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Gabapentin, a drug useful in several neurological and psychiatric disorders, decreased K(+) (15 mM)-induced [Ca(2+)](i) increase in Fura-PE3-loaded rat neocortical synaptosomes (IC(50)=9.7 microM; submaximal inhibition of 28.6%). This effect may indicate a selective modulation of presynaptic Ca(2+) influx in response to depolarizing (pathological) conditions causing excessive neurotransmitter release.
Gabapentin (GBP) and S(+)-3-isobutyl-gamma-aminobutyric acid (IBG) are anticonvulsant agents which are effective against many clinical and experimental neuropathic pain states. We examined the efficacy of these agents in a new rat model of secondary mechanical hyperalgesia generated by a mild thermal injury. Under brief halothane anesthesia, an injury was induced by applying one heel to a hot surface (52.5 degreesC) for 45 s. GBP, IBG or saline was injected i.p. just prior to the injury. Mean mechanical withdrawal threshold (MWT) was determined using von Frey hairs before and at 30 min intervals for 3 h following the injury. MWT outside the injury area decreased post-injury (secondary hyperalgesia, allodynia), but primary (site of injury) mechanical hyperalgesia was not observed. Secondary hyperalgesia exhibited a tendency toward recovery over time. Time to onset of the anti-allodynic effect of GBP was 30-60 min. The minimum effective GBP dose was 100 mg/kg; 300 mg/kg GBP totally inhibited the drop in MWT, but was accompanied by pronounced sedation. Anti-allodynic effects of IBG were apparent at the first post-injury measure of MWT (30 min). Thirty milligrams per kilogram was the minimum effective dose; 100 mg/kg IBG totally blocked the allodynia with minimal side effects. Our findings demonstrate a dose-dependent blockade of the mechanical sensitivity caused by a mild thermal injury by both GBP and IBG. Results indicate that IBG is more effective than GBP in this model at doses which do not cause sedation. These observations support the suggested use of these or related gamma-amino acid analogues as an effective treatment for post-operative pain.
Gabapentin (GBP) is a gamma-aminobutyric acid analog effective in the treatment of seizures. A high-affinity interaction between GBP and the alpha(2)delta subunit of the voltage-gated Ca(2+) channels has been documented. In this report, we examined the effects of the chronic treatment with GBP on neuronal recombinant P/Q-type Ca(2+) channels expressed in Xenopus oocytes. GBP did not affect significantly the amplitude or the voltage dependence of the currents. Exposure to the drug did, however, slow down the kinetics of inactivation in a dose-dependent fashion. In addition, biochemical analysis showed that the integrity of Ca(2+) channel complex is not apparently affected by GBP binding, suggesting that chronic treatment with the drug might cause the channel kinetic modification through subtle conformational changes of the protein complex.
The anticonvulsant action and the long-term effects on learning, memory and behavior of the new generation antiepileptic drug gabapentin (GBP) were investigated in immature animals. Kainic acid (KA) was administered to rats on postnatal day (P) 35. Animals were treated with GBP or saline from P36 to P75 and spontaneous seizure frequency was monitored. After tapering the drug, the rats were tested in the water maze and open field test. Brains were then analyzed for histological lesions. Animals treated with GBP following KA-induced status epilepticus had a reduced incidence of spontaneous recurrent seizures, a better pathology score, and less aggressiveness compared to saline-treated controls. Effectiveness of GBP on seizure threshold was tested using flurothyl inhalation in 10 separate age groups of animals ranging from the newborn period to adulthood. Furthermore, GBP plasma concentration peaks were determined in all age groups. At all ages, GBP pre-treated animals demonstrated a higher seizure threshold. Plasma GBP concentrations did not significantly change with age. These data suggest that acute administration of a single therapeutic dose of GBP increases the seizure threshold at all ages studied, while chronic treatment following the status reduces spontaneous seizure frequency and cell damage and has no long-term adverse consequences on cognitive processes during development.
