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PubMed1993

[3H]gabapentin may label a system-L-like neutral amino acid carrier in brain.

The ability of large neutral amino acids to interact with a site in mouse and pig brain labelled by [3H]gabapentin was examined. As previously described for rat tissue, [3H]gabapentin bound to synaptic plasma membranes prepared from mouse or pig cerebral cortex with high affinity (Kinetically derived KD = 14 and 17 nM for mouse and pig, respectively). Equilibrium binding in each species was inhibited by gabapentin and a range of large neutral amino acids. L-leucine (IC50 = 80 nM), L-isoleucine (IC50 = 72 nM), L-norleucine (IC50 = 40 nM) and L-methionine (IC50 = 50 nM) were the most potent of those tested. Binding was also inhibited by L-phenylalanine (IC50 = 380 nM), L-valine (IC50 = 310 nM) and the selective system-L substrate 2-amino-2-carboxy-bicycloheptane (IC50 = 420 nM) but not by the sodium-dependent System-A substrate methylaminoisobutyric acid. The presence of a submaximal concentration of leucine reduced [3H]gabapentin binding affinity but did not affect the maximum number of binding sites, suggesting a competitive interaction between leucine and the binding protein. The results suggest [3H]gabapentin may label a site in brain that resembles the large neutral amino acid transporter described in other tissues.

Acetates↗
PubMed2006

Oral gabapentin treatment for symptomatic Heimann-Bielschowsky phenomenon.

PURPOSE: To describe a patient with symptomatic Heimann-Bielschowsky phenomenon (HBP) treated successfully with oral gabapentin. DESIGN: Interventional case report. METHODS: A 57-year-old patient with retinitis pigmentosa had a 12-month history of vertical oscillopsia. The right visual acuity was 20/200 and the left visual acuity was 20/60 with glasses. He had a coarse, slow, pendular, vertical movement of the right eye consistent with Heimann-Bielschowsky phenomenon. His treatment commenced with oral gabapentin with gradual increase in dose to 2400 mg/d. Eye movement recordings were performed before and after treatment. RESULTS: He became considerably less symptomatic on gabapentin. The right visual acuity improved to 20/80 with glasses. Eye movement recordings confirmed markedly reduced vertical oscillations of the right eye. The patient continues on gabapentin with no side effects and sustained effect. CONCLUSIONS: The vertical nystagmoid movement in HBP can be considerably reduced and symptoms remarkably improved when treated with oral gabapentin.

Administration, Oral↗
PubMed2004

Estradiol-induced changes in the activity of hippocampal neurons in network culture are suppressed by co-incubation with gabapentin.

The ovarian steroid hormone estradiol, in addition to its function in the maintenance and regulation of reproductive capacity, can alter neuronal excitability. Estradiol is proconvulsant, increases neuronal excitability and decreases the threshold for seizure activity. Over one-third to one-half of women with epilepsy experience catamenial seizures, which are seizures influenced by cyclical hormone changes. These hormone-sensitive seizures respond to the anti-epileptic drug gabapentin, which is a structural analogue of the inhibitory amino acid neurotransmitter GABA. We studied the effects of 17-beta-estradiol alone and estradiol co-incubated with gabapentin on neuronal activity in network cultures of rat hippocampal neurons using a fluorescent calcium binding dye fluo-3 AM, FM 1-43 labeling of synaptic vesicles and electrophysiological recordings. Significant changes in the neuronal network activity were observed in the estradiol-treated neuronal cultures; the reactivity of the neurons to KCl depolarization induced intracellular calcium changes, and FM 1-43 destaining was increased as was the frequency of spontaneous miniature excitatory postsynaptic currents (mEPSC). All these excitatory effects of estradiol were nullified by co-incubating the neurons with a combination of estradiol and gabapentin. This suggests that gabapentin can indeed affect the estradiol-induced changes in neuronal network hyperexcitability by influencing the neuronal calcium levels, exocytosis and synaptic activity. Our findings could provide an understanding of the cellular basis of hormone-sensitive seizure control by gabapentin.

2-Amino-5-phosphonovalerate↗
PubMed2005

Effect of systemic and intrathecal gabapentin on allodynia in a new rat model of postherpetic neuralgia.

