– visual analogue scale is used

• It is a complex sensory modality essential for survival

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

• Paresthesia– An abnormal sensation, whether spontaneous or evoked

• Dysesthesia– An unpleasant abnormal sensation, whether spontaneous or evoked

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

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

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

sensibility to thermal sensation without pain )• Hyperalgesia

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

– A syndrome of sustained burning pain, allodynia, and hyperpathia after a traumatic nerve lesion, often combined with vasomotor and sudomotor dysfunction and later trophic changes

• Hyperpathia– a painful syndrome characterized by an abnormally painful reaction to a stimulus, especially

a repetitive stimulus, as well as an increased threshold• Neuralgia

– Pain in the distribution of a nerve or nerves

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

• 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 threshold– The minimum intensity of a stimulus that is perceived as painful.

• Transduction– Process of converting noxious stimulus to action

potentials

• Perception– Central processing of nociceptive impulses in order

to interpret pain

Dual nature of painfast and slow pain

• fast pain

– acute– pricking type– well localised– short duration– A fibres are involved– fast conduction 20 m/s– somatic pain

• slow pain

– chronic– throbbing type– poorly localised– long duration– unmyelinated C fibres are

involved– slow conduction 1-2 m/s– visceral pain

Stimuli • Physical– pressure etc

• Electrical

• Thermal– cold, hot

• Chemical– H+, lactic acid, K+, histamine, bradykinin, acetylcholine, proteolytic

enzymes

– Prostaglandins• these increase the sensitivity (decrease the threshold) for other nociceptive

stimuli

receptors• there are no specialised receptors

• free nerve endings are sensitive to pain stimuli

• free nerve endings are distributed everywhere• both somatic and visceral tissues• except brain tissue and lung parenchyma

• 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

• TRPV1 receptor (capsaicin receptor)– respond to capsaicin, heat, low pH– stimulation leads to painful, burning sensation

central connections• afferent fibre enters the spinal cord

• synapses in laminae I and II (substantia gelatinosa)• visceral fibres have more diffused distribution (I,V,X)

– (Large Ab fibres termiate in laminae layers III to V)

substantiagelatinosa

Neurotransmitter at the first synapse of the pain pathway is substance P

Pain

lateralspinothalamic tract

C fibre

substantiagelatinosa

• crosses the midline• ascends up as the lateral spinothalamic tract• pain originating from head and neck region travel through

trigeminal nerve, trigeminal nucleus and supply thalmus • spontaneous firing of trigeminal pathway may result in

“trigeminal neuralgia”

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

– discovery of morphine receptors– they were known to be present in the brain

stem areas

– discovery of endogenous opioid peptides

• eg. Endorphines, enkephalins, dynorphin

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

Naloxone is an opioid antagonist. It blocks the actions of opioid

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

midbrain

pons

medulla

spinal cord

periaqueductal

grey nucleus

nucleus raphe

magnus

substantia gelatinosa

• 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

• final pain perception depends on activity of the– ascending pain impulse transmitting tracts– descending pain modulatory (inhibitory) tracts

lateralspinothalamic tract

thalamus

sensory cortex

C fibre

thalamocorticaltracts

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

central control

transmission cell

touch

A fibre

pain

C & A fibres

Gate control theory

central control

transmission cell

touch

A fibre

when C fibre is stimulated, gate will be opened & pain is felt

pain

C & A fibres

pain is felt

+gate is opened

Gate control theory

central control

transmission cell

when A & C fibres are stimulated together, gate will be closed & pain is not felt

pain is

not felt

touch

A fibre

pain

C & A fibres

+ -

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 can be stimulated by pain stimuli 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

++++

+

++

• 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)

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

Neurotransmitters in the CNS

• Excitatory – Substance P– Glutamate (NMDA receptor)– Neurokinin A and B– calcitonin gene-related peptide– vasoactive intestinal polypeptide– Somatostatin– bombesin

Neurotransmitters in the CNS

• Inhibitory – GABA– Noradrenalin– Serotonin– Enkephalins

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