Physiology of pain involves nociceptors that detect actual or potential tissue damage and transmit signals along afferent nerve fibers. Nociceptive signals synapse in the dorsal horn and ascend via the spinothalamic tract. The brain perceives pain based on these signals. Pain is modulated by descending pathways that release inhibitory neurotransmitters like opioids. The gate control theory proposes that activity in large diameter fibers can inhibit pain transmission. Various methods aim to reduce pain transmission or enhance descending inhibition including NSAIDs, local anesthetics, TENS, opioids, and psychotherapy.

1. Physiology of pain
Prof. Vajira Weerasinghe
Senior Professor of Physiology, Faculty of Medicine, University of Peradeniya
www.slideshare.net/vajira54

2. Objectives
• Definition of “pain” and different types of pain
• Nociceptors
• Stimuli that can excite nociceptors and explain the role of PGE
• Ascending pathway
• Central projections
• Substance P
• Descending pain modulatory system
• Opioid peptides and their actions
• Gate-control theory of pain
• Other neurotransmitters
• “Referred pain”
• 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 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

5. 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
• Multidimensional nature of pain

6. 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

7. 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

8. 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

9. 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

10. 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

11. Transduction and perception
• Transduction
– Process of converting noxious stimulus to action
potentials
• Perception
– Central processing of nociceptive impulses in order
to interpret pain

12. 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)
Animation

13. 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

14. 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

15. 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

16. afferent fibres
• two types
– A (thin myelinated)
– C (unmyelinated)

17. 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
• Chronic pain: substance P
• Pain inhibitory neurotransmitters: opioids

18. Pain
lateral
spinothalamic
tract
C fibre
substantia
gelatinosa
• crosses the midline
• ascends up as the lateral spinothalamic
tract
ascending pathway

19. lateral
spinothalamic
tract
thalamus
C fibre
thalamo
cortical
tracts

20. 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

21. 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
Animation

22. midbrain
pons
medulla
spinal cord
periaqueductal
grey nucleus
nucleus raphe
magnus
substantia gelatinosa

23. • 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

24. • 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

25. substantia
gelatinosa
c fibre input
descending inhibitory tract
dorsal horn
substantia
gelatinosa cell

26. 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

27. Opioid action at the
spinal cord level
substance P
or glutamate
opioids
pain impulse
blocking of
pain impulse

28. 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

29. 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

31. • 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

32. C fibre
Final pain perception
depends on activity
of the
Ascending
pain impulse
transmitting
tracts
Descending
pain modulatory
(inhibitory) tracts

33. 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

34. 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’

35. Gate control theory
When pain fibre is stimulated, gate will be opened & pain is felt
pain
pain is felt
+
gate is
opened

36. 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

38. 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 ?

39. Gate control theory
• But the anatomcal basis for all the connections
of Wall’s original diagram is lacking
?
?

40. 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

41. WDR (wide dynamic range cells)
C fibre A fibre
pain &
mech mech
inhibitory
excitatory
WDR cell

42. 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

43. 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

44. 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
++
++
+
+
+

45. 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
++
++
+
+
+

46. 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

47. 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

48. Methods of pain relief
• Prostaglandin inhibition
• NSAIDS
• Local anaesthetics
• Gate control theory
• TENS
• Opioids
• Non-opioids
• Activation of descending pathway
• Central acting drugs
• Psychotherapy
• Nerve blocks
• Nerve decompression
• Multidisciplinary management