nociceptors 1. nociceptors are receptors that respond only to actual or imminent tissue damage...
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Nociceptors
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Nociceptors
Nociceptors are receptors that respond only to actual or imminent tissue damage
Several types:•High threshold mechanoreceptors: mostly Aδ•Thermal nociceptors: mostly Aδ•Polymodal nociceptors: mostly C: nociceptors that respond to more than one modality (mechanical, heat, chemical etc)
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Nerve fibres are of different diameters
•Large diameter, myelinated: fast conduction•Small diameter, unmyelinated: slow conduction•Conduction velocity also relates to function...
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Conduction velocity and function
Aα, AβLow threshold mechanoreceptorsLarge myelinated fibres - fast (>30 m/s)
AδFast nociceptors/cold receptors -bare nerve endingsSmall myelinated fibres - slower (5-30 m/s)
C:Slow nociceptors/warm and cold receptors - bare nerve endingsSmall unmyelinated fibres -very slow conduction (0.5-2 m/s)
NOCICEPTORS
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Nociceptor activation
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Responses of nociceptors
Polymodal nociceptor: response to mechanical stimulation
Polymodal nociceptor: response to heat 6
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Multiple stimuli activate (or sensitise) nociceptors
...how are they detected?
Inflammatory mediators (prostaglandins,
histamine, serotonin, substance P)
Substances released from damaged cells: ATP, K+, bradykinin
Stimuli causing direct tissue damage: heat,
low pH
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Pain pathways:- fast and slow pain- gate control theory- referred pain
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Fast and slow pain
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Reducing the pain: the gate control theory
•Light touch or rubbing inhibits pain: why?•Inhibitory connection in the spinal cord•Here’s how it works
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Reducing the pain: the gate control theory
•Aβ fibre inactive•Inhibitory interneurone inactive•C fibre strongly activates projection (second order) neurone
•Aβ fibre active•Inhibitory interneurone active•Inhibitory interneurone reduces C fibre activation of projection neurone
This is the basis of TENS (transcutaneous electrical nerve stimulation): widely used in pain controlTENS: stimulate here 11
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Referred pain (1)
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Referred pain (2)
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Nociceptor sensitisation causes hyperalgesia
Burn injury applied to A and D causes hyperalgesia at A, B and C: in the injured area and far beyond
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Nociceptor transduction: TRPV1
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How can we study nociceptor transduction?
•Not easy: terminals are small and buried in connective tissue•We need an alternative approach
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Partial solution: use the soma as a model of the terminal
DRG soma synthesises ion channels….
…which are transportedalong the axon
In vivo….
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In culture….
DRG soma synthesises ion channels….
No axon, so they appear in the soma
So we can record the ion channels by patch clamping the soma
Partial solution: use the soma as a model of the terminal
Useful points:
The soma is accessible so:
Can apply Ca2+ imaging
Can use all varieties of patch clamping
Problems:
Mixture of channels from terminal, soma and axon
Change of phenotype in culture
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Dorsal root ganglion (DRG) neurones in culture
Soma
Processes
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Cultured DRG neurone response to heat
see Cesare & McNaughton PNAS 1996; Current Opinion in Neurobiology 1997 20
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Cultured DRG neurone response to heat:heat-activated ion channels
Nagy & Rang 1999 21
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What kind of ion channel is activated by heat?
Heat-gated channel TRPV1 Voltage gated channel
They’re distant relatives: definite evolutionary relationship22
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Responses of TRPV1
Heat-activated current of TRPV1
see Caterina et al 1997; Tominaga et al 1998 23
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Responses of TRPV1
Chilli-activated current of TRPV1!
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Responses of TRPV1
TRPV1 also responds to acid pH - just like polymodal nociceptors
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Responses of TRPV1
Interaction between acid and heat response of TRPV1: acid sensitises TRPV1 to heat
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Innocuous thermal sensing
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warm
cold
Sensory spots on the back of the wrist
Blix 1882, taken from Norrsell et al Brain Res Bull 48:457-465 (1999)
Spots/cm2
Cold: 1.0 – 9.0Warm: 0.4 – 1.7
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Cold receptor(epidermis)
Warm receptor(dermis)
Skin thermoreceptors
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Warm receptor activity
Warm receptor activity Spike frequency
Darian-Smith et al J Neurophysiol 42:1297-1315 (1979)30
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Cold receptor activity
Cold receptor activity Spike frequency
Darian-Smith et al J Neurophysiol 36:325-346 (1973)31
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1 s
30 °C
25 °C
20 °C
15 °C
10 °C
5 °C
Recordings from human cold fibres
Cold receptors: Steady state firing vs. temperature
Campero et al J Physiol 535:855-865 (2001)
Spike frequency vs. temperature
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Warm and cold thermoreceptors
Warm receptors
Cold receptors
Patapoutian et alNature Rev Neurosci 4:529-539 (2003)
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Innocuous cold transduction: TRPM8
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Heat-activated
Cold-activated
Thermally activated TRP channels
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Thermosensitive TRP channels
TRPM8 TRPV3/4 TRPV1 (VR1) TRPV2 (VRL1)
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Cold-induced depolarisation is potentiated by menthol
From Reid & Flonta, Nature 413:480 (2001)37
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Cold activates an inward current which is sensitised by menthol
From Reid & Flonta, Nature 413:480 (2001)38
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Cold-activated current: adaptation and recovery
From Reid & Flonta, Nature 413:480 (2001)39
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Reading for this lecture:
•Purves et al chapter 9 (give particular emphasis to the part up to page 198, but please read the rest of the chapter too); chapter 10 (all)
•Nicholls et al chapter 17 pages 334-340 - see also chapter 18 pages 356-366
•Kandel et al chapters 21-24