Week 3: Central Sensitisation

Question 1

How does peripheral sensitisation contribute to central sensitisation?

Answer 1

Increased outputs from primary afferent terminals (ie nociceptor in the periphery?) increases the excitability of postsynaptic neurons directly and through activation of secondary mechanisms

Question 2

What happens broadly during central sensitisation?

What does this result in?

Answer 2

• State of hyper-excitability in the CNS
• Includes both dorsal horn of the spinal cord and the brain

Results in…
- Increases the response to input from injured/inflamed site (a sensitive CNS)

• Increases the response from regions adjacent to and remote from the injured site (smudging)

Question 3

What is dorsal horn sensitisation/wind up?

Answer 3

• Refers to the interaction between 1st order afferents and 2nd order neurons in the dorsal horn.
• Repetitive C fibre activation by noxious stimuli sensitises the dorsal horn (wind up)
• The volume is being turned up
• Disinhibition from higher centres

Question 4

At the dorsal horn what is the normal signalling?

How does this change in a sensitised state?

Answer 4

Normal signalling
- Electric impulses of 1st order afferent fibres arrive at the dorsal horn
- Calcium channels from 1st order neurons release neurotransmitters into the synaptic cleft (Glutamate = excitatory amino acid, substance P, peptide & CGRP - peptide)
- These neurotransmitters act on receptors on 2nd order neurons (AMPA) & (NMDA)

Sensitised state
- Brief nociceptive stimuli only activate AMPA receptors
- With sufficient nociception and subsequent release of peptides (substance P), the peptides produce membrane depolarisation and the magnesium ion block is removed from NMDA receptors
- Glutamate is now able to activate NMDA receptors as well as AMPA receptors
- Net result is increased activation of 2nd order neurons sending danger signals to brain (volume is turned up for a little while)

*Biologically advantageous - however with repeated nociceptive input this can result in long-term potentiation - a persistent increase of synaptic efficiency

Question 5

In a sensitised what type of receptors are activated? Why aren’t others activated?

Answer 5

AMPA only.

At resting state the NMDA receptors are blocked by magnesium ions.

Question 6

Central sensitisation occurs with repetitive firing of primary nociceptors. This leads to:

• Sustained release of …… and the …… substance P and CGRP by nociceptors leading to sufficient membrane …… to force Mg2+ to leave the ….. pore, allowing increased …. influx and increasing the …… rate of projector neurons (ie increasing ….. to higher centres)
• ….. oxide along with ……. can act as retrograde transmitters increasing the output from …… afferent terminals (ie more …. mediators from the primary nociceptor)
• ….. from the primary nociceptors can activate other nearby neurons (ie spreading of the signal)
• Sustained activation of the projection neuron leads to transcriptional changes that result in increased ….. and. ….. receptors which increase the ….. of the second neuron, thus ……. a state of central sensitisation

Answer 6

1. Glutamate, neuropeptides, depolarisation, NMDAR, calcium, firing, nociception.
2. Nitric, glutamate, primary, excitation.
3. CGRP
4. NMDA and AMPA-R, excitability & maintaining.

Question 7

Summarise dorsal horn sensitisation

Answer 7

Activation of NMDA receptors on 2nd order neurons (hyperalgesia)

A-delta afferents activate 2nd order neurons (allodynia)

Decreased inhibition (disinhibition)

Question 8

What is smudging?

Answer 8

Increased synaptic efficiency of primary afferents and their connectivity resulting in broader and less defined receptive fields.

Question 9

What is disinhibition?

Answer 9

Disinhibition occurs when dorsal horn neurons are more susceptible to activation by excitatory inputs including non-nociceptive a-fibres and is a key mechanism in triggering and maintaining central sensitisation.

Question 10

Features of disinhibition

Answer 10

• Noradrenergic projections synapse on the projection neurones and can excite projection neurons.
• There is reduction in inhibitory input from descending centres on excitatory interneurons
• There is reduction in excitatory input from descending centres on opioid interneurons which would inhibit primary nociceptors and excitatory interneurons