Patients with postherpetic neuralgia often have an increased sensitivity to a tactile stimulus but impaired thermal sensitivity in the same affected dermatomes. We recently found that depletion of capsaicin-sensitive afferents by systemic treatment with a potent TRPV1 agonist, resiniferotoxin, in adult rats produces long-lasting paradoxical changes in mechanical and thermal sensitivities, which resemble the unique clinical features of postherpetic neuralgia. The anticonvulsant gabapentin is effective in reducing the subjective pain score in patients with postherpetic neuralgia. In this study, we quantified the potential effect of systemic and intrathecal gabapentin on tactile allodynia induced by resiniferotoxin in rats. Intraperitoneal injection of 200 microg/kg resiniferotoxin produced a rapid and sustained increase in the paw withdrawal latency to a radiant heat stimulus. Profound tactile allodynia developed in all the resiniferotoxin-treated rats within 3 weeks. Intraperitoneal injection of 30-60 mg/kg of gabapentin in resiniferotoxin-treated rats significantly increased the withdrawal threshold in response to von Frey filaments. Furthermore, intrathecal administration of 10-30 microg of gabapentin also produced a significant effect on the mechanical withdrawal threshold in all resiniferotoxin-treated rats. These data provide complementary new information that gabapentin administered systemically and spinally can effectively relieve tactile allodynia in this animal model of postherpetic neuralgia.

Amines↗
PubMed2006

Randomized, placebo-controlled trial of baclofen and gabapentin for the treatment of methamphetamine dependence.

OBJECTIVE: To conduct a 16-week, randomized, placebo-controlled, double-blind trial of two GABAergic medications, baclofen (20 mg tid) and gabapentin (800 mg tid), for the treatment of methamphetamine dependence. METHODS: Adults with methamphetamine dependence were randomized to one of three conditions for 16 weeks: baclofen (n = 25), gabapentin (n = 26) or placebo (n = 37). All participants attended clinic thrice weekly to receive study medication and psychosocial counseling, complete study assessments, and provide urine samples. RESULTS: No statistically significant main effects for baclofen or gabapentin in reducing methamphetamine use were observed using a generalized estimating equation (GEE). A significant treatment effect was found in post hoc analyses for baclofen, but not gabapentin, relative to placebo among participants who reported taking a higher percentage of study medication (significant treatment group and medication adherence interaction in GEE model of methamphetamine use). CONCLUSIONS: While gabapentin does not appear to be effective in treating methamphetamine dependence, baclofen may have a small treatment effect relative to placebo. Future studies evaluating the effectiveness of baclofen and other GABAergic agents for treatment of methamphetamine may be warranted.

Adult↗
PubMed2006

Neurochemical evidence that supraspinally administered gabapentin activates the descending noradrenergic system after peripheral nerve injury.

We have previously demonstrated that gabapentin supraspinally activates the descending noradrenergic system to produce analgesic effects after peripheral nerve injury. To further establish the neurochemical basis for its supraspinally mediated analgesic action, concentrations of spinal noradrenaline, 4-hydroxy-3-methoxyphenylglycol (MHPG), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and dopamine were measured using high-performance liquid chromatography in a murine neuropathic pain model that was prepared by partial ligation of the sciatic nerve (the Seltzer model). Intracerebroventricularly (i.c.v.) administered gabapentin (100 and 300 microg) increased the spinal MHPG concentration and the MHPG/noradrenaline ratio and alleviated mechanical hypersensitivity, whereas the concentrations of noradrenaline, 5-HT, 5-HIAA and dopamine were unchanged. By contrast, i.c.v. gabapentin neither affected the spinal MHPG concentration and MHPG/noradrenaline ratio nor exhibited analgesic effects in animals subjected to a sham operation. In addition, spinal monoamine levels in ligated animals were not changed after intrathecal administration of gabapentin which however generated analgesic effects. Thus, the supraspinally mediated analgesic effects of gabapentin are correlated with an increase in spinal noradrenaline turnover.

Amines↗
PubMed2006

Gabapentin depresses C-fiber-evoked field potentials in rat spinal dorsal horn only after induction of long-term potentiation.

