Nociceptors And Peripheral Sensitisation

Question 1

What is the definition of pain?

Answer 1

An unpleasant sensory and emotional experience associated with actual or potential tissue damage

Question 2

What is Nociception?

Answer 2

• The neural processes of encoding and processing an actual or potential tissue-damaging event
• Nociception is sensory dimension of pain and is not necessary to experience pain
• peripheral Nociception can occur without the perception of painful sensation

Question 3

What is the Mature Organism Model (MOM) for nociception?

Answer 3

• tissue damage is the input
• scrutinised by brain
• brain experiences/beliefs analyse input
• output/response goes back to the tissue and environment

Question 4

How does the pain (nociceptive) pathway work?

Answer 4

• tissue damage
• activation of PNS through nociceptors
• transmission to brain via dorsal root ganglion
• activation of CNS at spinal cord (Spinothalamic - pain/heat or DCML - vibration/touch/joint position sense)
• input sent to thalamus in brain + cortex to identify where pain is coming from via nociceptive facilitating neurons
• output from brain via nociceptive inhibiting neurons back down the spinal cord
• modulation of pain

Question 5

What are the different types of nociceptive stimulus?

Answer 5

• temperature e.g. heat/cold
• chemical e.g. acid
• pressure e.g. hit with hammer/injection/touch

Question 6

What are the different types of (nociceptive )nerve fibres and what do they transmit?

Answer 6

• a alpha => proprioception = myelindated = diameter (d) = 13-20 = aeroplane (80-120m/s)
• a beta => touch = myelindated = d = 6-12 = racing car (35-90m/s)
• a delta => mechanical + thermal = d = 1-5 = myelinated = Tour de France (5-40m/s)
• c = (silent) mechanical + thermal + chemical = d = 0.2-1.5 = non-myelindated = walking (0.5-2m/s)

Question 7

Where does the medial pathway go through for nociception?

Answer 7

• archispinothalamic tract
• passes through medial thalamus
• to limbic system producing emotional reactions to pain

Question 8

Where does the lateral pathway go through for nociception?

Answer 8

• neospinothalamic tract
• passes through lateral thalamus
• goes to somatosensory cortex
• gives discriminating aspect of pain (location)

Question 9

What are nociceptors?

Answer 9

• travel through the dermis to the epidermis
• free nerve endings in the epidermis

Question 10

What is the receptive field of a neuron?

Answer 10

• the region that can be stimulated and affects the neuron’s response
• neurons have fixed receptive fields

Question 11

What does it mean for nociceptors to be multimodal?

Answer 11

• contain both c-fibres and a-delta fibres
• majority of nociceptors are sensitive to both mechanical and heat stimulus (CMH = C fibres or AMH = a delta fibres)
• mechanically insensitive afferents (MIAs) only become sensitive to touch when inflamed (neurogenic inflammation)
• C fibres are ‘silent’ nociceptors responding only when injured (allodynia)

Question 12

Explain first and second pain in Nociception

Answer 12

• faster relaying a-delta fibres cause 1st pain sensation
• delayed slower sensation c-fibres cause second pain
• a-fibres recover faster from fatigue than c-fibres
• tonic pressure pain due to c-fibre MIAs (mechanically insensitive afferents)

Question 13

Explain what it means for Nociceptor so to have firing thresholds

Answer 13

• nociceptors have fixed thresholds of firing, however this varies between nociceptors e.g. heat pain threshold is variable due to neurogenic inflammation

Question 14

What is neurogenic inflammation?

Answer 14

• initiation of inflammation in response to tissue damage e.g. bradykinins, histamine, serotonin, cytokines, neutrophils, mast cells
• nociceptors activated by tissue damage
• neuropeptides (substance p, CGRP) from vesicles in nerve endings are released into tissues
• neuropeptides (substance p, CGRP) act on capillaries, mast cells and smooth muscle
• cascade of events similar to acute inflammation e.g. vasodilation, oedema, heat, muscle spasm

Question 15

What happens during neurogenic inflammation at the axon?

Answer 15

• Nociceptor activated by tissue insult
• normal alkaline-phosphate inflammatory reaction initiated (healing response)
• speacialised area of axon hillock causes antidromic impulse back to periphery
• can also begin at proximal nerve terminal i.e. along the entire nerve length
• peptidergic = release of neuropeptides e.g. substance P & CGRP

Question 16

What is the normal transmission of neurogenic inflammation and how can this lead to peripheral sensitisation?