Despite identification of GABA(B) receptors with gb1a-gb2 composition and the alpha2delta calcium channel subunit as putative molecular targets for gabapentin (GBP), its cellular mechanism of action has remained elusive. Therefore, we have used an in vitro spinal cord slice preparation to study the effects of GBP on lamina II neurons. The frequency and amplitude of spontaneous EPSCs and IPSCs were unaffected by GBP, suggesting presynaptic neurotransmitter release is not regulated. Direct modulation of postsynaptic membrane excitability is also unlikely since the level of holding current required to maintain neurons at -70, 0 and +45 mV was unaffected by GBP. Effects on excitatory and inhibitory synaptic transmission were variable across the population. Primary afferent-evoked fast glutamatergic EPSCs were unaffected by GBP, while evoked NMDA receptor-mediated EPSCs and IPSCs were variably affected. In contrast, GBP enhanced responses to bath applied NMDA in 71% of neurons. Thus, in adult rat dorsal horn, synaptic and extrasynaptic NMDA receptors may be differentially regulated by GBP perhaps due to differences in subunit composition.
The development of tolerance to therapeutic effects of antiepileptic drugs can be a problem in the treatment of epilepsy, bipolar disorder, and pain syndromes. In the present study, acute treatment with the new antiepileptic drug lamotrigine (LTG, 15 mg/kg) markedly suppressed seizure stage and seizure duration in amygdala-kindled rats; but this antiseizure effect was rapidly lost following 4-8 days of repeated treatment. When gabapentin (GBP, 20 mg/kg) was coadministered with LTG, the ability of LTG to suppress seizure stage, seizure duration, and after-discharge (AD) duration was markedly extended. In addition, GBP coadministration with LTG decreased the number of animals that developed LTG-related running fits (Stage 6 seizures) and lengthened the number of days required to develop running fits or complete tolerance. Neither acute nor repeated treatment with MK-801 (0.3 mg/kg), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, had effects on kindled seizures. However, cotreatment with MK-801 markedly extended the anticonvulsant effects of LTG on the three seizure indices and reduced running fits. These data indicate that cotreatment with either GBP or MK-801 slows tolerance development to the anticonvulsant effects of LTG on kindled seizures. Therapeutic implications of the present study remain to be explored.
PURPOSE: To date, only one case of asterixis associated with the use of gabapentin (GBT) has been reported. No data, instead, are available on the occurrence of asterixis related to a dementing encephalopathy during GBT therapy in the elderly. METHODS: Case reports of two elderly patients, one with asterixis, the other with asterixis and encephalopathy, associated with the use of GBT, as adjunctive therapy, at dosages of 900 to 3600 mg/day are given. In one patient, GBT was added to oxcarbazepine (OXCBZ). FINDINGS: Both patients experienced resolution of the clinically apparent asterixis, and of the toxic encephalopathy, on discontinuation or reduction of GBT dosages. One patient developed asterixis after drug rechallenge. In the patient on OXCBZ, the analysis of the electromyogram (EMG) activity showed the occurrence of a subclinical asterixis. CONCLUSIONS: Our study indicates that high doses of GBT may induce asterixis related to a reversible encephalopathy. Low doses of GBT, instead, may induce a disabling asterixis when given in combination with OXCBZ because of a synergistic interaction between these drugs.
Male CF-1 mice were tested 48 h after training on a one trial step-through inhibitory avoidance task. Immediately post-training, intraperitoneal (i.p.) injections of the antiepileptic gabapentin (1-(aminomethyl) cyclohexaneacetic acid) (GBP, 10 mg/kg) enhanced retention performance. The effect was prevented by atropine, a central muscarinic cholinergic receptor antagonist (0.5 mg/kg, i.p.) administered after training but 10 min prior to GBP treatment. In contrast, neither methylatropine (0.5 mg/kg, i.p.), a peripherally acting muscarinic receptor blocker, nor mecamylamine (5 mg/kg, i.p.) or hexamethonium (5 mg/kg, i.p.), two cholinergic nicotinic receptor antagonists, prevented the effects of post-training GBP on retention performance. Low subeffective doses of the central acting anticholinesterase physostigmine (35 mg/kg, i.p.) administered immediately after training, and GBP (5 mg/kg, i.p.), given 10 min after training, significantly enhanced retention performance. The effects of GBP (5 mg/kg, i.p.) were not influenced by the peripherally acting anticholinesterase neostigmine (150 mg/kg, i.p.). Considered together, these findings suggest a disinhibitory action of GBP on the activity of central muscarinic cholinergic mechanisms that are involved in memory consolidation.
