Pain, Nociception and analgesia 2

Question 1

Describe transmission at nociceptor terminals- c and Adelta

Answer 1

1. Both primarily glutamatergic
2. C fibres also release substance P- Some also release CGRP
3. Activation of NMDA and NK-1 receptors causes central sensitisation

Question 2

What do different properties of AMPA and NMDA cause

Answer 2

1. glutamate binds both kinds of receptors at most synapses

2. The different properties of AMPA and NMDA receptors gives a fast and slow time course to the postsynaptic EPSP

Question 3

What does substance p do

Answer 3

1. Substance p activates Nk receptors
2. Gq protein is recruited and activates PIP2
3. PIP2 activates IP3 and DAG
4. IP3 increases Ca2+
5. DAG increase PKC
6. Activation of ion channel by Gq protein
7. Opening of ones permeable to Na/Ca
8. Inhibition of K+ ion channels

Question 4

Describe “Wind-up” of nociceptive transmission

Answer 4

1. First time primary afferent fibre is stimulated
2. Glutamate is released and substance p activates NK receptor
3. Causes depolarisation
4. If enough then action potential
5. If done multiple times the post synaptic response gets bigger each time
6. Similar to LPT
7. Synaptic plasticity

Question 5

Describe gate control of nociceptive transmission

Answer 5

1. Inhibitory interneurons release GABA
2. Mechanoreceptor has offshoot which activates inhibitory interneurone which inhibits nociceptive input
3. Why rubbing part of hurt body feels good

Question 6

Describe Supraspinal control of pain

Answer 6

1. Brain stimulation in animals inhibited nociceptive spinal neurones
2. Similar stimulation sites reduced behavioural response to noxious stimuli
3. In humans brainstem stimulation caused pain relief

Question 7

Describe descending pain pathway

Answer 7

1. Offshoots
2. Goes to area called PAG- periactal grey
3. Periaqueductal grey to raphe nucleus to spinal cord
4. Other goes to RVM-rostral ventromedial medulla
5. Locus coeruleus provides inhibitory input to spinal cord
6. Cortex, amygdala, thalamus provide input to PAG
7. Allows state control of pain
8. System allows you to push through pain

Question 8

Describe role of opioids

Answer 8

1. More periphery nerves activated more pain you feel
2. Opioid receptors on free nerve endings which are inhibitory
3. Less glutamate
4. Less nociceptive input
5. Opioid receptors in descending inhibitory pathway
6. PAG activates raphe nucleus which inhibits 5HT- less pain
7. Locus coeruleus inhibits noradrenaline production so less pain
8. Opioids excite PAG and Medulla- increases raphe nucleus- increases inhibition
9. All anti-nociceptive
10. Central sites of ENDOGENOUS analgesia – role of opioids

Question 9

What are some endogenous ligands of Opioid receptors

Answer 9

1. enkephalin and dynorphin are released by neurons

2. Beta-endorphin is a hormone released into the blood

Question 10

Which of the opioid receptors is the most important

Answer 10

1. All play a role in descending inhibitory
2. Nu is most important-
3. supraspinal site of analgesia is most prominent

Question 11

Describe Opioid receptors

Answer 11

1. All of opioid receptors are GPCRs- Gi/o type
2. If one opioid is released and activates receptors
3. Inhibition of AMP- reduction in cAMP
4. Inhibits PKA
5. Inhibition of Ca2+ ion channels
6. Activates k+ channels

Question 12

Describe actions of opioids in PAG

Answer 12

1. Opioid receptors are inhibitory
2. But have excitatory effect
3. From cortex/hypothalamus input into PAG
4. Provides positive excitatory input to PAG
5. Provides descending input
6. GABA inhibitory interneuron is activated and inhibits PAG neuron
7. Enkephalinergic/ endorphins activate opioid receptors on glutamatergic nerve terminal and on post synaptic terminal on gabanergic interneuron
8. Inhibit amount of glutamate released
9. Cause hyperpolarisation of interneuron
10. Inhibiting something which is inhibitory- net affect is excitatory

Question 13

Describe Opioid inhibition in the dorsal horn

Answer 13

1. Descending input from PAG/ raphe nuclei
2. Reaches spinal cord
3. First synapse in spinal cord where nociceptive input releases glutamate into second order projection neuron
4. Input from raphe nucleus releases 5HT generally 5HT3- ligand gates permeable to Na- excitatory
5. Enkephalin interneurone are inhibitory and are excited by 5HT3
6. Causes release of enkephalin and causes hyperpolarisation – inhibiting synapse
7. Input from locus coeruleus- is noradrenergic and goes straight to synapse where it releases noradrenaline and activates alpha 2 receptors
8. Alpha 2 receptors are Gi/o coupled and so also inhibitory

Question 14

Describe the Modulation of neuronal excitability in primary afferent

Answer 14

1. Action potential in primary afferent

2. Enkephalin decreases duration of action potential as it opens K+ channels

Question 15

Describe the Modulation of neuronal excitability in Post synaptic neuron electrical activity

Answer 15

1. At nerve terminal- depolarise post synaptic neuron
2. Enkephalin decreases depolarisation- opioid receptors inhibits amount of glutamate released
3. Opioid receptors activate k+ channels- hyperpolarisation of postsynaptic neuron