Lecture 30; Pain transduction One;

Question 1

What transduces pain?

Answer 1

Free nerve endings: Receptor channels are specific for stimulus

Question 2

Write some notes on free nerve endings;

Answer 2

◦Varying stimuli (heat, mechanical and chemical)
◦Pseudounipolar
◦AdFibers (first or fast pain) (more myelinated)
◦C Fibers (second or slow)

Question 3

Write some notes on the pains a delta afferents;

Answer 3

◦Medium diameter and myelinated
◦Type I: (HTM, chemical and Temp >50C) Mech
◦Type II: (lower temp and higher mechanical threshold) Temp

Different thresholds to stimulus in different fibres

Question 4

Write some notes on pain type c afferents

Answer 4

C Fibers
◦Small diameter and unmyelinated
◦Polymodal (CMHs) (multiple modes/stimuli)
◦Silent nociceptor (subset) (mediate pleasant touch)

Question 5

Write short notes on silent nocioceptors, a subset of type c fibres;

Answer 5

Heat responsive and Mechanically insensitive
More responsive to Chemical
◦Capsaicin (heat/spicy) ◦Histamin

Probably activated during inflammation

Question 6

How can polymodal nocioceptors be further subdivided?

Answer 6

Based on mechanism of communication:

Peptidergic

non-peptidergic

Question 7

Write notes on pepterdgic nocioceptors;

Answer 7

Can release molecules to regulate its environment

◦Releases Substance P and calcitonin-gene related peptide
◦Has TrkA neurotrophin receptor for NGF

Can respond to inflammation factors

Question 8

Write notes on non-peptidergic nocioceptors;

Answer 8

◦c-Ret neurotrophinreceptor for Glial-derived NF

◦P2X3 receptor for ATP

Question 9

What is the heat receptor?

Answer 9

TRPV1

Question 10

Write notes on TRPV1;

Answer 10

◦TRPV1 (threshold approx 43 degrees C)
Capsaicin and Heat Sensitive and currents similar
Enhanced by proalgesic and proinflammatory agents

Mice lacking channes INsensitive to noxious heat

TRPV 2,3 and 4 provide differing thresholds (multiple isoforms)

Question 11

What are proalgesic?

Answer 11

Something that enhances perception of pain

Question 12

Write notes on TRPV1 function;

Answer 12

Capsacin molecule binds intracellularly to the recptor

Ion channel

Heat opens it (Na and Ca influx)

Depolarisation (transient as multiple channels must be opened)

Question 13

What are the types of cold receptors?

Answer 13

TRPM8
TRPA1
K+ channels TREK1 and TRAAK8

Question 14

Write some notes on TRPM8;

Answer 14

TRPM8 (Activation 25 degrees C)

Cold and Menthol sensitive
Deficient mice lack cold sensitivity (96%)
Not in same region as TRPV1

Question 15

Write some notes on TRPA1

Answer 15

TRPA1 (Activation 12 degrees C)
Cold, Icilinand Menthol sensitive
Could contribute to TRPM8 insensitive cold

Question 16

Write some notes on K+ channels TREK1 and TRAAK8

Answer 16

Modulate cold sensitivity

Question 17

What are the type of pain mechanoreceptors in the skin?

Answer 17

◦High threshold mechanoreceptors type C and slow adapting Ad fibers

Question 18

Describe how pain mechanoreceptors function;

Answer 18

◦Lack evidence as a mechanosensor function, suggestions;
Acid Sensitive Ion Channels (ASICs)
TRPV 2 & 4 (Mainly osmotic stretch)
TRPA1 (May modulate)
KCNK

Question 19

Where do type c and a delta fibres project to in the dorsal horn?

