Current Neuropharmacology, Vol. 1, No. 3, 2003
Contents
Neuropharmacology
of Gabapentin
Guest
Editor: Roderick H. Scott
Pharmacology and Therapeutics of Gabapentin in the
Treatment of Psychiatric Disorders; Present and Future Perspectives Pp.
187-197
J.L. Megna , M.M. Iqbal
and A. Aneja
Symptomatic Treatment of Chronic Neuropathic Pain with
Gabapentin Clinical Practice and Research Prospective Pp. 199-202
Misha-Miroslav Backonja
Anticonvulsant Action and Long-term Effects of Gabapentin
Pp. 203-208
M.R. Cilio
Calcium Channel a2d Subunits: Structure, Functions and Target
Site for Drugs Pp. 209-217
Carles Cantí, Anthony Davies and Annette C. Dolphin
Cellular Actions of Gabapentin and Related Compounds on
Cultured Sensory Neurones Pp. 219-235
Roderick H. Scott , Duncan J. Martin and David McClelland
Gabapentin-Mediated Effects on Voltage- and Ligand-Gated
Currents Pp. 237-244
Alessandro Stefani and Atticus Henry Hainsworth
Molecular Mechanisms Determining Opposed Functional
States of Microglia Pp. 245-265
Kazuyuki Nakajima , Tadashi Kurihara and Shinichi Kohsaka
Role of the GABAA Receptor in Anxiety:
Evidence from animal models, molecular and clinical psychopharmacology, and
brain imaging studies Pp. 267-283
Abstracts
[Back to top]
Pharmacology and Therapeutics of Gabapentin in the Treatment of Psychiatric
Disorders; Present and Future Perspectives
J.L. Megna , M.M. Iqbal and A. Aneja
Gabapentin is an antiepileptic drug, which decreases neuronal excitability and may act by increasing the availability of gamma-aminobutyric acid or by inhibiting Ca2+ channels. It has safe pharmacokinetic and side effect profiles. Not surprisingly, it has been tested as a treatment in a number of psychiatric conditions. The most robust evidence exists for it as an efficacious treatment in both social phobia and panic disorder. However, the extant literature indicates that it also holds promise in the treatment of other anxiety disorders, alcohol and cocaine dependence, nonrefractory bipolar disorder, as well as in behavioral agitation. Further, controlled, investigations of gabapentin’s effectiveness in these disorders/conditions merit due consideration, especially given their associated morbidity and lost productivity.
[Back to top]
Symptomatic Treatment of Chronic Neuropathic Pain with Gabapentin Clinical
Practice and Research Prospective
Misha-Miroslav Backonja
[Back to top] Anticonvulsant
Action and Long-term Effects of Gabapentin
M.R. Cilio
Gabapentin (GBP), one of the newer antiepileptic drugs (AEDs), is a structural analogue of gamma –aminobutyric acid (GABA), initially approved for add-on treatment of partial seizures in patients 12 years and older and now widely used also in younger patients. Recent studies demonstrated its efficacy not only as adjunctive therapy but also as monotherapy for patients with partial seizures. GBP has an extremely low propensity to cause drug interactions and is well tolerated. The main adverse effects reported are behavioral disorders, such as hostility and mood swings. Recent data, showing increased GBP clearance in children, indicate the potential need for higher doses in young patients. The goal of seizure control in pediatric patients with epilepsy must be balanced against the long-term effects of AEDs on brain function and development. The anticonvulsant action and the long-term effects of GBP on learning, memory and behavior were investigated in studies on immature animals using models of temporal lobe epilepsy and status epilepticus (SE). These data demonstrated that acute administration of a single dose increases the seizure threshold at all ages studied, while chronic treatment following SE reduces spontaneous seizure frequency and cell damage and has no long-term adverse consequences on cognitive processes during development.
[Back
to top] Calcium Channel a2d
Subunits: Structure, Functions and Target Site for Drugs
Carles Cantí, Anthony Davies and Annette C. Dolphin
In this review we describe the genes encoding a2bsubunits, their topology and predicted structure. We then review the electrophysiological effects of a2bsubunits. It is clear from most studies that a2bsubunits increase channel density at the plasma membrane, but there is less agreement between studies and between channel subtypes concerning the effects of a2bsubunits on voltage-dependence of activation and inactivation. Most studies agree that a2bsubunits increase the kinetics of inactivation, for a number of different calcium channel subtypes. We also discuss the link between a2bsubunits and disease, particularly in terms of Ducky, the spontaneously occurring mutant mouse strain that has mutations in a2b2, and exhibits cerebellar ataxia and absence epilepsy. Finally, we will examine the evidence that a2b subunits are the site of action of the anti-epileptic, anti-nociceptive drug gabapentin.
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Cellular Actions of Gabapentin and Related Compounds on Cultured Sensory
Neurones
Roderick H. Scott , Duncan J. Martin and David McClelland
In this review we outline the actions of gabapentin and pregabalin on the excitability of sensory dorsal root ganglion (DRG) neurones in culture and compare these effects with those seen in other neuronal and cultured cell preparations. We also consider the potential mechanisms of action of gabapentin and pregabalin that may contribute to their anti-nociceptive effects.
