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Gabapentin, a novel anticonvulsant and analgesic, is a γ-aminobutyric acid (GABA) analogue but was shown initially to have little affinity at GABAA or GABAB receptors. It was recently reported to be a selective agonist at GABAB receptors containing GABAB1a-GABAB2 heterodimers, although several subsequent studies disproved that conclusion. In the present study, we examined whether gabapentin Gabapentin was designed as a GABA analog, and some studies have suggested that it modulates the action of the GABA synthetic enzyme, glutamic acid decarboxylase (GAD) and the glutamate synthesizing enzyme, branched-chain amino acid transaminase, resulting in increased GABA synthesis. 139 Gabapentin increases non-synaptic GABA responses from Gabapentin increases non-synaptic GABA responses from neuronal tissues in vitro. In vitro, gabapentin reduces the release of several mono-amine neurotransmitters. Gabapentin prevents pain responses in several animal models of hyperalgesia and prevents neuronal death in vitro and in vivo with models of the neurodegenerative disease amyotrophic Here we identify the neuronal thrombospondin receptor involved in CNS synapse formation as α2δ–1, the receptor for the anti-epileptic and analgesic drug gabapentin. This study suggested that the antiepileptic GABA analogue gabapentin (Neurontin) is an agonist at GABA(B) receptors expressing the GABA(B1a) but not the GABA(B1b) receptor subunit. Although it is rapidly absorbed, readily crosses the blood–brain barrier and is orally active in several animal models of epilepsy, gabapentin neither binds to GABA A or GABA B receptors nor is Gabapentin enhanced expression of δGABA A receptors and increased a tonic inhibitory conductance in neurons. This increased expression likely contributes to GABAergic effects as gabapentin caused ataxia and anxiolysis in wild-type mice but not δ subunit null-mutant mice. Although gabapentin was originally modeled after the structure of GABA, it does not modulate GABA receptor function like conventional GABAergic drugs, and it is inactive at GABA receptors. This review outlines several potential mechanisms of pharmacological action of gabapentin. Although gabapentin was designed as a structural analogue to γ-aminobutyric acid (GABA), it is inert at GABA receptors and synapses ().Instead, gabapentin binds with high affinity to the α2δ-1 protein and exerts its primary therapeutic effects through selective blockade of presynaptic voltage-gated calcium channels containing the α2δ-1 subunit (). Gabapentin, on the other hand, does not directly interact with GABA receptors. Instead, it binds to a specific subunit of voltage-gated calcium channels, known as the alpha-2-delta subunit. By binding to this subunit, Gabapentin reduces the release of excitatory neurotransmitters, such as glutamate, thereby decreasing neuronal excitability. Gabapentin selectively inhibits voltage-gated calcium channels, increases GABA transmission, and modulates excitatory amino acids at N-methyl-d-aspartic acid receptor sites . Thus opiates and gabapentin have certain shared mechanisms affecting analgesia. It is concluded that gabapentin is not an agonist at GABA(B) receptors that are functional in baclofen-induced antiallodynia in the postoperative pain model in vivo and in GIRK channel activation in ventrolateral PAG neurons in vitro. Although gabapentin does not directly modify GABA-A receptor function, it may indirectly increase tonic inhibition via enhanced expression of extrasynaptic receptors in specific brain regions including the cerebellum and hippocampus. The gabapentinoid drugs gabapentin and pregabalin are key front‐line therapies for various neuropathies of peripheral and central origin. Originally designed as analogs of GABA, the gabapentinoids bind to the α 2 δ‐1 and α 2 δ‐2 auxiliary subunits Generic Name Gabapentin DrugBank Accession Number DB00996 Background. Gabapentin is a structural analogue of the inhibitory neurotransmitter gamma-aminobutyric acid that was first approved for use in the United States in 1993. 16 It was originally developed as a novel anti-epileptic for the treatment of certain types of seizures 14,5 - today it is also widely used to treat neuropathic pain. 8 Gabapentin is a structural analog of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Its anticonvulsant, analgesic and anxiolytic properties suggest that it increases GABAergic inhibition; however, the molecular basis for these effects is unknown as gabapentin does not directly modify GABA type A (GABA A) receptor function, nor does it modify synaptic inhibition. The gabapentin receptor α2δ-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell 2009; 139: 380–392. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] In this study, we have investigated the effects of gabapentin on recombinant GABA(B(1a)) and GABA(B(1b)) receptors coexpressed with GABA(B(2)) in five different functional recombinant assays, its ability to inhibit [(3)H]GABA binding in a GABA(B) receptor-selective binding assay using rat synaptic membranes, and its ability to inhibit transient Gabapentin was formed by the addition of a cyclohexyl group to GABA, which allowed this form of GABA to cross the blood–brain barrier. Despite its structural similarity to GABA, gabapentin does interact with GABA receptors in the CNS. Its mechanism of action is unknown, but may involve enhanced neuronal GABA synthesis. Gabapentin, marketed for the treatment of seizures and neuropathic pain, has been shown to increase in vivo GABA concentration in the brain of both rodents and humans. Gabapentin effects on glutamate are not known.
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