Molecular Mechanisms of Pain 2

Question 1

what laminae do peptidergic neurones synapse and what do they release ?

Answer 1

synapse in laminae 1 and outer laminae 2

produce substance P, neurokinases and CGRP

Question 2

what laminae do a delta myelinated fibres synapse ?

Answer 2

outer laminae 2 and lamina 5

Question 3

what laminae do non-peptidergic c fibres synapse in ?

Answer 3

inner laminae 2

Question 4

in the spinal pain pathway where do 2nd order neurons project to ?

Answer 4

branches projecting to the thalamus but also to other regions such as rostral lateral ventral medulla, PAG, parabrachial nucleus and amygdala and limbic system
amygdala and limbic system is involved in emotional pain- fear and panic
PAG- major hub for descending inhibitory pathways

Question 5

what is the gate control theory of pain ?

Answer 5

it is like a gate in the spinal cord which can reduce nociceptive inputs to the brain - it suppresses nociceptive inputs
SG is heavily involved
- it contains inhibitory interneurons which cause inhibition of 2 nd order neurones = suppress excitation
- receives inputs fro the descending inhibitory pathways from PAG
- receives inputs from non-noxious fibres such as a beta fibres

Question 6

describe the trigeminal pathway for pain and temperature ?

Answer 6

trigeminal system is the 5th cranial nerve

• 1st order afferent from the face project to pars interpolaris and pars caudalis of medulla/upper cervical cord
• 2nd order neurones ascend contralaterally to the thalamus (via trigemino-thalamic tract)
• 3rd order neurones project to the cortex

Question 7

what is innervated by the trigeminal pain pathway ?

Answer 7

innervate specialised structures e.g. tooth pulp has only c and a-delta fibres

Question 8

what are the types of pain ?

Answer 8

physiological= acute 
pathological= inflammatory and chronic 

chronic pain is persistant and hard to treat

Question 9

what does central sensitisation cause ?

Answer 9

chronic pain e.g. pain produced from damage to peripheral fibres or central fibres
- sometimes the peripheral fibres can fire spontaneously= ectopic firing and this causes the 2nd order neurones to become more excitable

Question 10

define central sensitization:

Answer 10

refers to the process through which a state of hyperexcitability is established in the CNS, leading to enhanced processing of nociceptive message (woolf, 1983)
- it can cause hyperalgesia or allodehnia

Question 11

what is the NMDA mediated signalling involved in central sensitization ?

Answer 11

stimulation of c and a-delta fibres increases the release of Glutamate, substance P, CGRP and ATP which increases NMDA signalling and it causes upregulation of NMDA receptors and this makes the cells more sensitive to glutamate and therefore more excitable

Question 12

how is disinhibition involved in central sensitisation ?

Answer 12

it causes reduced signalling because it is inputs from descending inhibitory pathways
these release glycine and GABA

Question 13

how is microglia activation involved in central sensitisation ?

Answer 13

like macrophages in the immune system, when inflammation occurs microgia infiltrate the area and they release lots of trophic factors such as BDNF and this causes expression of NMDA receptors
- they also release lots of cytokines which can directly activate 2nd order neurones

glia contribute massively to pathological pain

Question 14

what is the role of glia in central sensitisation ?

Answer 14

microglia cause the release of TNF-alpha which stimulates astrocytes to release CCL2 which causes the activation of neurons
t
- the ccl2 bins to ccr2 receptors and somehow this talks to NMDA receptors to potentiate them

Question 15

what happens when chemokines are released by glial cells after neuropathic injury ?

Answer 15

the activity of NMDA receptors in the dorsal horn neurones increases

the 2nd order response is twice as large

Question 16

what is FHM?

Answer 16

familial hemiplegic migraine

it is an autosomal dominant subtype of severe migraine accompanied by visual disturbances known as aura

Question 17

what causes aura ?

Answer 17

it is caused by cortical spreading depression - a slowly advancing wave of tissue depolarisation in the cortex

Question 18

what are the majority of cases of FHM caused by ?

Answer 18

caused by gain of function mutations within the neuronal cav2.1 voltage gated calcium channel gene -PQ channel
- this mutation causes increased calcium flow into dendrites and excessive release of excitatory neurotransmitter glutamate

Question 19

what ignites CSD?

Answer 19

ignited by local elevation of extracellular potassium levels in pockets of intense excitatory transmission- this shifts the equilibrium state to more depolarised voltages

Question 20

what happens to CSD in FHM ?

Answer 20

the threshold for CSD initiation is reduced with mutations in the CAV2.1 calcium channel because the higher calcium levels in the dendrites facilitates glutamate release and therby increases the likelihood that potsssium will reach the CSD threshold

Question 21

how does phantom pain occur ?

Answer 21

its caused by an amputated limb

• the nerve which is severed is still connected to the brain and this stump will be able to generate ectopic firing
• if the nerve injury is extensive then it caan cause permanent damage and which can produce constant ectopic firing and this will cause constant pain

Question 22

what mechanisms are involved n neuropathic pain ?

Answer 22

both central and peripheral

Question 23

where do afferent terminals synapse ?

Answer 23

synapse onto neurones of lamina 1 and 2 (substantia gelatinosa)