Answer 16

• injury to tissue
• area of red flare contains neuropeptides which can lead to changes in tissue caused by back dumping (retrograde transport) of substance p/CGRP
• signal sent to dorsal column up to brain -> central neuron remains unchanged
• threshold of firing lowered => increased sensitivity => caused by peripheral sensitisation

Question 17

How is this clinically relevant?

Answer 17

• misdiagnosis of cause of pain due to perceived tenderness and swelling of local tissue e.g. referred knee tenderness from hip arthritus
• referred change in tissue structure e.g. increased joint destruction in rheumatoid arthritus
• e.g. eczema, interstitial cystitis (bladder pain syndrome), fibromyalgia, inflamed spinal segments

Question 18

Describe hyperalgesia

Answer 18

• painful sensation from a normally painful stimuli i.e. noxious

Question 19

Describe allodynia

Answer 19

• painful sensation from a non-noxious stimuli i.e. innocuous

Question 20

Name the 2 types of molecular receptors

Answer 20

• gene protein coupled receptor (GPCR) - receptor in the phospholipid bilayer of cell
• ligand gated ion channel (LGIC) - channel through phospholipid bilayer of cell

Question 21

What happens to the 2 types of molecular receptors (GPCRs & LGIC) in peripheral sensitisation?

Answer 21

• gene protein coupled receptors (GPCR) lower firing threshold of ligand gated ion receptors (LGIR)
• neurotransmitter lands on GPCR and binds to receptor on outside of cell
• on inside of cell internal transduction pathways and cellular responses are activated e.g. serotonin, histamine, prostaglandin receptors
• lead to a messenger that can open or close LGIC (ion channels) letting in substances from outside the cell inside, or inside the cell outside

Question 22

How does up regulation of existing receptors contribute to sensitisation?

Answer 22

• tissue damage
• persistent activation by endogenous agonists (internal chemical agonists)
• sensitisation by inflammatory mediators
• inherited polymorphisms of signal trandsducers (inflammatory chemical cascade)
• changes in membrane excitability (GPCR + LGIC)

Question 23

What contributes to sensitisation?

Answer 23

• production of new receptors (back dumping of nociceptors)
• up regulation of new receptors

-> therefore you have an injury => results in inflammation

-> internal efferent chemical signals increase inflammatory stimulus

-> there are more nociceptors due to back dumping => increasing stimulus and further increasing inflammation => peripheral sensitisation

Question 24

What leads to hyperalgesia?

Answer 24

• sensitisation of nociceptors leads to mechanical hyperalgesia (painful sensation from a normally painful stimulus)

Question 25

What is peripheral sensitisation?

Answer 25

• tissue injury causes damage to cells locally e.g. a burn
• local area becomes sensitive to both heat and touch
• area adjacent becomes sensitive to touch => mechanical hyperalgesia
• produces ‘red flare’ response due to breaches of nociceptors dumping out neuropeptides (substance P and CGDP)

Question 26

What is the clinical relevance of peripheral sensitisation?

Answer 26

• tissue damage + inflammation leads to peripheral sensitisation
• firing threshold of nociceptors lowered (increased sensitivity)
• C fibres (silent nociceptors/MIAs) become activated
• acute tissue damage will be red, hot and swollen
• sensitive to both mechanical and heat stimuli = heat hyperalgesia
• e.g. sunburn leads to pain with warm water, whereas ice and cold coverings are soothing

Question 27

What stimuli do nociceptors detect?

Answer 27

• a delta = mechanical + heat
• c = mechanical + heat + chemical

Question 28

What is a free nerve ending?

Answer 28

• nociceptor that end in the epidermis and travel through the dermis

Question 29

How does a free nerve ending differ from other sensory nerve endings?

Answer 29

• are encapsulated
• have no complex sensory structures

Question 30

What are the main differences between nociceptors and non-noxious sensory neurons?

Answer 30

• non-nociceptive neurones => respond to non-noxious, low intensity, normally non-painful stimuli
• nociceptive neurones => respond to noxious, high intensity, normally painful stimuli

Question 31

What is neurogenic inflammation and how does it come about?

Answer 31

• localised stimulation of the PNS
• injury to tissue
• results in inflammatory cascade e.g. bradykinins, histamine etc. which is detected by nociceptors
• nociceptors release substance P and CGDP into surrounding tissues, further increasing inflammation
• signal sent up to brain to make sense

Question 32

What are the characteristics of nociceptive pain?

Answer 32

• sensitive to heat + pressure
• sharp, aching, throbbing