We previously reported that gabapentin (GBP), a widely prescribed analgesic, enhances N-methyl-aspartate (NMDA) receptor mediated currents only when the intracellular level of protein kinase C is elevated. However, it is unclear how the potentiation of NMDA responses by GBP can lead to pain relief. To resolve this issue, we combined immunocytochemical and patch recording techniques to study the actions of GBP on NMDA receptors in dorsal horn cells isolated from rats with inflammation and to determine the gamma-aminobutyric acid (GABA) content in the recorded cells. We found that all GBP-responsive cells are GABA-immunoreactive and none of the GABA-negative neurons respond to GBP. Thus, GBP appears to enhance NMDA currents in GABAergic neurons. These observations suggest that GBP exerts its antinociceptive action by increasing the activity of these inhibitory neurons.
Gabapentin (Neurontin) (GBP) is a widely prescribed analgesic used in treating pain patients with peripheral nerve injuries, diabetic neuropathy and cancer. To understand the mechanism of its action, we used the whole-cell patch recording technique to study the effects of GBP on N-methyl-D-aspartate (NMDA)-evoked currents in single dorsal horn neurons isolated from normal rats and from rats with inflammation induced by the injection of complete Freund adjuvant (CFA) to the hindpaw. We found that GBP enhanced NMDA currents in normal neurons only when protein kinase C (PKC) was added to these cells. The enhancement resulted from an increase in the affinity of glycine for NMDA receptors by GBP. In contrast, in neurons isolated from CFA-treated rats, GBP enhanced NMDA responses without any PKC treatment. Since endogenous PKC in inflamed tissue is elevated, these results suggest that GBP exerts its effects only on those cells affected by inflammatory injuries. Thus, the effects of GBP on NMDA receptors are plastic; they depend on the phosphorylation states of cells or receptors. These observations point to a new strategy for drug design. A chemical whose action depends on the state of cells would maximize its effectiveness while keeping its side-effects to a minimum.
Gabapentin (GP) has been shown to have antihyperalgesic properties and the site of drug action is reported to be the central nervous system. The goal of the present study was to determine whether GP also has a peripheral site of action. Rats received intraplantar 20-microl injections of 6, 60 or 600 microg GP + 2% formalin, 300 or 600 microg S-(+)-3-isobutylgaba + 2% formalin, 600 microg R-(-)-3-isobutylgaba + 2% formalin or formalin alone. The two lower doses of GP significantly reduced flinching and lifting/licking behavior during phase 2; however, phase 1 behaviors were unaffected, 600 microg GP significantly reduced these nociceptive behaviors during both phases. 600 microg S-(+)-3-isobutylgaba also reduced formalin-induced nociceptive behaviors; however, 600 microg of the isomer R-(-)-3-isobutylgaba had no effect. The antihyperalgesic effect of GP (1) was not due to a systemic effect since animals injected with 600 microg GP in one hindpaw and 2% formalin into the contralateral hindpaw developed nociceptive behaviors which were no different than those seen in animals injected with formalin alone; (2) was not due to a local anesthetic effect since needle sticks within the drug-injected region evoked paw withdrawal behavior which was not different from pre-drug levels; (3) was blocked by 20 microl D-serine but not by L-serine. Although the mechanism of action of GP has yet to be elucidated, these results indicate that GP has a peripheral site of action and thus may offer a novel therapeutic agent for topical or local treatment of pain of peripheral origin.
