The termination of action of biogenic amines norepinephrine (NE) and serotonin (5-HT) is determined by reuptake into the presynaptic terminal. Drugs that block reuptake, such as tricyclic antidepressants, increase the efficacy of those transmitters by allowing them to remain in the synaptic cleft and activate the receptors longer (Figure I-51).
It should be noted that although the exact mechanism of action of TCAs as analgesics is not known, there appears to be a close relationship between the inhibitory reuptake effects on biogenic amines and analgesic potency. While selective inhibitors of serotonin reuptake are less effective in treating pain, the ability to inhibit norepineprine reuptake is associated more strongly with analgesia. The dose of TCAs is lower than those dosages used to treat depression, suggesting that the analgesic properties are independent of their antidepressant properties.
Aside from TCAs specific antidepressant activity, neuronal hyperexcitability associated with pain is reduced through the mechanism of a decrease in sodium channel activity and GABAa-receptor channel activation. The net effect of these actions by anticonvulsants is to reduce the excitatory synaptic transmission or to enhance the inhibitory synaptic transmission. For instance GABA, which is an inhibitory ligand binds to the GABAA-receptor, thus opening the GABAA-channel, which hyperpolarizes the cell and inhibits further impulse generation. The GABAA-channel has at least five different binding sites (Figure I-52).
In addition, there are three different kinds of sites at which anticonvulsants exert their action:
1. Voltage-gated ion channel of the sodium/calcium type
2. Ligand-gated ion channel receptors
3. Combination of voltage-gated and ligand-gated ion channel/receptors
The ligand-gated ion channel binds excitatory neurotransmitters such as glycine and glutamate on the extracellular portion of the receptor. Via secondary intracellular phosphorylation process of protein kinases, a nearby ion channel opens for Na+-and K+-ions, causing an end-plate potential with either depolarization or hyperpo-larization of the postsynaptic neuron, depending on whether the ligand which binds to them is of excitatory or inhibitory nature (Figure I-53).
There are four main types of voltage-dependent calcium channels, each composed of several subunits: L-Type, T-Type, N-Type and P-Type. Each type of calcium channel is activated and inactivated at different voltage ranges and at different rates. Representative examples are ethosuximide and valproic acid which inhibit ion flow through the calcium T-channel (Figure I-54). The newer voltage dependent calcium
Figure I-50. Summary of schematic representation of the targets receptor sites and their mode of action of different analgesics
channel blocker pregablin acts via the alpha2-subunit resulting in a modulation of the hyperexcited neuron (Figure I-54).
Another type of a voltage-gated channel is selective for the sodium ion. The sodium channels open in response to membrane depolarization, allowing an inward shift of sodium ions into the neuron, thus increasing neuronal depolarization and the spread of action potentials. After the channel closes, it remains inactive for a certain
Activity in tigand-gated ion channel
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