C-fiber-evoked field potentials in response to electrical stimulation of the sciatic nerve were recorded in the dorsal horn of the rat lumbar spinal cord, and their long-term potentiation (LTP) was induced by high-frequency stimulation applied on the sciatic nerve as a synaptic model of hypersensitivity underlying an increased efficacy of nociceptive transmission. We evaluated the effect of gabapentin on the basal C-fiber-evoked field potentials and their established LTP. Intravenously administered gabapentin (10 and 30 mg/kg, i.v.) reduced the LTP of C-fiber-evoked field potentials in a dose-dependent manner when applied 60 min after establishment of the LTP. However, gabapentin did not affect the basal C-fiber-evoked field potentials or induction of the LTP. Thus, gabapentin was effective only in sensitized conditions. By contrast, morphine HCl (1 and 3 or 10 mg/kg, i.v.) reduced both the basal responses and their established LTP. The combination of gabapentin and morphine at lower doses of each drug appeared to result in a stronger reduction on the established LTP than that of each drug alone, suggesting that combination therapy can generate better analgesia in the treatment of chronic pain.

Amines↗
PubMed2004

Gabapentin may inhibit synaptic transmission in the mouse spinal cord dorsal horn through a preferential block of P/Q-type Ca2+ channels.

Gabapentin is a lipophilic analog of gamma-amino butyric acid (GABA) with therapeutic activity against certain forms of epilepsy and neuropathic pain. Despite its structural similarity to GABA, it does not bind GABAA or GABAB receptors and the mechanism, especially of its analgesic action, has remained elusive. Here, we have studied its effects on synaptic transmission mediated by the major spinal fast excitatory and inhibitory neurotransmitters, L-glutamate and glycine, in the superficial layers of the spinal cord dorsal horn, a CNS area, which is critically involved in nociception. Gabapentin reversibly reduced evoked excitatory postsynaptic currents mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA-EPSCs) and inhibitory postsynaptic currents mediated by glycine (gly-IPSCs). Inhibition of AMPA-EPSCs and gly-IPSCs occurred with similar potencies (approximately 10-50 nM) and by about the same degree (approximately 40% at 1 microM). Gabapentin did not affect membrane currents elicited by exogenously applied glutamate or glycine arguing against a postsynaptic site of action. Selective blockade of N-type Ca2+ channels with omega-conotoxin GVIA dramatically increased and blockade of P/Q-type channels with omega-agatoxin IVA strongly attenuated inhibition of evoked synaptic transmission by gabapentin. These results show that gabapentin affects both excitatory and inhibitory spinal neurotransmission via a presynaptic mechanism which preferentially involves P/Q-type Ca2+ channels.

Acetates↗
PubMed2005

Spinal-supraspinal serotonergic circuits regulating neuropathic pain and its treatment with gabapentin.

Not all neuropathic pain patients gain relief from current therapies that include the anticonvulsant, gabapentin, thought to modulate calcium channel function. We report a neural circuit that is permissive for the effectiveness of gabapentin. Substance P-saporin (SP-SAP) was used to selectively ablate superficial dorsal horn neurons expressing the neurokinin-1 receptor for substance P. These neurons project to the brain as shown by retrograde labelling and engage descending brainstem serotonergic influences that enhance spinal excitability via a facilitatory action on 5HT(3) receptors. We show the integrity of this pathway following nerve injury contributes to the behavioural allodynia, neuronal plasticity of deep dorsal horn neurons and the injury-specific actions of gabapentin. Thus SP-SAP attenuated the tactile and cold hypersensitivity and abnormal neuronal coding (including spontaneous activity, expansion of receptive field size) seen after spinal nerve ligation. Furthermore the powerful actions of gabapentin after neuropathy were blocked by either ablation of NK-1 expressing neurones or 5HT(3) receptor antagonism using ondansetron. Remarkably, 5HT(3) receptor activation provided a state-dependency (independent of that produced by neuropathy) allowing GBP to powerfully inhibit in normal uninjured animals. This circuit is therefore a crucial determinant of the abnormal neuronal and behavioural manifestations of neuropathy and importantly, the efficacy of gabapentin. As this spino-bulbo-spinal circuit contacts areas of the brain implicated in the affective components of pain, this loop may represent a route by which emotions can influence the degree of pain in a patient, as well as the effectiveness of the drug treatment. These hypotheses are testable in patients.

