Anatomy And Physiology Of Pain

Front 1

What is pain?

Back 1

Pain: An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage; it is what a patient says it is!

A cerebral construct, pain is a perception usually but not always associated with tissue-damaging stimuli (nociceptive information)

Front 2

What are the somatosensory receptors?

Back 2

Front 3

How is pain sensed via nociceptors?

Back 3

Membranes of nociceptors have receptor proteins that allow response to tissue-damaging stimuli: signal transduction.

Temp - TRPV1,2,3, TREK1. Acid - TRPV1, ASIC, DRASIC. Force/sting - MDEG, DRASIC, TREK-1. Cold - TRPM8.

-> DRG

Front 4

What are the pain fibres?

Back 4

Adelta - thinly myelinated, 1.5um, 5-35m/s - sharp pricking FAST pain - thermal/mechanical

C - unmyelinated, .2-1.5 diameter, .5-2m/s - SLOW burning pain

Front 5

How are sensory peripheral fibres classified?

Back 5

Front 6

What is the effect of Ad pain sensation?

Back 6

Precise localisation of insult

Reflex withdrawal

Front 7

What is the effect of C fibre pain sensation?

Back 7

Autonomic effects: vasoactive, inflammatory, neurogenic info, healing.

Front 8

What are the 2 types of C fibres?

Back 8

1. peptidergic: release peptides peripherally e.g. substance P/CGRP

2. Peptide poor: distinct receptors - P2X3 ATP receptors + projections

Front 9

What genetic defects prevent pain sensation?

Back 9

NaV1.7 - sodium channel subunit congenital insensitivity to pain

CIPA (trkA - NGF receptor mutation) congenital insensitivity to pain with anhydrosis

Front 10

What is the cause of prolonged pain?

Back 10

Inflammation - sensitisation of area of injury: hyperalgesia/allodynia - enables protection + facilitates healing.

Front 11

What are the 4 cardinal signs of inflammation?

Back 11

Calor (heat)

Rubor (redness)

Dolor (pain)

Tumor (swelling)

Front 12

What are hyperalgesia, allodynia and spontaneous pain?

Back 12

Hyperalgesia - increased pain in response to painful stimulus

Allodynia - pain in response to innocuous stimulus, change in perception

Spontaneous - absence of stimulus.

Front 13

What are the effects of burns and pressure pain to further pain perception?

Back 13

Burns: primary thermal hyperalgesia increased sensitivity at SITE

Pressure: Increased sensitivity to pressure pain: both at site and adjoining i.e. primary and secondary mechanical hyperalgesia + allodynia

Front 14

What happens to pain sensation upon tissue injury/ prolonged noxious stimulation?

Back 14

Peripheral sensitisation - reduction in activation threshold, increase in responsiveness of peripheral ends of nociceptors.

Occurs via upregulation inflamm mediators - mast cell histamine, neuropeptide release: SP/CGRP

Front 15

What is the effect of inflammatory mediators on peripheral sensitisation?

Back 15

Stimulate nociceptive fibre endings and prolong activity. Modification and increased expression ion channels and receptors via intracellular messenger cascades i.e. phosphorylation and transcriptional activation.

TTXr Na channels change threshold for opening + kinetics, K+ close, TRPV1 increase sensitivity to heat. Some nociceptors tonically active.

Front 16

Describe prostaglandin synthesis and the effects on peripheral nerves.

Back 16

Phospholipase --PLA2--> arachidonic acid --COX1&2--> PGs.

COX1 present at low levels all the time, COX2 only in inflammation.

PGs sensitise nerves by increasing number of other receptors and increasing number open Na channels.

Front 17

How do steroids inhibit inflammation?

Back 17

Inhibit PLA2

Front 18

What occurs upon prolonged nociceptor input to the dorsal horn?

Back 18

Central sensitisation - activity dependent increase in excitability of dorsal horn neurones (outlasts stimulus) -> modified responsiveness - low threshold mechanoreceptor AB fibre input produce response -> pain allodynia, hyperalgesia

Front 19

What are triggers of central sensitisastion?

Back 19

Nociceptor afferents release GLUT and peptides. Depolarisation relieves block on NMDA GLUT receptors.

Front 20

What immune cells contribute to peripheral amplification?

Back 20

Mast cells

Macrophages

Neutrophils

Front 21

What examples of clinically relevant stimuli cause pain amplification?

Back 21

Tissue trauma, surgery, joint inflammation in RA

Front 22

What is chronic pain?

Back 22

Pain > 12wks - associated underlying condition

Front 23

What is abnormal/bad pain?

Back 23

Abdnormal activity in nerve/CNS i.e.

NEUROPATHIC PAIN - dysfunction/lesion PNS/CNS

DYSFUNCTIONAL PAIN - no known neural lesion/ongoing peripheral inflamm - triggered non nociceptive inputs/spontaneous. Causes - stroke, infection (postherpetic neuralgia), drug treatments, diabetes, chronic alcoholism.

Front 24

Describe the phenomenon of referred pain. i.e. CONVERGENCE

Back 24

Pain from internal organs is difficult for the brain to comprehend as it has no body schema or ‘map’ of the interior of the body to project the pain on to. Normally the pain is felt in the region of the body surface that has its afferent input in the same spinal segment (dermatome) as that where the active visceral pain fibres terminate.

Front 25

Describe the path of pain from noxious stimulus to brain.

Back 25

Free nerve endings of slow C/fast Ad fibres -> afferent nerve fibre -> DRG -> synpase to lateral ST tract in SC -> reticular formation in midpons -> synapse in thalamus -> SS cortex + limbic system.

Front 26

What other insults stimulate C fibres?

Back 26

Mechano, thermo, chemo + crude/gentle touch

Front 27

What is the composition of the DRG?

