Nociceptors And Peripheral Sensitisation Flashcards
What is the definition of pain?
An unpleasant sensory and emotional experience associated with actual or potential tissue damage
What is Nociception?
- 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
What is the Mature Organism Model (MOM) for nociception?
- tissue damage is the input
- scrutinised by brain
- brain experiences/beliefs analyse input
- output/response goes back to the tissue and environment
How does the pain (nociceptive) pathway work?
- 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
What are the different types of nociceptive stimulus?
- temperature e.g. heat/cold
- chemical e.g. acid
- pressure e.g. hit with hammer/injection/touch
What are the different types of (nociceptive )nerve fibres and what do they transmit?
- 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)
Where does the medial pathway go through for nociception?
- archispinothalamic tract
- passes through medial thalamus
- to limbic system producing emotional reactions to pain
Where does the lateral pathway go through for nociception?
- neospinothalamic tract
- passes through lateral thalamus
- goes to somatosensory cortex
- gives discriminating aspect of pain (location)
What are nociceptors?
- travel through the dermis to the epidermis
- free nerve endings in the epidermis
What is the receptive field of a neuron?
- the region that can be stimulated and affects the neuron’s response
- neurons have fixed receptive fields
What does it mean for nociceptors to be multimodal?
- 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)
Explain first and second pain in Nociception
- 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)
Explain what it means for Nociceptor so to have firing thresholds
- nociceptors have fixed thresholds of firing, however this varies between nociceptors e.g. heat pain threshold is variable due to neurogenic inflammation
What is neurogenic inflammation?
- 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
What happens during neurogenic inflammation at the axon?
- 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
What is the normal transmission of neurogenic inflammation and how can this lead to peripheral sensitisation?
- 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
How is this clinically relevant?
- 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
Describe hyperalgesia
- painful sensation from a normally painful stimuli i.e. noxious
Describe allodynia
- painful sensation from a non-noxious stimuli i.e. innocuous
Name the 2 types of molecular receptors
- gene protein coupled receptor (GPCR) - receptor in the phospholipid bilayer of cell
- ligand gated ion channel (LGIC) - channel through phospholipid bilayer of cell
What happens to the 2 types of molecular receptors (GPCRs & LGIC) in peripheral sensitisation?
- 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
How does up regulation of existing receptors contribute to sensitisation?
- 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)
What contributes to sensitisation?
- 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
What leads to hyperalgesia?
- sensitisation of nociceptors leads to mechanical hyperalgesia (painful sensation from a normally painful stimulus)
What is peripheral sensitisation?
- 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)
What is the clinical relevance of peripheral sensitisation?
- 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
What stimuli do nociceptors detect?
- a delta = mechanical + heat
- c = mechanical + heat + chemical
What is a free nerve ending?
- nociceptor that end in the epidermis and travel through the dermis
How does a free nerve ending differ from other sensory nerve endings?
- are encapsulated
- have no complex sensory structures
What are the main differences between nociceptors and non-noxious sensory neurons?
- non-nociceptive neurones => respond to non-noxious, low intensity, normally non-painful stimuli
- nociceptive neurones => respond to noxious, high intensity, normally painful stimuli
What is neurogenic inflammation and how does it come about?
- 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
What are the characteristics of nociceptive pain?
- sensitive to heat + pressure
- sharp, aching, throbbing
