Nociceptors 1. Nociceptors are receptors that respond only to actual or imminent tissue damage...
-
Upload
roberta-bryan -
Category
Documents
-
view
215 -
download
0
Transcript of Nociceptors 1. Nociceptors are receptors that respond only to actual or imminent tissue damage...
Nociceptors
1
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)
2
Nerve fibres are of different diameters
•Large diameter, myelinated: fast conduction•Small diameter, unmyelinated: slow conduction•Conduction velocity also relates to function...
3
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
4
Nociceptor activation
5
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
7
Pain pathways:- fast and slow pain- gate control theory- referred pain
8
Fast and slow pain
9
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
10
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)
12
Referred pain (2)
13
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
14
Nociceptor transduction: TRPV1
15
How can we study nociceptor transduction?
•Not easy: terminals are small and buried in connective tissue•We need an alternative approach
16
Partial solution: use the soma as a model of the terminal
DRG soma synthesises ion channels….
…which are transportedalong the axon
In vivo….
17
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
18
Dorsal root ganglion (DRG) neurones in culture
Soma
Processes
19
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!
24
Responses of TRPV1
TRPV1 also responds to acid pH - just like polymodal nociceptors
25
Responses of TRPV1
Interaction between acid and heat response of TRPV1: acid sensitises TRPV1 to heat
26
Innocuous thermal sensing
27
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
28
Cold receptor(epidermis)
Warm receptor(dermis)
Skin thermoreceptors
29
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
32
Warm and cold thermoreceptors
Warm receptors
Cold receptors
Patapoutian et alNature Rev Neurosci 4:529-539 (2003)
33
Innocuous cold transduction: TRPM8
34
Heat-activated
Cold-activated
Thermally activated TRP channels
35
Thermosensitive TRP channels
TRPM8 TRPV3/4 TRPV1 (VR1) TRPV2 (VRL1)
36
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