We investigated the effects of gabapentin (GBP) on glutamatergic synaptic transmission in the dorsal horn of the rat spinal cord. Patch clamp whole cell recordings were made from superficial and deep dorsal horn neurons of rat spinal cord slices. In the majority of neurons in the superficial lamina, GBP decreased the amplitudes of evoked excitatory postsynaptic currents (evoked EPSCs) mediated by either non-NMDA or NMDA receptors. In contrast, neurons in the deep lamina showed variable effects, with a lower incidence of decrease in amplitude of evoked EPSCs and a subset of neurons showing an increase in amplitude of evoked NMDA receptor-mediated EPSCs. No enhancement of evoked non-NMDA receptor-mediated EPSCs was observed in either lamina. To determine whether the observed effects of GBP are presynaptic and/or postsynaptic, spontaneous miniature excitatory postsynaptic currents (mEPSCs) were studied. In neurons that showed a decrease in its frequency of mEPSCs by GBP, no change in the amplitude or shape accompanied the effect. On the other hand, in neurons that showed an increase in the frequency of NMDA receptor-mediated mEPSCs, the effect accompanied an increase in amplitude. These results suggest that GBP presynaptically inhibits glutamatergic synaptic transmission predominantly in the superficial lamina, while postsynaptically enhancing NMDA receptor-mediated transmission in some neurons of the deep lamina. The antinociceptive effects of GBP may involve the inhibition of the release of excitatory amino acids from presynaptic terminals.
Gabapentin (GBP) is a new antiepileptic drug approved for clinical treatment of partial seizures in the USA. Serum GBP concentrations in 283 patients were studied using high-performance liquid chromatography with fluorescence detection. The standard curves were linear over a range of 60 ng to 15 microg/ml. The coefficient of variations were 3.4 to 8.8% and 1.4 to 9.8% for intra- and inter-assay studies, respectively. The lower limit of quantitation was 10 ng/ml. Of the 283 patients studied, 72.5% had GBP levels between 2 and 10 microg/ml, 14.8% were below 2 microg/ml and 12.7% above 10 microg/ml. The mean+/-S.E. of GBP in 283 patients was 5.38+/-0.23 microg/ml. Peak concentrations of more than 15 microg/ml and trough levels as low as 0.1 microg/ml were not uncommon. The method described was rapid, simple, highly sensitive and reproducible. Other antiepileptic drugs and endogenous compounds did not interfere with the assay.
A stability-indicating, sensitive, simple and selective spectrofluorimetric method was developed for the determination of vigabatrin (VG) and gabapentin (GB). The method is based on the reaction between the two drugs and fluorescamine in borate buffer of pH 8.2 to give highly fluorescent derivatives that are measured at 472 nm using an excitation wavelength of 390 nm for both drugs. The optimum conditions were ascertained and the method was applied for the determination of VG and GB over the concentration range of 0.20-4.00 and 0.1-1.0 microg/ml, respectively with detection limits of 0.05 microg/ml (2.9 x 10(-7) M) and 0.06 microg/ml (2.3 x 10(-7) M) for VG and GB, respectively. The suggested method was applied, without any interference from the excipients, to the determination of the two drugs in their pharmaceutical formulations. Furthermore, the method was extended to the in-vitro determination of both drugs in spiked human urine. Interference from endogenous amino acids could be eliminated through selective complexation with copper acetate, the % recovery (n=4) is 98.0 +/- 7.05. Co-administered drugs such as lamotrigine, phenobarbitone, valproic acid, clopazam, carbamazepine, clonazepam and cimitidine did not interfere with the assay. The method is also stability-indicating; as the degradation product of vigabatrin: 5-vinylpyrrolidin-2-one, produced no interference with its analysis.
Self-injurious behavior is a common clinical problem in children with Lesch-Nyhan syndrome, an X-linked disorder of purine metabolism. This behavior is not observed in other conditions associated with increased serum concentrations of uric acid, hypoxanthine, and xanthine. Various neurotransmitters appear to play a pivotal role in self-injurious behavior. The authors present a patient with Lesch-Nyhan syndrome, whose self-injurious behavior was effectively treated with gabapentin, and discuss possible mechanisms of action.