Answer 19

Type C;
- Zone one and interneurons in zone 2- (regulates zone one second order neuron)

A delta fibres;
- Zone one and seperate zone 5 pathway

Question 20

Describe type c fibre projection into the dorsal horn;

in depth

Answer 20

C-Fibers: LaminaeI & dorsal part of II
Non-peptitergic: mid-region of II
Interneurons: Ventral part of II (enhanced pain sensitivity)
◦Excitatory: PKC
◦Linked with persistent pain
◦Targeted by myelinated non-pain afferents

(can take non-pain fibres to generate pain i.e sun-burn is touched and this response is transferred into a pain stimulus too to prevent further damage)

Question 21

What other fibres in the dorsal horn are associated with type c fibres but dont terminate in region 1,2

Answer 21

Wide dynamic range neurons = C-fibers in LaminaeV
◦Responds to wide range of stimuli
◦Convergence of Somatic and Visceral (generation of referred pain)

Idea; pain integration starts at the dorsal horn.

Question 22

What is the pain pathway in the spine?

Answer 22

Anterolateral System (ALS)

Question 23

What systems are within the ALS?

Answer 23

◦Direct-spinothalamic (a delta)
◦Indirect-spinoireticular (type c)
◦Spinomesencephalic
◦Spinotectal
◦spinohypothalamic

First word is where from, second is where to

Demonstrates potential integration points

Question 24

Describe the direct-spinothalamic pathway;

Answer 24

◦Ad Afferents synapse with second order neurons
◦Adfibers in Lamina V
◦Axons of 2ndorder neurons cross midline
◦Ascends along the anterolateralpathway
◦Along lateral and anterior spinothalamic tracts
◦Ventral posterior lateral and inferior nucleus

Question 25

Write some notes on the spinoreticular tract;

Answer 25

Indirect pathway
◦85% of nociceptive information
◦C fibers synapse at Lamina I and II
◦Lamina I 2ndOrder Lamina II Interneuron
◦Suggestion Interneuron synapse multiple
◦2ndorder ipsilateral and contralateral

Question 26

Go to greys and just learn the pathways by drawing and noting down land marks

Answer 26

now

Question 27

What is of note of the spinoreticular pathways;

Answer 27

Multiple reticular formation synapse prior to thalamic projection.

This is to allow reflexes, thalamic sensing, motor responses Intergration!!!!!

Question 28

Write some notes on the spinomesenphelic pathway;

Answer 28

Spinomesencephalic (multiple intergration points including;)
◦Terminate in periaqueductal grey (PAG) and Raphe
◦Descending pain inhibition pathway

Also goes via parabrachial nucleus (PB) to amygdala
◦Emotional processing (enhancement to perceive pain is a learnt process)

Question 29

What is the function of the spinohypothalamic and spinotectal pathways?

Answer 29

Autonomic and reflex responses

Question 30

What is the visceral pain pathway?

Answer 30

Dorsal Column-Medial lemniscus pathway

Question 31

Write some notes on the Dorsal Column-Medial lemniscus pathway

Answer 31

◦Visceral afferents synapse to 2ndorder neuron
◦Dorsal horn of lumbar-sacral spinal cord
◦Some 2ndorder transmit via ALS (Referred pain)
◦Some through dorsal column (Medial)

Question 32

What causes referred pain?

Answer 32

Second order neurons (convergance with peripheral pain pathways)
◦Transmitting via ALS peripheral pain pathway
◦Terminating in regions associated with pain
◦Regional distribution
◦Based on where afferent synapse with 2ndorder

Question 33

What can mediate acute pain transduction?

Answer 33

Voltage gated Na and Ca channels

Question 34

Write notes on voltage gated Na channels in acute pain

Answer 34

Subtypes alter sensitivity

Targeted for pain relief

Question 35

Write notes on voltage gated Ca channels in acute pain

Answer 35

Up regulated in nerve injury

Question 36

Describe the second order neuron synapses;

Answer 36

Second order neurons
◦Transmitting via ALS peripheral pain pathway
◦Terminating in regions associated with pain
◦Regional distribution
◦Based on where afferent synapse with 2ndorder

Question 37

What is gate theory?

Answer 37

Type c second order neuron inhibition via GABA (interneurons mediate this)