Mechanism of immobility

[Ref: SH4:p35-38]

• Inhalational anaesthetic agents produce immobility
  * By acting on the spinal cord
  * NOT by acting on higher centres

Mechanisms

• Depression of excitation
  * e.g. AMPA and NMDA receptor-mediated currents
• Enhancement of inhibition
  * e.g. GABAa and glycine receptor-mediated currents
• Actions of Na+ channel (but not K+ channel)

However,

• Cholinergic receptors do not play a significant role
• Opioid receptors are not involved

NB:

From [SH4:p36]

"Overall, no inhaled anaesthetic action on a single group of receptors can explain immobility, and immobility as a result of concurrent actions on many receptors is unlikely"

--> ???

Inhibitory receptors

• Glycine receptors are major mediators of inhibitory neurotransmission in the spinal cord
  --> Mediates part of the immobility produced by inhalational anaesthetics
• GABAa receptors mediate immobility produced by IV anaesthetics

GABA and inhalational agent

• GABAa receptors probably do not mediate immobility produced by inhaled AA [SH4:p36]
• But at the same time, maximal enhancement of GABAa receptors also occurs at the partial pressure of AA used in clinical practice. [SH4:p38]

Excitatory receptors

• Glutamate is the principle excitatory neurotransmitter in CNS
• Glutamate receptors include G-protein coupled receptors and ligand-gated receptors
• Ligand-gated glutamate receptors include:
  * NMDA receptors
  * AMPA receptors
  * kainate receptors
• NMDA receptors are important mediators of immobility produced by inhaled AA
• AMPA mediates the initial (fast) component of excitatory postsynaptic transmission
  --> Likely to be also involved in immobility produced by inhaled AA
• Role of kainate receptors on MAC is unclear

NB:

[SH4:p37]

??? Inhaled AA acts on NMDA and AMPA receptors in the spinal cord

??? Inahled AA does not act on the same receptors in the brain

Sodium channel

• Inhaled AA does not inhibit voltage-dependent Na+ channels
• Inhaled AA inhibits presynaptic Na+ channel and/or voltage-gated calcium ion channel
  --> Inhibition of presynaptic release of neurotransmitter (especially glutamate)
• Thus, IV lidocaine decreases MAC (via its antagonism action on Na+ channels)