Gabapentin and pregabalin have similar actions and at saturating concentrations do not have additive effects suggesting that they act at the same or closely associated sites. The only high affinity binding sites yet identified for these drugs are a2d-subunits (types 1 and 2 but not 3 and 4) of voltage-activated Ca2+ channels. Consistent with this are the findings that gabapentin and pregabalin both attenuate Ca2+ influx through voltage-activated channels and these inhibitory actions may in part provide a mechanism by which multiple firing of action potentials in sensory neurones is reduced. However, it is clear that gabapentin and pregabalin have a number of novel characteristics. Although structural analogues of GABA they appear to act independently of GABA receptor activation in sensory neurones. The actions of gabapentin and pregabalin on sensory neurones are not consistent with selective effects on particular high voltage-activated Ca2+ channel subtypes (L, N, P, Q and R) yet a significant proportion (at least 50%) of the whole cell Ca2+ current is insensitive to these drugs. Cell culture conditions can alter Ca2+ channel subunit expression in such a way as to reduce sensitivity to gabapentin and this can be used to identify potential sites of action of this drug. Analysis of subunit mRNA in cell populations with different sensitivities to gabapentin surprisingly indicated that Ca2+ channel b2-subunits as well as a2d-subunits may determine Ca2+ channel sensitivity to gabapentin in DRG neurones.
In addition to Ca2+ channels, gabapentin and pregabalin modulate other whole cell currents, and in particular a delayed enhancement of voltage-dependent K+ conductances has been observed in cultured DRG neurones. The delayed and prolonged features of this enhancement of voltage-activated K+ currents may reflect gabapentin and pregabalin modulating channel activity via intracellular signalling pathways either via a surface receptor interaction leading to the production of a second messenger or by directly acting at intracellular sites.
The wide variety of therapeutic effects achieved with gabapentin and pregabalin offer a considerable challenge when trying to determine cellular mechanisms of action of these apparently simple synthetic compounds.
[Back to top] Gabapentin-Mediated
Effects on Voltage- and Ligand-Gated Currents
Alessandro Stefani and Atticus Henry Hainsworth
Gabapentin (°Neurontin) is currently utilised in the treatment of a range of neurological and psychiatric conditions, including partial epilepsy, neuropathic pain and bipolar disorders. Gabapentin (GBP) mechanisms of action, although extensively investigated, are only partially known. This review examines GBP-mediated effects on voltage- and ligand-gated neuronal ionic currents. GBP binds in vivo to the alpha-2-delta sub-unit of the calcium channel and, in dorsal root ganglia, GBP-induced modulation of calcium conductance plays a central role in the drug’s inhibitory effect on pain transmission. Less clear is the relevance of GBP as a calcium current modulator in central neo-cortical neurons and the potential use of GBP as add-on therapy for resistant seizures. GBP is also reported to interact with NMDA receptor currents, inwardly rectifying potassium channels and a subtype of baclofen-sensitive-receptors. The potential utility of GBP in modifying the balance among released endogenous amino-acids, and also in neuroprotection, has been suggested. It is, however, unclear whether - and through which cellular pathways - GBP might give therapeutic benefit in the course of neurodegenerative disorders.
[Back to top] Molecular
Mechanisms Determining Opposed Functional States of Microglia
Kazuyuki Nakajima , Tadashi Kurihara and Shinichi Kohsaka
Microglia are bone marrow-derived, monocyte-lineaged cells in the central nervous system (CNS). They are considered to serve as sensor cells, receiving a variety of alterations in the circumstances and responding with morphological and functional transformations. These responses of microglia in the injured or the pathologically damaged brain have been generally described as "microglial activation". The main function of the activated microglia is to serve at the defense line of the CNS as brain macrophages/scavengers, and as immune or immunomodulator cells. Furthermore, microglia are supposed to regulate the survival, growth, and functions of neurons and other glial cells by producing a wide variety of physiologically active substances. They can actually produce both deleterious factors to induce neuronal cell death/degeneration and the trophic/protective molecules for neurons. The molecular mechanism by which the activated microglia are oriented in a harmful or a protective state was investigated by comparing both signal transduction molecules and the secretion of harmful and trophic molecules. As a result, p38MAPK activation was proved to be crucial for the induction of harmful factors, and PKC activity to be additionally required for the harmful state. In conclusion, the signal transduction pathway including p38MAPK activation linked to PKC activity is required for the induction of deleterious factors in microglia.
[Back to top] Role
of the GABAA Receptor in Anxiety: Evidence from animal models,
molecular and clinical psychopharmacology, and brain imaging studies
Several converging lines of evidence from molecular, animal, and clinical studies have demonstrated that the gamma-aminobutyric type A (GABAA) receptor complex plays a central role in the modulation of anxiety. While currently available therapeutic agents that act on this receptor (e.g., benzodiazepines) are effective anxiolytics, they are limited by side effects, tolerance, and abuse potential. Promising strategies to address these limitations include the development of subunit-selective agonists and partial agonists, which specifically ameliorate anxiety without causing sedation or motor impairment. In vivo neuroimaging studies have identified several limbic and paralimbic brain regions involved in the generation or modulation of anxiety and fear responses, suggesting that the neuroinhibitory processes of GABAA receptors may be localized in certain brain areas which may serve as specific sites for drug action. Indeed, neurochemical brain imaging studies have reported decreased ligand binding to GABAA benzodiazepine receptors in prefrontal and medial temporal cortex in a variety of anxiety disorders. This paper reviews recent findings from molecular neuropsychopharmacology and in vivo neuroimaging of GABAA benzodiazepine receptors which offer novel perspectives on the genesis of normal anxiety and on pathophysiology of anxiety disorders. Collectively, these findings suggest several potentially successful avenues for future development of GABAA receptor-mediated anxiolytic treatments, and prompt further exploration of this neurochemical system in pathogenesis of anxiety disorders.