Back 27

C mechanoheat nociceptors 40%

C mechano nociceptors 20%

AM nociceptors 12%

SA 12%

RA 10%

D hair 6%

Front 28

What are silent nociceptors?

Back 28

Population of skin C fibres that become active in inflammation to then be sensitised to inocuous stimuli.

Front 29

What spinal fibre levels do pain afferents synapse in?

Back 29

Ad - I

C/Ad peptidergic - I-IIo

C non peptidergic - II

Ad hair follicle afferents - IIi - III

Ab hair follicle and tactile - IIi - V

Front 30

Where do spinothalamic tract cells arise from?

Back 30

Lamina I, IV + V.

Front 31

What is the neospinothalamic tract?

FIRST DISCRIMINATIVE PAIN

Neospinothalamic tract: signals acute (fast) pain and localisation of pain so that remedial action can be taken (eg remove limb from damage)

Back 31

Projection neurones in lamina IV/V innvervated by Ad fibres + convergent input C/Ab fibres. - wide dynamic range cells.

ANTERIOR STT -> lateral thalamus - VPL/VPM -> 1oSS cortex, VPI - 2oSS, Central lateral -> anterior cingulate cortex, emotion + prefrontal cortex + striatum - cognitive function + strategy.

Front 32

What is the paleospinothalamic tract?

SECOND PUNISHING PAIN

Paleospinothalamic tract: signals slow pain; activates emotional and autonomic aspects of pain.

Back 32

LATERAL - projection neurones in lamina 1 - mainly C fibres directly + indirectly from interneurons in lamina II + cells with input from Ad - nociceptive specific cells.

-> medial posterior thalamus. MDvc nucleus, posterior thalamus - medial subnucleus POm + ventral medial nucleus posterior VMpo. Few fibres to ventral posterior.

MDvc -> ACC. POm, Vmpo -> rostral insula

Front 33

What functions do the ACC, 1oSS, PFC, Insula and amygdala have in pain?

Back 33

ACC - emotional, motivation/aversive learning

1oSS - somatosensory discrimination

PFC - cognition, evaluation

Insula - pain map, integration, emotion

Amygdala - emotion/memory

Front 34

What are the targets of neoSTT and paleoSTT?

Back 34

Neo - 1o + 2o SSC

Paleo - anterior cingulate C + rostral insular C

Front 35

What are other non-perceptual elements of nociception?

Back 35

Spinoreticular - reticular formation: arousal, autonomic, behavioural reflex arcs, to PAG - descending pain modulation and autonomic/motor output

Spinomesencephalic - to parabrachial nucleus - lamina I to amygdala - limbic activation and visceral integration

Front 36

What are 4 physiological mechanisms of pain?

Back 36

1. Transduction - noxious stimuli translated to electrical activity at sensory nerve endings

2. Transmission - propogation of impulses along pain pathways

3. Perception - affective/motivation

4. Modulation - Stages 1-3 modified

Front 37

How can pain be modulated at different levels of the pain pathway?

Back 37

Front 38

What is Melzack and Wall's revised gate control theory of pain?

Back 38

Black circle inhibitory and white circle excitatory links from substantia gelatinosa to the transmission cells in dorsal horn of SC

Front 39

Why can tissue damage sometimes not result in pain?

Back 39

Tissue damage does not always result in pain because the nociceptor input can be ‘gated off’ in the dorsal horn by innocuous stimuli & descending pathways from the brainstem

Front 40

How does the gate theory present on a neuronal scale?

Back 40

Ad + C fibres synapse on Lamina I + lamina IV/V cells releasing GLUT + excitatory peptide substance P.

Inhibitory interneurones in lamina II activated by non-pain afferents and also descending aminergic fibres from the brain stem inhibiting terminals and lamina I cels by releasing enkephalins (peptides) + GABA

Front 41

Where are opiate/enkephalin receptors located?

Back 41

Primary afferents + lamina I dendrites. If afferents destroyed enkephalin receptors lost + opiates mostly ineffective

Front 42

How do centrally acting analgesics e.g. opiates/ clonidine work?

Back 42

By mimicking the actions of lamina II (substantia gelatinosa) dorsal horn cells.

Opiates (morphine, codeine, heroin) are agonists for μ (mu) enkephalin receptors on lamina I cells and C fibre afferents. They block the excitatory action of the C fibres on the lamina I cells.

Somework by mimicking descending amine pathways that switch on lamina II cells-- noradrenaline a2 agonists e.g. clonidine

Front 43

What is the analgesic basis of transcutaneous electrical nerve stimulation (TENS) and acupuncture?

Back 43

stimulation of non-noxious/mildly stimulate lamina II cels which inhibit lamina II cells.

Front 44

What is the PAG?

Back 44

Region around cerebral aqueduct rich in enkephalin containing neurones. Electrical stimulation produces powerful analgesia.

Region activates locus coeruleus and raphe nucleus of rostal ventromedial medulla and controls descending inhibition of pain.

Receives input from hypothalamus and other limbic regions.

Front 45

What do the superior parietal cortex SPC-insula-amygdala and ACC-PFC-PAG pathway moderate?

Back 45

SPC-insula-amygdala - cognitive attention control of intensity.

ACC-PFC-PAG - emotion/placebo control of unpleasantness - sensitive to opiate antagonists.

Front 46

Where is central nociceptor termination located?

Back 46

C fibres inner are lamina I projection neurones and inter neurones in lamina II.

Ad fibres inner are laminae I and V projection neurones

Lamina V projection neurones also receive AB input and C fibre input.

Axons of projection neurones decussates close to where the nociceptors enter the spinal cord and form the anterolateral system/ST tract

Front 47

What are the two distinct aspects of the experience of pain?

Back 47

Back (Definition)