Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chemical structure of gabapentin (Neurontin) is derived by addition of a cyclohexyl group to the backbone of gamma-aminobutyric acid (GABA). Gabapentin prevents seizures in a wide variety of models in animals, including generalized tonic-clonic and partial seizures. Gabapentin has no activity at GABAA or GABAB receptors of GABA uptake carriers of brain. Gabapentin interacts with a high-affinity binding site in brain membranes, which has recently been identified as an auxiliary subunit of voltage-sensitive Ca2+ channels. However, the functional correlate of gabapentin binding is unclear and remains under study. Gabapentin crosses several lipid membrane barriers via system L amino acid transporters. In vitro, gabapentin modulates the action of the GABA synthetic enzyme, glutamic acid decarboxylase (GAD) and the glutamate synthesizing enzyme, branched-chain amino acid transaminase. Results with human and rat brain NMR spectroscopy indicate that gabapentin increases GABA synthesis. Gabapentin increases non-synaptic GABA responses from neuronal tissues in vitro. In vitro, gabapentin reduces the release of several mono-amine neurotransmitters. Gabapentin prevents pain responses in several animal models of hyperalgesia and prevents neuronal death in vitro and in vivo with models of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Gabapentin is also active in models that detect anxiolytic activity. Although gabapentin may have several different pharmacological actions, it appears that modulation of GABA synthesis and glutamate synthesis may be important.
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PMID:Mechanisms of action of gabapentin. 968 47

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.
Pain 1998 May
PMID:Attenuation of formalin-induced nociceptive behaviors following local peripheral injection of gabapentin. 969 74

This report describes the effectiveness of gabapentin, a recently approved anticonvulsant, in seven patients with MS experiencing trigeminal neuralgia refractory to treatment with conventional medical therapy. Gabapentin relieved pain completely in six and significantly in the seventh patient. Gabapentin may be a valuable addition to pharmacologic therapy in trigeminal neuralgia, particularly in patients with MS and in refractory cases.
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PMID:Gabapentin relieves trigeminal neuralgia in multiple sclerosis patients. 971 50

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.
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PMID:Systemic gabapentin and S(+)-3-isobutyl-gamma-aminobutyric acid block secondary hyperalgesia. 981 59

Anticonvulsants are widely used in the treatment of neuropathic pain, and are assumed to act preferentially on lancinating, shooting pain. In the present study, the effects of gabapentin, a novel anticonvulsant, were evaluated systematically on both spontaneous and evoked pain in 18 patients with peripheral nerve injuries or central lesions. Gabapentin was administered orally in gradually increasing doses up to a maximum of 2,400 mg/day. Evaluations of spontaneous ongoing and paroxysmal pain, allodynia and hyperalgesia were performed at the beginning of the study ('baseline') and 6 weeks after the steady-state dose had been reached. Quantitative sensory tests were used to measure detection and pain thresholds to mechanical and thermal stimuli and the responses to suprathreshold stimuli. Gabapentin induced a moderate and statistically significant relief of ongoing spontaneous pain and was particularly effective in reducing paroxysmal pain. A striking finding was the significant effect on brush-induced and cold allodynia. In contrast, no effects were observed on detection and pain thresholds to static mechanical and hot stimuli. Side effects were generally minor and did not interfere with everyday activities. The present study suggests that gabapentin has preferential antihyperalgesic and/or antiallodynic effects, and is equally effective in pain due to peripheral nerve injuries and central lesions.
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PMID:Effects of gabapentin on the different components of peripheral and central neuropathic pain syndromes: a pilot study. 981 1

Repetitive ectopic discharges from injured afferent nerves play an important role in initiation and maintenance of neuropathic pain. Gabapentin is effective for treatment of neuropathic pain but the sites and mechanisms of its antinociceptive actions remain uncertain. In the present study, we tested a hypothesis that therapeutic doses of gabapentin suppress ectopic afferent discharge activity generated from injured peripheral nerves. Mechanical allodynia, induced by partial ligation of the sciatic nerve in rats, was determined by application of von Frey filaments to the hindpaw. Single-unit afferent nerve activity was recorded proximal to the ligated sciatic nerve site. Intravenous gabapentin, in a range of 30 to 90 mg/kg, significantly attenuated allodynia in nerve-injured rats. Furthermore, gabapentin, in the same therapeutic dose range, dose-dependently inhibited the ectopic discharge activity of 15 injured sciatic afferent nerve fibers through an action on impulse generation. However, the conduction velocity and responses of 12 normal afferent fibers to mechanical stimulation were not affected by gabapentin. Therefore, this study provides electrophysiological evidence that gabapentin is capable of suppressing the ectopic discharge activity from injured peripheral nerves. This action may contribute, at least in part, to the antiallodynic effect of gabapentin on neuropathic pain.
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PMID:Gabapentin suppresses ectopic nerve discharges and reverses allodynia in neuropathic rats. 1002 39