Action Potentials↗
PubMed2002

Clinical predictors of response to lamotrigine and gabapentin monotherapy in refractory affective disorders.

BACKGROUND: The objective of the current study was to examine possible clinical predictors of positive response to lamotrigine or gabapentin monotherapy in treatment-refractory affectively ill patients. METHODS: Forty-five patients with treatment refractory bipolar (n = 35) or unipolar (n = 10) affective disorder participated in a clinical study evaluating six weeks of treatment with lamotrigine, gabapentin, or placebo monotherapy given in a double-blind, randomized fashion with two subsequent cross-overs to the other agents. Patients received daily mood ratings and weekly cross-sectional scales. Much or very much improved on the Clinical Global Impression scale modified for bipolar illness was considered a positive response. Degree of response was correlated with a number of baseline demographic and course of illness variables in a univariate analysis and then by linear regression. RESULTS: Response rates to lamotrigine (51%) exceeded those to gabapentin (28%) and placebo (21%). A positive response to lamotrigine monotherapy was associated with a bipolar diagnosis; fewer hospitalizations; fewer prior medication trials; and male gender (of which the latter two variables survived logistic regression). For gabapentin, degree of response correlated with shorter duration of illness; younger age; and lower baseline weight (with the latter two surviving linear regression). CONCLUSIONS: In this highly treatment-refractory population, lamotrigine appeared most effective for male patients with fewer prior medication trials. Gabapentin monotherapy, although not better than placebo, appeared most effective in those with younger age and lower baseline weight. These preliminary data in a treatment refractory subgroup may help in the further definition of the range of clinical utility of these widely used anticonvulsants.

Acetates↗
PubMed2000

A microdialysis study on the mechanism of action of gabapentin.

To gain insight into the mechanism of action of the anti-epileptic, gabapentin, the effects of gabapentin on the in vivo extracellular gamma-aminobutyric acid (GABA) levels in the rat substantia nigra reticulata were studied using microdialysis. In order to investigate possible interference with different GABA-ergic compartments in the substantia nigra reticulata, we studied the effects of gabapentin under basal, K(+)-, nipecotic acid- and glutamate-stimulated conditions. Intraperitoneally (i.p.) administered gabapentin, at a dose of 100 mg/kg, did not significantly affect extracellular GABA levels under any condition. Thus, our data do not support the involvement of nigral GABA release in the mechanism of action of the anti-epileptic gabapentin.

Acetates↗
PubMed1999

Gabapentin decreases the severity of dystonia at low doses in a genetic animal model of paroxysmal dystonic choreoathetosis.

The effects of the gamma-aminobutyric acid (GABA)-potentiating drug gabapentin (1-(aminomethyl) cyclohexaneacetic acid) on severity of dystonia were examined in a hamster model of idiopathic paroxysmal dystonic choreoathetosis. In the genetically dystonic hamster (dt(sz)) recent pharmacological and neurochemical studies suggested that disturbed GABAergic inhibition is involved in the pathogenesis. In line with a case report of beneficial effects in human paroxysmal dystonic choreoathetosis, gabapentin reduced the severity of dystonia in mutant hamsters at doses of 5 and 10 mg kg(-1) i.p. At higher doses (20 and 100 mg kg(-1)), gabapentin, however, failed to exert antidystonic effects. The GABApotentiating activity of gabapentin could explain the antidystonic effects of low doses, while the loss of efficacy at higher doses may be due to other mechanisms of gabapentin.

Acetates↗
PubMed1998

The natural history and the effects of gabapentin in amyotrophic lateral sclerosis.