Gabapentin (GBP) has been shown to reduce paired-pulse inhibition in the dentate gyrus of the urethane-anesthetized rat, which is a proconvulsant effect, and to shorten the afterdischarge duration, which is an antiepileptic effect. The mechanism by which GBP exerts these effects is not known, but a number of possibilities have been proposed. Here we tested the ability of vigabatrin (VGB), a GABA transaminase inhibitor, and SKF89976A, a selective GAT-1 blocker, to alter the effectiveness of GBP in the dentate gyrus in urethane-anesthetized adult Sprague-Dawley rats. VGB, alone at 100 mg/kg, had no effect on the evoked potentials or paired-pulse inhibition in the dentate gyrus, but did block lengthening of the afterdischarge. Pretreatment with VGB had no effect on the ability of GBP to reduce paired-pulse inhibition, but blocked the effect of GBP on seizure duration. SKF89976A, alone at 10 mg/kg, increased paired-pulse inhibition and blocked the lengthening of the afterdischarge in the seizure model. Pretreatment with SKF89976A had no effect on the actions of GBP on either paired-pulse inhibition or seizure duration. These results suggest that the action of GBP is not mediated through an inhibition of the GAT-1 transporter and probably not through an increase in basal levels of GABA. The data also suggest that the combination of VGB and GBP may be clinically less effective than the use of GBP alone.
Fifty patients with refractory partial seizures took part in a prospective, observational study of adjuvant gabapentin (GBP) in increasing doses. Thirty-three were started on 400 mg GBP daily with further weekly increments of 400 mg until seizures came under control for at least 6 months or to the limit of tolerability. A further 17 patients, not fully controlled on low dose GBP, followed the same regimen. All patients took the drug three times daily. Comparisons were made with seizure numbers during a 3-month baseline during which antiepileptic medication remained unchanged. Overall, 24 of the 50 patients documented a seizure reduction of 50% or more. Fifteen did so at or below 2400 mg GBP daily. Three of these patients became seizure-free. The remaining nine appeared to respond to higher daily doses of GBP (1:2800 mg; 3:3600 mg; 1:4000 mg; 1:4800 mg; 3:6000 mg), with two becoming seizure-free. Side-effects most commonly reported included tiredness, dizziness, headache and diplopia. On GBP doses exceeding 3600 mg daily, three patients developed flatulence and diarrhoea and two more had myoclonic jerks. Mean circulating GBP concentrations (mg/l) at each 1200 mg dose level were as follows: 1200 mg-4.1; 2400 mg-8.6; 3600 mg 13.2; 4800 mg 15.5; 6000 mg-17.2. In six patients, including three taking 6000 mg daily, GBP concentrations continued to rise linearly at each dosage increment. Although limited, our results do not support the suggestion that GBP absorption is saturable. High dose GBP may be effective in controlling seizures in patients with refractory partial epilepsy.
Gabapentin (GBP) is a recently licensed antiepileptic, drug whose mode of action remains to be fully elucidated. The following studies were designed to investigate the effects of GBP on several gamma-aminobutyric acid (GABA) related neurochemical parameters in mouse brain. GBP (0-75 mg/kg) was administered by intraperitoneal injection either as a single dose or twice daily for 8 days. Animals were sacrificed 4 h after the final administration and their brains removed and analysed for concentrations of GABA, glutamate and glutamine and the activities of GABA-transaminase (GABA-T) and glutamic acid decarboxylase (GAD). Single dose GBP increased brain GABA-T activity and glutamine concentration but was without effect on GAD activity or the concentrations of GABA and glutamate. Following repeated treatment with GBP, brain GABA-T activity was consistently decreased and there was also a decrease in brain glutamate concentration. Repeated drug treatment was without effect on the activity of GAD or on the concentrations of GABA and glutamine. These results suggest that GBP has effects on the GABAergic system which may contribute to its antiepileptic and/or neuroprotective actions.