Transcript Document

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, Aβ
Low threshold mechanoreceptors
Large myelinated fibres - fast (>30 m/s)
NOCICEPTORS
Aδ
Fast nociceptors/cold receptors bare nerve endings
Small myelinated fibres - slower (5-30 m/s)
C:
Slow nociceptors/warm and cold
receptors - bare nerve endings
Small unmyelinated fibres very slow conduction (0.5-2 m/s)
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
Stimuli causing direct
tissue damage: heat,
low pH
Inflammatory mediators
(prostaglandins,
histamine, serotonin,
substance P)
Substances released
from damaged cells:
ATP, K+, bradykinin
...how are they detected?
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
TENS: stimulate here
This is the basis of TENS
(transcutaneous electrical nerve
stimulation): widely used in pain
control
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
In vivo….
DRG soma synthesises ion channels….
…which are transported
along the axon
17
Partial solution: use the soma as a model of the
terminal
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
Useful points:
Problems:
 The soma is accessible so:
 Mixture of channels from
terminal, soma and axon
 Can apply Ca2+ imaging
 Can use all varieties of
patch clamping
 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 relationship
22
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
Sensory spots on the back of the wrist
warm
Spots/cm2
cold
Blix 1882, taken from Norrsell et al Brain Res Bull 48:457-465 (1999)
Cold: 1.0 – 9.0
Warm: 0.4 – 1.7
28
Skin thermoreceptors
Cold receptor
(epidermis)
Warm receptor
(dermis)
29
Warm receptor activity
Warm receptor activity
Darian-Smith et al J Neurophysiol 42:1297-1315 (1979)
Spike frequency
30
Cold receptor activity
Cold receptor activity
Darian-Smith et al J Neurophysiol 36:325-346 (1973)
Spike frequency
31
Cold receptors: Steady state firing vs. temperature
Recordings from human cold fibres
30 °C
25 °C
20 °C
15 °C
10 °C
5 °C
Spike frequency vs. temperature
1s
Campero et al J Physiol 535:855-865 (2001)
32
Warm and cold thermoreceptors
Warm receptors
Cold receptors
Patapoutian et al
Nature Rev Neurosci 4:529-539 (2003)
33
Innocuous cold transduction: TRPM8
34
Thermally activated TRP channels
Heat-activated
Cold-activated
35
Thermosensitive TRP channels
TRPM8
TRPV3/4
TRPV1 (VR1) TRPV2 (VRL1)
36
Cold-induced depolarisation is potentiated by menthol
37
From Reid & Flonta, Nature 413:480 (2001)
Cold activates an inward current which is sensitised by menthol
38
From Reid & Flonta, Nature 413:480 (2001)
Cold-activated current: adaptation and recovery
39
From Reid & Flonta, Nature 413:480 (2001)
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