Glutamate excitotoxicity seems to play an important role in the aetiopathogenesis and progression of Amyotrophic Lateral Sclerosis (ALS). Gabapentin is a modulator of the glutamatergic system and has been shown to prolong survival in the transgenic model of familial ALS. It has also been demonstrated to slow the decline of arm strength in human sporadic cases. The aim of our study was to assess the effects of different dosages and duration of treatment of gabapentin on the natural history and survival of ALS patients. A total of 110 patients affected by definite ALS entered the study. After a 6-12 month period of observation, patients were randomly assigned to receive oral gabapentin 500 mg/day (Group A) or 1000 mg/day (Group B) for 6 months. In addition a group of patients received gabapentin 500 mg/day for 6 months and 1000 mg/day for a further 6 months (Group C). A group of 121 patients referred to our Institute, who received only symptomatic treatment, was considered as the control group (Group D). Each patient was seen at entry and every 3 months. All average slopes were negative but the comparison of all slopes showed a trend toward a slower rate of decline of muscle strength loss in all treated groups of patients compared with the control group. The differences were statistically significant. Analysis between the pretreatment and treatment period showed a statistically significant decrease of the decline of muscle strength and Norris score during the treatment period. Survival analysis showed a significantly longer survival in treated patients of Groups B and C. Our study suggests that gabapentin may be an effective drug for ALS; hence a controlled trial involving a sufficient large number of patients is warranted.

Acetates↗
PubMed2001

Gabapentin is not a GABAB receptor agonist.

Recent experiments have demonstrated that formation of functional type B gamma-aminobutyric acid (GABA(B)) receptors requires co-expression of two receptor subunits, GABA(B1) and GABA(B2). Despite the identification of these subunits and a number of associated splice variants, there has been little convincing evidence of pharmacological diversity between GABA(B) receptors comprising different subunit combinations. However, Ng et al. [Mol. Pharmacol., 59 (2000) 144] have recently suggested a novel and important pharmacological difference between GABA(B) receptor heterodimers expressing the GABA(B1a) and GABA(B1b) receptor subunits. 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. The importance of this finding with respect to identifying novel GABA(B) receptor subunit specific agonists prompted us to repeat these experiments in our own [35S]-GTPgammaS binding and second messenger assay systems. Here we report that gabapentin was completely inactive at recombinant GABA(B) heterodimers expressing either GABA(B1a) or GABA(B1b) receptor subunits in combination with GABA(B2) receptor subunits. In addition, in both CA1 and CA3 pyramidal neurones from rodent hippocampal slices we were unable to demonstrate any agonist-like effects of gabapentin at either pre- or post-synaptic GABA(B) receptors. In contrast, gabapentin activated a GABA(A) receptor mediated chloride conductance. Our data suggest that gabapentin is not a GABA(B)-receptor agonist let alone a GABA(B) receptor subunit selective agonist.

Acetates↗
PubMed1997

The novel anticonvulsant, gabapentin, protects against both convulsant and anxiogenic aspects of the ethanol withdrawal syndrome.

The effects of the anticonvulsant, gabapentin, were investigated, in mice, on the withdrawal convulsive behaviour and anxiety-related behaviour that are produced by cessation of prolonged intake of ethanol. When given at 50 or 100 mg/kg, this compound decreased the rise in handling-induced hyperexcitability which occurs during the withdrawal period; the effects were most pronounced for the first 4 hr after administration. Gabapentin also decreased the convulsive response to an audiogenic stimulus during the withdrawal period. The elevated plus-maze, with both traditional and ethological indices of activity was used as a test of anxiety-related behaviour after cessation of chronic ethanol treatment. Gabapentin, at 50 and 100 mg/kg, was found to decrease some, although not all, of the signs of withdrawal-induced anxiety. At doses up to and including 200 mg/kg, gabapentin had no effect on motor co-ordination or spontaneous locomotor activity in control animals. The results demonstrated that gabapentin has a selective action in decreasing both convulsive and anxiety-related aspects of withdrawal behaviour after chronic ethanol treatment. It is possible that further studies with this compound may shed further light on the mechanisms involved in the withdrawal syndrome.

Acetates↗
PubMed2003

Gabapentin dosing for neuropathic pain: evidence from randomized, placebo-controlled clinical trials.

