Pregabalin [S-[+]-3-isobutylGABA or (S)-3-(aminomethyl)-5-methylhexanoic acid, Lyrica] is an anticonvulsant and analgesic medication that is both structurally and pharmacologically related to gabapentin (Neurontin; Pfizer Inc., New York, NY). Previous studies have shown that pregabalin reduces the release of neurotransmitters in several in vitro preparations, although the molecular details of these effects are less clear. The present study was performed using living cultured rat hippocampal neurons with the synaptic vesicle fluorescent dye probe FM4-64 to determine details of the action of pregabalin to reduce neurotransmitter release. Our results indicate that pregabalin treatment, at concentrations that are therapeutically relevant, slightly but significantly reduces the emptying of neurotransmitter vesicles from presynaptic sites in living neurons. Dye release is reduced in both glutamic acid decarboxylase (GAD)-immunoreactive and GAD-negative (presumed glutamatergic) synaptic terminals. Furthermore, both calcium-dependent release and hyperosmotic (calcium-independent) dye release are reduced by pregabalin. The effects of pregabalin on dye release are masked in the presence of l-isoleucine, consistent with the fact that both of these compounds have a high binding affinity to the calcium channel alpha(2)-delta protein. The effect of pregabalin is not apparent in the presence of an N-methyl-d-aspartate (NMDA) antagonist [D(-)-2-amino-5-phosphonopentanoic acid], suggesting that pregabalin action depends on NMDA receptor activation. Finally, the action of pregabalin on dye release is most apparent before and early during a train of electrical stimuli when vesicle release preferentially involves the readily releasable pool.
"These compounds are useful in the treatment of a number of disorders, including epilepsy, but their modes of action are nonselective , and therefore, conclusions regarding the effects on GABA, particularly synaptic, are difficult to draw. The activity of these anticonvulsants include, but are not limited to, sodium and calcium channel modulation, mitochondrial neuroprotection, manipulation of the equilibrium with other neurotransmitters , and enzymatic induction or inhibition (Hendrich et al., 2008; Kudin et al., 2004; Micheva et al., 2006; Petroff et al., 1999a; Rogawski, 2006). More selective compounds, which modulate GABA directly, provide more pertinent tests of MRS sensitivity . "
"This binding inhibits the influx of Ca 2+ into the presynaptic terminals, which leads to a subsequent reduction in the release of neurotransmitters such as glutamate and substance P  . Experiments on cultured hippocampal neurons loaded with fluorescent dye in synaptic vesicles, have shown that calciumindependently occurring release of fluorescent dye is inhibited by PGB . Additionally, the frequency of spontaneously occurring miniature excitatory postsynaptic currents, which is independent of presynaptic Ca 2+ influx, is inhibited by gabapentin in the entorhinal cortex . "
[Show abstract][Hide abstract] ABSTRACT: Pregabalin is widely used as an analgesic for the treatment of neuropathic pain. In the present experiments using mouse spinal slices, we recorded electrically-evoked glutamatergic excitatory postsynaptic currents (eEPSCs) from superficial dorsal horn neurons. Pregabalin reduced the amplitude of eEPSCs, and increased the paired pulse ratio. Pregabalin also inhibited the frequency of spontaneously occurring miniature EPSCs without affecting their amplitude. Partial ligation of the sciatic nerve increased the expression of the calcium channel α2δ-1 subunit, and increased the presynaptic inhibitory action of pregabalin. Intrathecal injection of antisense oligodeoxynucleotide against the α2δ-1 subunit, decreased the expression of α2δ-1 mRNA in the spinal dorsal horn, and decreased pregabalin's action. These results provide further evidence that pregabalin exerts its presynaptic inhibitory action via binding with the α2δ subunit in a state-dependent manner. Furthermore, presynaptic actions of pregabalin were attenuated in knockout mice lacking the protein syntaxin 1A, a component of the synaptic vesicle release machinery, indicating that syntaxin 1A is required for pregabalin to exert its full presynaptic inhibitory action. These observations might suggest that direct and/or indirect interactions with the presynaptic proteins composing the release machinery underlie at least some part of pregabalin's presynaptic actions.
"It binds to the α2-δ subunit of presynaptic, voltage-dependent calcium channels that are widely distributed throughout the central and peripheral nervous system.[17–20] Pregabalin binds to the α2-δ subunit six times more potently than gabapentin and thereby reduces the release of several neurotransmitters like glutamate, norepinephrine, serotonin, dopamine, and substance P.[22–27] As with gabapentin, pregabalin is inactive at GABAA and GABAB receptors, is not metabolically converted into GABA, and does not alter the GABA uptake or degradation.[28–30] "
[Show abstract][Hide abstract] ABSTRACT: Pregabalin is a gamma-amino-butyric acid analog shown to be effective in several models of neuropathic pain, incisional injury, and inflammatory injury. In this review, the role of pregabalin in acute postoperative pain and in chronic pain syndromes has been discussed. Multimodal perioperative analgesia with the use of gabapentinoids has become common. Based on available evidence from randomized controlled trials and meta-analysis, the perioperative administration of pregabalin reduces opioid consumption and opioid-related adverse effects in the first 24 h following surgery. Postoperative pain intensity is however not consistently reduced by pregabalin. Adverse effects like visual disturbance, sedation, dizziness, and headache are associated with higher doses. The advantage of the perioperative use of pregabalin is so far limited to laparoscopic, gynecological, and daycare surgeries which are not very painful. The role of the perioperative administration of pregabalin in preventing chronic pain following surgery, its efficacy in more painful surgeries and surgeries done under regional anesthesia, and the optimal dosage and duration of perioperative pregabalin need to be studied. The efficacy of pregabalin in chronic pain conditions like painful diabetic neuropathy, postherpetic neuralgia, central neuropathic pain, and fibromyalgia has been demonstrated.
Journal of Anaesthesiology Clinical Pharmacology 07/2011; 27(3):307-14. DOI:10.4103/0970-9185.83672
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