J.D. Flashcards
What is the ultimate relevance/aim of classifying nociceptors?
Possibility of selectively targeting subpopulations
If separate populations that deliver acute protective pain from those that deliver central sensitisation & chronic disabling pain then may allow people to function without risk of hurting themselves
If you stimulate a whole nerve what fibres make up the AP?
First = large & fast (Aα [efferent] and Aβ neurons)
Small blip after = Aδ
After = C fibres
Which nerves do adaptation and sensitisation occur in?
Adaptation occurs in NON-NOCICEPTORs e.g. wooly jumper = adaption in low threshold mechanoreceptor
Sensitisation occurs in SOME nociceptors: can be injury (cuts/burns) or chemical
- can be primary sensitisation or secondary sensitisation, and can cause primary hyperalgesia & secondary hyperalgesia
What is the effect of capsaicin?
Agonist at TRPV1
Doesn’t necessarily activate all afferents - some biologists think TRPV1 is a ‘nociceptive marker’ i.e. marks all the nociceptors - this is an oversimiplification
What is primary hyperalgesia / how is it mediated?
Enhanced response to HEAT & MECHANICAL stimuli
Mediated by sensitisation of PRIMARY AFFERENTs (primary sensitisation)
What is secondary hyperalgesia / how is it mediated?
Enhanced response to MECHANICAL stimuli (mechanical allodynia + punctate mechanical hyperalgesia)
Initiated by primary afferent nociceptors, leading to sensitisation of spinal neurons (interneuron or projection neuron) - central sensitisation
Sensitised CENTRAL neurons amplifies the response from both NON NOCICEPTIVE afferents and NOCICEPTIVE afferents
What happens when you inject capsaicin? Different zones on skin
Algesic bleb: development of sensory distubance
Area of primary hyperalgesia (increased pain to heat and mechanical stimuli) via primary sensitisation
Flare (around primary area): mediated by class of nociceptors with efferent function (release substance P, cGRP - vascular changes & hyperaemia, seen as flare + temperature increase)
Outside flare: secondary area of MECHANICAL ALLODYNIA (mediated by low-threshold, non-nociceptive afferents) & PUNCTATE MECHANICAL HYPERALGESIA (mediated by nociceptive afferents passing impulse to sensitised spinal neurons)
What is teased fibre?
Anaesthetise rat, expose the saphenous nerve - can tease fine filaments of the nerve away from the rest of nerve, hang on recording electrodes & start to record single unit activity
Record extracellular action potentials arising from 1-3 primary afferent neurons
Stimulate receptive field e.g. thermal/electrical, or can stimulate whole nerve nearer to the teased filaments
If stimulate in periphery than can use distance between stimulating electrode and recording electrode to calculate latency / speed of conduction (e.g. A vs C)
Teased fibre - advantages and disadvantages
✔︎ Very stable recording, good for classifying afferents and finding out how they respond (but can’t be taken much further)
✔︎ Big signal:noise ratio (very clean trace)
╳ no measure of perception (but in rats, can only do this through behaviour anyway)
╳ cut central terminal - degree of nerve injury has occurred
╳ cannot easily relate unit you are recording from to a particular cell body within the DRG, so ability to apply molecular biology techniques or genetics is very limited
╳ ethical considerations - terminally anaesthetised rats
What is microneurography? What are the advantages and disadvantages?
Introduce fine micro-electrode into nerve body itself - again record extracellular action potentials
✔︎ Can be done in humans
╳ can’t physically separate units - always get multiunit activity
╳ signal to noise ratio is low (lower quality of recording)
Low quality has led to development of the marking technique..
What is the marking technique?
C fibres exhibit activity-dependent slowing (when stimulated, their conduction velocity slows down)
- If stimulating nociceptor, then have some physical stimulation e.g. thermal stimulus, mechanical stimulus - see the slow latency is slowed even further, then comes back to normal when thermal/mechanical stimulation is removed: *this indicates that the unit you have stimulated, is the unit you have recorded from
How can selective blocks & selective activation be used?
Manipulating populations of afferents to infer whether they are involved in what you are studying
1) Compression to cutaneous branch of radial nerve: sensory changes to skin: first lose input from large myelinated A fibres
- → thinner, lightly myelinated A delta fibres → C fibres
2) Lidocaine/LA: blocks smaller afferents before they block larger afferents (C fibres → A delta → A beta)
Temporal method of segregating conduction velocity classes
3) Capsaicin: small dose = selective activation of subpopulation, high dose = selective desensitisation/ablation of subpopulation (clinically Quitenza 8% - used on allodynia patches in NP pain)
Broadly - what techniques should be brought together to get a global picture of nociception from molecular level to spinal pathways?
Psychophysics: multi fibre / multi level
Selective blocks: separate fibre populations
Electrophysiology: single fibres (teased fibre & microneurography with marking technique)
What is the difference between volar forearm & palm?
VF: thinner, different nociceptor population, hairy
Palm: densely innervated by low threshold afferents, glabrous (not hairy)
What kind of experiment was used to distinguish between fibre types in hairy/glabrous skin?
Psychophysics (Campbell + LaMotte): CO2 laser thermal stimulus, asked what they felt
Two peaks of response (latency vs number of responses: very hot temps (48), clear and quick pain response, lower temps (40)- slower onset pain response.
In between temps (42-45?) = two distinct sensations
First heat pain: clear quick response (first heat pain): well-localised, sharp, pricking
Second heat pain: slower onset, less well localised, burn/ache
Temporal distinction fits with faster & slower conducting fibres, and with different spinal circuits (discriminatory vs general discomfort)
What do A fibres respond to?
Most to innocous stimuli
Most AB = tactile afferents
SOME A delta = thermoreceptors & low threshold non-nociceptive mechanoreceptors
(note - it is not a case of C = nociception and A = not, also not a case of ad = nociceptive and ab = not)
What sensations do A fibre nociceptors serve?
- First / fast heat pain in hairy skin
- Fast / sharp mechanical pain
Pathology = PRIMARY heat hyperalgesia in HAIRY skin & TRANSMISSION of PUNCTATE MECHANICAL HYPERALGESIA (onto sensitised spinal neurons)
How do we know what purpose A fibres serve?
Treede et al. teased fibre single fibre recording in monkeys: looked at A and C fibres in hairy and glabrous skin
Laser, quick onset heat simulus: subcut and surface temp increased - frequency histogram against timecourse of stimulus - showed two types of AMH fibre (A mechano-heat nociceptors) response in HAIRY skin:
- Type II AMH (heat sensitive)
- Type I AMH (heat ‘insensitive’)
In glabrous skin, only type I response found* - controversy
Based on Treede’s work - what are the characteristics of the AMH Type II fibres?
Fire quickly at pain onset, then activity diminishes (little bit of baseline activity then drop off even with stimulus)
- Slower conduction velocity (CV) = 15m/s
- Lower heat threshold = 46°C (easier to activate)
- ‘Higher’ mechanical threshold
- Fast utilisation time
- Not seen in glabrous skin? (CONTROVERSY - depends on experimental design)
Based on Treede’s work - what are the characteristics of the AMH Type I fibres?
At onset of temp ramp, not much activity, then slowly builds then drops off
- Faster CV = 25m/s (like Aβ nociceptor range)
- Higher heat threshold >53°C
- ‘Lower’ mechanical threshold (easier to activate)
- Slow utilisation time
