Bind ligand


Figure I-52. Basic mechanism of action of anticonvulsants in pain therapy at the GABAA-channel resulting in a hyperpolarization and an inhibition of further impulse generation

Ligand-gated ion channel

Figure I-53. Activity of anticonvulsants on ligand-gated ion channels, whereby an agent binds to the extracellular portion of the receptor, and via proteinkinases or phosphatases induced activation of ion channels results in an inward shift of sodium or potassium, resulting in depolarization or hyperpolarization of the postsynaptic neuron

Mnrfutfillan of HypcfCXOilPti Xlcurnn

With Pregabalm'

Mnrfutfillan of HypcfCXOilPti Xlcurnn

With Pregabalm'

Voltage-gated calcium channel Ca2+






Dimothtftone EltWiusiTWa

Figure I-54. Mode of action of analgesics on voltage-gated calcium channels resulting in a closure with a reduced inward shift oltage-gated sodium channel

Open Inactivated


A = »ctivBtion gale; I - Inacttvalion gale.

Figure 1-55. The voltage-gated sodium ion channel as a target for antiepileptic agents in the treatment of pain via inactivation of the sodium channel period (it is refractory), during which membrane depolarization cannot reopen it. During neuronal hyperactivity, such as in seizures and in neuropathic pain, the neuron undergoes depolarization and fires action potentials at higher frequencies. Inhibition of firing with drugs is due to the ability of the sodium channel to recover from inactivation, the refractory period is prolonged and the frequency of action potentials reduced. Carbamazepine, lamotrigine, phenytoin and valproic acid all work at this mechanism (Figure I-55).

The NMDA subtype of the glutamate receptor is an ion channel, which operates both by a ligand-gated and voltage gated mechanisms. In order to operate, the NMDA-receptor channel has to bind glutamate in the presence of glycine. In addition, non-NMDA-induced depolarization is needed to remove the magnesium. This is done through activation of the NK1- (substance P) receptor, after which sodium and calcium pass through the open channel. NMDA-receptor antagonists, which are able to inhibit this transfer act as anticonvulsants (e.g. carbamazepine, felbamate), at the same time are potent analgesics (Figure I-56).

In addition to the NMDA subtype of the glutamate receptor, there is the AMPA and the kainite (KA) receptor subtype. Both induce sensitivity and lower the threshold for activation of the excitatory NMDA-receptor. Decreasing the threshold for sensitivity via blockade of the non-NMDA-receptors will result in a reduced excitation with a reduced activation of nociceptive afferents (Figure I-57).

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