BACKGROUND: Pain is one of the most common reasons for seeking medical attention, and neuropathic pain is among the most common types of pain. Despite its prevalence, neuropathic pain is often underrecognized and inadequately treated. Many cases are refractory to the medications traditionally used for pain, such as nonsteroidal anti-inflammatory drugs. Tricyclic antidepressants are considered first-line agents for neuropathic pain, but their use is limited by unwanted side effects and a risk of cardiovascular mortality. OBJECTIVES: The goals of this article were to review data on the efficacy and tolerability of gabapentin in the treatment of neuropathic pain in adults and to determine the optimal dosing schedule. METHODS: Randomized controlled studies of gabapentin for neuropathic pain were identified through a search of PubMed and MEDLINE from 1966 to the present using the search terms gabapentin, randomized, placebo, and pain. Abstracts of identified articles were screened for study size (>100 patients per treatment arm) and use of appropriate efficacy measures. A separate review based on information provided by the manufacturer of gabapentinaand clinical trial Web sites was conducted to ascertain whether there had been any other relevant industry- or government-sponsored trials. The manufacturer provided additional unpublshed study data. RESULTS: Data from 5 randomized, placebo-controlled trials were included in the review, 1 of which has not yet been published. Gabapentin was effective in the treatment of painful diabetic neuropathy, postherpetic neuralgia, and other neuropathic pain syndromes. It relieved symptoms of allodynia, burning pain, shooting pain, and hyperesthesia. Adverse effects were typically mild to moderate and usually subsided within approximately 10 days from the initiation of treatment. Based on available data, it appears that treatment should be started at a dose of 900 mg/d (300 mg/d on day 1, 600 mg/d on day 2, and 900 mg/d on day 3). Additional titration to 1800 mg/d is recommended for greater efficacy. Doses up to 3600 mg/d may be needed in some patients. The effective dose should be individualized according to patient response and tolerability. CONCLUSION: At doses of 1800 to 3600 mg/d, gabapentin was effective and well tolerated in the treatment of adults with neuropathic pain.

Acetates↗
PubMed2001

Adjunctive gabapentin in treatment-resistant depression: a retrospective chart review.

BACKGROUND: Previous studies in predominantly bipolar patients have suggested that gabapentin may be useful in treating mood disorders. This report describes its efficacy and tolerability as an adjunctive agent in treatment-resistant depression. METHODS: A chart review was conducted on 27 outpatients presenting with a depressive disorder in whom gabapentin was added to ongoing treatment with a conventional antidepressant to which patients had not responded after at least 6 weeks. The majority of patients had either prominent anxiety or a history of soft bipolar features, but patients with bipolar I disorder were excluded. Clinical state and adverse effects were assessed retrospectively at each visit. RESULTS: Mean gabapentin trial duration was 15.2+/-7.8 weeks, with a mean final dose of 904+/-445 mg/day (range, 300-1800 mg/day). Clinician-rated measures of clinical state improved significantly from baseline to endpoint. Overall, 37.0% (n=10) of patients were responders at endpoint; another 18.5% (n=5) manifested a transient response not sustained to endpoint. Gabapentin was well tolerated; the most common adverse effects were fatigue, sedation, dizziness, and gastrointestinal symptoms. LIMITATIONS: Treatment was uncontrolled and efficacy assessments were retrospective. CONCLUSION: These findings suggest that gabapentin may be of adjunctive benefit in the management of treatment-resistant depression.

Acetates↗
PubMed2000

Inhibition of K(+)-evoked glutamate release from rat neocortical and hippocampal slices by gabapentin.

Gabapentin (Neurontin((R))) has preclinical and clinical efficacy as an anticonvulsant, antihyperalgesic, anxiolytic, and neuroprotective drug. Since L-glutamic acid (GLU) is involved in various CNS (central nervous system) disorders, gabapentin may attenuate the release of this neurotransmitter possibly by interacting with the auxiliary alpha(2)delta subunit of voltage-sensitive calcium channels (VSCC). The effects of gabapentin, pregabalin (S-(+)-3-isobutylgaba) and its enantiomer R-(-)-3-isobutylgaba, and N- and P/Q-type VSCC-targeting peptide ligands (omega-conotoxin MVIIA, omega-conotoxin MVIIC, omega-agatoxin TK) were assessed in vitro on K(+)-evoked (endogenous) GLU release from rat neocortical and hippocampal slices. Gabapentin and pregabalin decreased GLU release by 11-26% with R-(-)-3-isobutylgaba being less effective than pregabalin. The reference N- and P/Q-type VSCC-targeting ligands reduced GLU release by 19-55% to implicate these VSCC in this Ca(2+)-dependent process. The inhibitory effect of gabapentin and related compounds on GLU release may reflect a subtle modulation of VSCC function which normalizes pathological changes in neurotransmitter release.

Acetates↗