Gabapentin and Pregabalin are both 3-alkylated gamma-amino butyric acid (GABA) analogs. Gabapentin was designed as a lipophilic GABA analog and was first synthesized as a potential anticonvulsant and was launched in 1994 as add-on therapy for the treatment of epilepsy. In this review the discovery and development of gabapentin as an anticonvulsant are discussed. During human trials and while in clinical use, it became apparent that gabapentin induced some other potentially useful therapeutic effects in chronic pain states and behavioral disorders. A review of animal and clinical data relating to these other potential therapeutic utilities is presented. Pregabalin was identified after an investigation into other 3-substituted GABA analogs. It has since been shown to have a similar pharmacological profile to gabapentin with greater potency in preclinical models of pain and epilepsy. Studies of the mechanism(s) of action of these compounds are discussed. Work towards identifying new analogs of both gabapentin and pregabalin is also reviewed.
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PMID:3-substituted GABA analogs with central nervous system activity: a review. 1018 76

The anticonvulsant agent gabapentin exhibits antihyperalgesic properties in animal models of neuropathic pain. Diabetic rats display increased nocifensive behavior during the formalin test of persistent chemical irritation to the paw, suggesting the presence of abnormal pain processing mechanisms. We therefore, investigated the efficacy of gabapentin on formalin-evoked behavior in diabetic rats. Diabetic rats showed increased (P < 0.05) flinching during the normally quiescent phase of the 5.0% formalin test. Gabapentin (50 mg/kg i.p. 30 min pre-test) suppressed flinching during phases 1 and 2 of the formalin test in both control and diabetic rats but not the increased flinching of diabetic rats during the quiescent phase. When 0.5% formalin was used, diabetic rats exhibited increased flinching during both the quiescent phase and phase 2. Gabapentin was without effect in controls but suppressed (P < 0.01) the increased flinching in diabetic rats. Gabapentin displays efficacy against abnormal sensory processing in diabetic rats and may be of benefit for treating painful diabetic neuropathy.
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PMID:Gabapentin prevents hyperalgesia during the formalin test in diabetic rats. 1020 41

In this study, we investigated the effectiveness of gabapentin (Neurontin), administered spinally with a microdialysis fiber, in reducing nociceptive behavioral responses induced by a knee joint inflammation model. This model is produced by injection of the knee joint with kaolin and carrageenan in rats. The resultant knee joint inflammation produces a secondary hyperalgesia to radiant heat applied to the hindpaw. Both pretreatment and post-treatment protocols were examined. Spinal administration of gabapentin (10 mg/ml) infused 1.5 h before induction of knee joint inflammation, although having no effect on the baseline, prevented the development of heat hyperalgesia. Gabapentin also prevented the development of other pain-related behaviors scored subjectively. Gabapentin had no effect, however, on the joint circumference increase typical in this model. In animals with fully developed knee joint inflammation, gabapentin produced a reversal of heat hyperalgesia. The paw withdrawal latency responses and subjective pain scores were no longer significantly different from baseline, but joint circumference increases remained. These data suggest that gabapentin is an effective antinociceptive agent when administered either before or after induction of knee joint inflammation acting through a central neurogenic mechanism.
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PMID:Gabapentin attenuates nociceptive behaviors in an acute arthritis model in rats. 1038 78

Gabapentin was administered as an "add on" therapy to 22 patients with neuropathic cancer pain only partially responsive to opioid therapy. Global pain, burning pain, shooting pain episodes, and allodynia were assessed separately. Gabapentin was given for at least a week and efficacy was assessed after 7 to 14 days of therapy. Global pain score decreased from a mean (+/- SD) of 6.4 (+/- 1.5) to 3.2 (+/- 1.3) (95% confidence interval of the baseline minus final score differences [95% CI] = 1.0-2.4). Burning pain intensity decreased from a mean (+/- SD) of 5.1 (+/- 3.6) to 2.0 (+/- 2.3) (95% CI = 1.5-3.8), and episodes of shooting pain decreased in frequency from 7.2 (+/- 3.7) to 2.2 (+/- 2.2) daily episodes (95% CI = 1.8-4.3). Allodynia was found in 9 patients and disappeared in 7 during gabapentin administration. Twenty patients judged the new drug efficacious in relieving their symptoms. The potential role of gabapentin as an adjuvant to opioid analgesia in cancer pain is discussed.
J Pain Symptom Manage 1999 Jun
PMID:Gabapentin as an adjuvant to opioid analgesia for neuropathic cancer pain. 1103 90


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