Gabapentin is a medicine that may be used for the treatment of certain seizure disorders or nerve pain.
Gabapentin belongs to a class of drugs called anticonvulsants. A class of drugs is a group of medications that work in a similar way. These drugs are often used to treat similar conditions.
It’s not fully understood how gabapentin works. For postherpetic neuralgia, it seems to prevent the increase in sensitivity to pain that occurs. For seizures, it may alter the effect of calcium (low levels of calcium may cause seizures).
Experts aren’t sure exactly how gabapentin works, but research has shown that gabapentin binds strongly to a specific site (called the alpha2-delta site) on voltage-gated calcium channels. This action is thought to be the mechanism for its nerve-pain relieving and anti-seizure properties.
Gabapentin enacarbil (brand name Horizant) is a prodrug of gabapentin which has been designed to overcome the limitations of gabapentin, such as poor absorption and a short duration of action. Gabapentin enacarbil is effective for restless legs syndrome (RLS) and postherpetic neuralgia (nerve pain that occurs following Shingles).
Gabapentin belongs to the group of medicines known as anticonvulsants.
Gabapentin is a new chemical compound designed as a structural analog of GABA that is effective in the treatment of partial seizures. In contrast to GABA, gabapentin readily penetrates the blood–brain barrier. In man, gabapentin has been demonstrated to increase GABA concentrations [126]. Most probably the mechanism of action is related to events modulated through its interaction with a receptor thought to be associated with the L-system amino acid carrier protein. However, the primary mechanism of action remains to be defined.
The mechanism of gabapentin in neuropathic pain
Gabapentin is an anti-epileptic agent but now it is also recommended as first line agent in neuropathic pain, particularly in diabetic neuropathy and post herpetic neuralgia. α2δ-1, an auxillary subunit of voltage gated calcium channels, has been documented as its main target and its specific binding to this subunit is described to produce different actions responsible for pain attenuation.
The binding to α2δ-1 subunits inhibits nerve injury-induced trafficking of α1 pore forming units of calcium channels (particularly N-type) from cytoplasm to plasma membrane (membrane trafficking) of pre-synaptic terminals of dorsal root ganglion (DRG) neurons and dorsal horn neurons.
Furthermore, the axoplasmic transport of α2δ-1 subunits from DRG to dorsal horns neurons in the form of anterograde trafficking is also inhibited in response to gabapentin administration. Gabapentin has also been shown to induce modulate other targets including transient receptor potential channels, NMDA receptors, protein kinase C and inflammatory cytokines. It may also act on supra-spinal region to stimulate noradrenaline mediated descending inhibition, which contributes to its anti-hypersensitivity action in neuropathic pain.
Gabapentin has no direct GABAergic action and does not block GABA uptake or metabolism. Gabapentin blocks the tonic phase of nociception induced by formalin and carrageenan, and exerts a potent inhibitory effect in neuropathic pain models of mechanical hyperalgesia and mechanical/thermal allodynia.
Gabapentin binds preferentially to neurons in the outer layer of the rat cortex at sites that are distinct from other anticonvulsants [20]. It is likely that gabapentin acts at an intracellular site as the maximal anticonvulsant effect is achieved 2 h after an intravenous injection of gabapentin in rats. This occurs after the plasma and interstitial fluid concentrations have peaked and reflects the additional time required for intraneural transport .
Several theories have been proposed to explain the cellular mechanism of its anticonvulsant effect. The most favoured theory involves an interaction with an as yet undescribed receptor linked with the l‐system amino acid transporter protein.
Suman Chauhan et al. demonstrated that l‐amino acids potently inhibited binding of an␣active enantiomer of gabapentin ([3H]gabapentin). This was further supported by Taylor et al. who showed that the potent anticonvulsant, 3‐isobutyl GABA (an analogue of gabapentin) potently and stereoselectively bound to the same receptor. These findings renewed interest in the isolation of the receptor protein that may responsible for this anticonvulsant effect.
