Molecular mechanisms of pain 1

Question 1

define nociception :

Answer 1

refers to the physiological processes involved in detecting and transducing sensory signals from tissue injury - sensory processing

Question 2

what is the bell theory of pain ?

Answer 2

idea was that there was a bell in the brain with cords attached spreading throughout the body

Question 3

why is normal pain healthy?

Answer 3

because it is protective and prevents you hurting yourself

Question 4

why are nociceptive nerves interesting ?

Answer 4

because they are very long but they are still just a single nerve= pseudounipolar
- can be 1m loong in mammals and go from PNS all the way to CNS

Question 5

what is pregabalin ?

Answer 5

drug that acts at voltage gated calcium channels - dont know how it works though

Question 6

what are the different types of pain ?

Answer 6

physiological and pathological

• acute pain is part of physiological pain - it is healthy because it helps you to avoid bodily harm and the pain is only persistant for a short time - it overlaps with inflammatory pain
• inflammatory ad chronic pain are part of pathological pain- inflammatory pain can be both helpful and unhelpful because it can tell you when something is wrong
• chronic pain is not useful or healthy, it is pain that surpasses its necessary signalling e.g. neuropathic pain or arthritic pain- it is resilient to treatment with analgesics

Question 7

what is the major nt in pain circuitry /

Answer 7

glutamate

Question 8

how does pain start ?

Answer 8

starts with excitation of peripheral nerves

- initiation can occur from CNS but it is rarer

Question 9

when is a primary nociceptive signal formed ?

Answer 9

when an action potential is fired by a nociceptive neuron - it requires ion channels to produce excitation in response to pain
- the majority of the channels are non-selective

Question 10

what are specific sensory ion channels ?

Answer 10

specific for sensory nerves - sensory SO ligang gated channels

• they are mechanosensitive channels that respond to external stimulation- piezo 1 and 2
• can respond to chemical mediators and this is a component of inflammation

Question 11

what are the single modality receptors ?

Answer 11

thermal and mechanical

Question 12

what are polymodal receptors /

Answer 12

they are mechanical, thermal and chemical

Question 13

what are the afferents involved in pain?

Answer 13

unmyelinate c or thinly myelinated A delta fibres

• c = slow dull pain
• A delta= sharp fast pain

Question 14

what are the majority of fibres in the DRG ?

Answer 14

c fibres -60-70%

Question 15

what are a alpha/beta fibres ?

Answer 15

large diameter fibres associated with low threshold mechanoreceptors
- some fraction of A beta fibres contribute to nociception

Question 16

what are a delta and c fibres ?

Answer 16

small diameter slow conducting afferents associated with nociceptors and thermoreceptors

Question 17

what does CGRP label ?

Answer 17

labels specifically peptidergic nociceptors - those that express substance P, neurokinin and CGRP
- the releasee of these substances in the periphery can cause neurogenic inflammation

Question 18

what does IB4 label?

Answer 18

this is a marker of small non-peptidergic neurones

Question 19

what does NF200 label ?

Answer 19

labels only large neurones

Question 20

what is TRPV1 are marker for ?

Answer 20

small nociceptive neurones

it is a heat sensitive channel

Question 21

what did labelling with both NF200 and Kv7.2 show ?

Answer 21

NF200 labels non-nociceptive neurons and Kv7.2 is a gene associated with pain neurones so there was bascically no overlap between them

Question 22

what are immunohistochemical markers used for ?

Answer 22

used for characterisation of proteins expressed in various nociceptor types
- detetc which neurones express which ion channels

Question 23

what is different about the ion channels expressed in nociceptors ?

Answer 23

nociceptors tend to express channels that are rarely expresssed in other parts of the body

Question 24

what sodium channels are expressed in nociceptors ?

Answer 24

voltage gated sodium channels
Nav 1.7, 1.8 and 1.9
they are necessary for APs
they are almost exclusively expresssed in pain neurons
problem with just targetting these ones is that they are very simila to the other sodium channels

Question 25

what sensory TRP channels are present in nociceptors ?

Answer 25

TRPV1 - reacts to capsaicin, nociceptve heat is >42 and it also responds to inflammation TRPM8- responds to cold pain and inflammation TRPA1- this is the true noxious cold sensory, also sensitive to menthol

Question 26

what purinergic ligand gated channels are present in nociceptors ?

Answer 26

P2X2 and P2X3 these are ATP sensitive channels they are not exclusively expressed in nociceptors but they are more highly expressed there

Question 27

what is the cold plate test ?

Answer 27

mice are placed on a cold plate which the controller can alter the temperature of observe the changes in the number of jumps in the mice

Question 28

what happens to mice on the cold plate test when TPRA1 is knocked out ?

Answer 28

they dont jump on the cold plate because they are insensitive to the cold

Question 29

what is congenital indifference to pain ?

Answer 29

rare disease characterised by an inability to experience the feeling of pain - this is very dangerous because you cause damage to your self

Question 30

what gene appears to be mutated in congenital pain disease ?

Answer 30

mutation in the Nav 1.7 gene - the patients have nociceptors but they aree unable to send APs - the majority of these mutations are loss of function mutations

Question 31

how are mediators involved in pain ?

Answer 31

they can be released during the immune response and can affect peripheral nerves enabling the sensation of pain - they can induce inflammation - bradykinin, substance P, histamine, interleukins - there are many different receptors present to bind these chemical mediators

Question 32

what are type 1 inflammatory mediators?

Answer 32

act to directly activate ligand gated ion channels - ATP - act at P2X receptors - H+ - act at TRPV1 and ASIC receptors

Question 33

what are the type 2 inflammatory mediators ?

Answer 33

act via activation of GPCRs - prostaglandins - substance P - bradykinin - proteases- act at PARs - histamine

Question 34

what are type 3 inflammatory mediators?

Answer 34

act via activatio of receptor tyrosine kinases - TREK A and TREK B - NGF - BDNF

Question 35

what are the type 4 inflammatory mediators ?

Answer 35

gasotransmitters - CO - NO - H2S

Question 36

what are the different signalling cascades involved in inflammatory nociception ?

Answer 36

- activation/sensitisation of sensory channels to cause APs - modulation of ion channels through intracellular signalling cascades - modulation of gene expression - greater expression can lead to hyperalgesia

Question 37

explain the events that occur due to activation of p2 receptors by ATP ?

Answer 37

the alpha-beta-me ATP agonist for P2X receptors activates the channels and causes a transient burst of activity UTP actiivates the P2Y receptors and P2Y receptor is a GPCR so this activation causes much longer burst of activity

Question 38

what doe NGF, insulin and IGF-1 do to TRPV1 channels ?

Answer 38

induce production of more of these channels | - increase P13K which causes Sre to increase TRPV1

Question 39

what is alodenhia ?

Answer 39

something that is not normally painful but becomes painful e.g pain from sunburn in the shower

Question 40

what does bradykinin do ?

Answer 40

it inhibits voltage gated potassium channels - M channels | - causes resting membrane potential to become less controlled

Question 41

define pain :

Answer 41

an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage is the perceptual experience arising from nociception and has both psychological and physiological components