PREFACE [ Hot Topic: Neuropharmacology of Gabapentin (Guest Editor: Roderick H. Scott)]

The role of serendipity in scientific research and in drug development is significant; if under appreciated. It is reported that we all make our own luck. The rational design of a drug that might mimic the actions of a major inhibitory neurotransmitter γ-aminobutyric acid) formed part of an antiepilepsy drug discovery program. The finding that this drug didn't mimic the transmitter but had antiepileptic properties anyway must have made some folk smile. Subsequently, the discoverers of gabapentin must have jumped with joy as this antiepileptic drug was found to have such diverse uses in pain clinics and in psychiatry. A major part of this impressive success story has been the ground-breaking off-label use of gabapentin for clinical cases that have escaped sensitivity to established therapies. This strategy, of investigating a spectrum of potential applications of drugs that dampen down neuronal excitability, has proved fruitful. The low incidence of reversible minor side effects produced by gabapentin makes gabapentin particularly exciting as a therapy for a wide variety of nervous system disorders. Therefore the clinical studies of gabapentin have been driving our understanding of the actions of gabapentin and related drugs. The basic understanding of the biological actions of the gabapentin particularly at the molecular level, really lags behind the clinical work. Substantial further investigations are required. However, a major success has been the discovery of high affinity binding sites for gabapentin and related compounds such as pregabalin. Tantalisingly, the binding sites are α2δ accessory sub-units of voltage-activated Ca2+ channels but there are some ugly anomalies in this near fairy story. Understanding the modulatory mechanism by which gabapentin and pregabalin attenuate Ca2+ flux, through differently assembled voltage-activated channels is starting to appear like quite a mountain to climb. Important areas of research are detailed studies of the molecular and cellular actions of gabapentin to improve our understanding of the drug's actions, to enable the design and evaluation of compounds with similar or better activities. However, it appears likely that gabapentin produces a number of complex molecular responses and one unifying theory of action may not be enough for this apparently simple molecule. This issue of Current Neuropharmacology includes six review articles in which the authors report and explore the recent findings in clinical and basic research on gabapentin. The paper by J.L. Megna, M.M. Iqbal & A. Aneja reviews aspects of the recent clinical use of gabapentin in psychiatry. A personal account is then presented by M.- M. Backonja of his experiences with gabapentin in a specialist pain clinic. These have been breakthrough clinical areas of research, and to quote Misha Backonja, “gabapentin has set a new standard in neuropathic pain research and therapy”. M.R. Cilio presents a review on the use of gabapentin as an antiepileptic drug and particularly considers its use in young people and assessments in animal models. In this review M.R. Cilio also discusses potential long-term adverse consequences of chronic gabapentin treatment on cognitive processes during development. The other end of the spectrum, on cellular and possible molecular actions of gabapentin and related compounds is the focus of the other reviews. C. Canti, A. Davies & A.C. Dolphin present a detailed and highly focused review on the α2δ accessory sub-units of voltage-activated Ca2+ channels; the highest affinity binding site for gabapentin, so far identified. Some of their data raises rather a spectre for gabapentin researchers! R.H. Scott, D.J. Martin & D. McClelland provide a review of cellular actions of gabapentin on cultured sensory neurones in the context of other studies carried out to investigate potential molecular mechanisms of action of this drug. A. Stefani & A. Hainsworth describe the cellular actions of gabapentin both in peripheral and central neurones and they evaluate our present understanding of the relationship between the effects of gabapentin on neuronal ion channels with the drug's clinical usage.