Other proposed biochemical events in the central nervous system (CNS) that may explain its anti‐epileptic effect include the increased extracellular GABA concentrations in some regions of the brain caused by an increase in activity of glutamic acid decarboxylase that produces GABA, and a decreased breakdown by GABA decarboxylase. Although a study , using magnetic resonance imaging (MRI) spectroscopy showed a global increase in GABA in the brain after the administration of gabapentin, there is no evidence that gabapentin increases intraneuronal GABA concentrations, binds GABAA or GABAB receptors, or exerts any GABA‐mimetic action .
Other effects of gabapentin have been described but are not considered to play a significant pharmacodynamic role. These include small decreases in the release of monoamine neurotransmitters (dopamine, noradrenaline and serotonin) and the attenuation of sodium‐dependent action potentials (suggesting sodium channel blockade) after prolonged exposure to gabapentin .
The mode of action of gabapentin in the treatment of neuropathic pain has not been fully elucidated. Although early studies indicated that gabapentin had only a central anti‐allodynic effect, gabapentin has been shown to inhibit ectopic discharge activity from injured peripheral nerves .
The mechanisms of the anti‐allodynic effects of gabapentin proposed include: CNS effects (potentially at spinal cord or brain level) due to either enhanced inhibitory input of GABA‐mediated pathways (and thus reducing excitatory input levels); antagonism of NMDA receptors; and antagonism of calcium channels in the CNS and inhibition of peripheral nerves [29-46]. Of these, antagonism of the NMDA receptor and calcium channel blockade have the most supporting evidence. Field et al.
Discounted an antihyperalgesic action via opioid receptor binding after demonstrating that morphine tolerance does not alter the efficacy of gabapentin and naloxone does not reduce its antihyperalgesic effect.
Research into a peripheral site of action for gabapentin has produced contradictory results . Intrathecal administration of gabapentin blocks thermal and mechanical hyperalgesia without affecting sympathetic outflow or acute nociception, and this suggests a spinal site of action . Patel et al. demonstrated a presynaptic site of action for gabapentin in the rat spinal cord.
Although gabapentin does not bind to GABAA or GABAB receptors, increased synthesis and reduced breakdown of GABA have been described . Potentiation of inhibitory GABA‐ergic pathways seems unlikely to be responsible for its anti‐allodynic effect because GABA receptor antagonists do not reduce this effect .
The NMDA receptor complex is a ligand‐gated ion channel that mediates an influx of calcium ions when activated. The NMDA receptor complex has a number of binding sites for various ligands that regulate its activity, including the strychnine‐insensitive glycine binding site, phencyclidine binding site, polyamine binding site, redox modulatory site and a proton‐sensitive site. Partial depolarisation of the neuron after glutamine activation will release a magnesium plug and allow calcium influx into the neuron.
These receptors are known to be found in high concentrations in the hippocampus and have been attributed a key role in the process of central sensitisation of painful stimuli, commonly known as the ‘wind‐up’ phenomenon, leading to hyperalgesia.
Evidence linking gabapentin to the NMDA receptor follows research demonstrating the reversal of the antihyperalgesic effect of gabapentin by d‐serine, an agonist at the NMDA‐glycine binding site . However, receptor binding studies have failed to demonstrate a direct binding site for gabapentin at the NMDA receptor .
The α2δ subunit of the voltage‐dependent calcium channel is a binding site for gabapentin and the S‐isomer of pregabolin (S‐(+)‐3‐isobutylgaba) . Because only gabapentin and the S‐isomer of pregabolin produce antihyperalgesic effects, it is postulated that the antihyperalgesic action for gabapentin is mediated by its binding to this site on the voltage‐dependent calcium channel. Fink et al. showed that, in the rat neocortex, gabapentin inhibits neuronal calcium influx in a concentration‐dependent manner by inhibiting P/Q‐type calcium channels.
The decreased calcium influx reduces excitatory amino acid (e.g. glutamate) release leading to decreased AMPA receptor activation, and noradrenaline release in the brain.
These findings support the hypothesis that calcium channel inhibition mediates the analgesic effects of gabapentin in chronic neuropathic pain. A decrease in potassium ion‐evoked glutamate release from rat neocortical and hipppocampal slices by gabapentin has been demonstrated .
