nociceptors 1. nociceptors are receptors that respond only to actual or imminent tissue damage...

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

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

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

Cultured DRG neurone response to heat:heat-activated ion channels

Nagy & Rang 1999 21

What kind of ion channel is activated by heat?

Heat-gated channel TRPV1 Voltage gated channel

They’re distant relatives: definite evolutionary relationship22

Responses of TRPV1

Heat-activated current of TRPV1

see Caterina et al 1997; Tominaga et al 1998 23

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

Cold receptor activity

Cold receptor activity Spike frequency

Darian-Smith et al J Neurophysiol 36:325-346 (1973)31

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

Cold activates an inward current which is sensitised by menthol

From Reid & Flonta, Nature 413:480 (2001)38

Cold-activated current: adaptation and recovery

From Reid & Flonta, Nature 413:480 (2001)39

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