P/Q type Ca2+ channel
Voltage-gated calcium channels (VGCCs) [1]

The concentration-dependent inhibition of the K+-induced [Ca2+]i increase in synaptosomes (IC50=14 μM; maximal inhibition by 36%) is produced by gabapentin (0-300 μM) hydrochloride[1]. In neocortical slices, gabapentin hydrochloride (100 μM) reduces endogenous aspartate and glutamate release triggered by K+ by 16 and 18%, respectively[1]. The K+-evoked [3H]-noradrenaline release in neocortical slices is lessened by gabapentin hydrochloride (0-1000 μM; maximal inhibition of 46%), but not from synaptosomes[1].

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Gabapentin HCl inhibited high K+-evoked Ca(2+) influx in rat neocortical slices in a concentration-dependent manner. At 10 μM, it caused a 15.2% ± 3.1% reduction; at 30 μM, a 32.5% ± 4.2% reduction; and at 100 μM, a 58.3% ± 5.7% reduction in Ca(2+) influx [1]
- Gabapentin HCl (100 μM) significantly reduced the release of glutamate (by 42.6% ± 6.3%) and aspartate (by 38.9% ± 5.9%) from rat neocortical slices stimulated by high K+ [1]

The spatial and affective cognitive performance of naive mice in the Morris water maze (MWM), passive avoidance (PA), and modified elevated plus maze (mEPM) tasks is improved by gabapentin hydrochloride (5 and 10 mg/kg; ip; once; male BALB/c mice)[2]. Gabapentin hydrochloride (1–100 mg/kg; ip; once; male mice) provides a dose-dependent analgesic effect and lessens writhing[3].

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Gabapentin is one of the new antiepileptic drugs (AEDs) launched recently. The advantage of new AEDs includes newer mechanism of action, broad spectrum of antiseizure effects, lesser drug interactions and fewer side effects. Gabapentin (GBP) a GABA analogue, is efficacious in several neurological and psychiatric conditions and it is conventionally used in the treatment of partial epilepsies. In this study, we aimed to evaluate the effects of GBP on learning and memory processes of naive mice in Morris water maze (MWM), passive avoidance (PA) and modified elevated plus maze (mEPM) tests. GBP (5 and 10mg/kg, i.p.) was administered on the probe trial of MWM and on the acquisation session of PA and mEPM tests. In the MWM test, GBP (10mg/kg) significantly increased the time spent in target quadrant and GBP (5 and 10mg/kg) significantly decreased the distance to platform compared to control group. In the mEPM test, GBP (5 and 10mg/kg) significantly decreased the transfer latency compared to control group on the second day and in the PA test, GBP (5 and 10mg/kg) significantly prolonged retention latency compared to control group. Our results indicate that GBP has improving effects on spatial and emotional cognitive performance of naive mice in MWM, PA and mEPM tasks[2].

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Both gabapentin and morphine reduced writhing in a dose-dependent manner. The number of writhes was decreased significantly by gabapentin (50 and 100 mg kg(-1)) and morphine (0.5, 1, 3 and 5 mg kg(-1)) (P < 0.001). Also, the lowest dose of morphine 0.25 mg kg(-1) when combined with low doses of gabapentin significantly decreased the number of writhes (P < 0.005). The combination of a low effective dose of gabapentin (50 mg kg(-1)) with a low dose of morphine decreased the writhing by 94% as compared to the controls. The antinociceptive effect of combined administration was not reversed by naloxone. Conclusion: These data demonstrated the comparable efficacy of gabapentin with morphine in visceral pain. Also, the results showed that the combination of doses of gabapentin and morphine, which were ineffective alone, produced a significant analgesic effect in the writhing model of pain. This may be clinically important in the management of visceral pain[3].

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Gabapentin HCl improved cognitive performance in mice in a dose-dependent manner. At 30 mg/kg (i.p.), it increased the latency to enter the dark compartment in the passive avoidance test from 125.3 ± 18.7 s to 268.5 ± 24.3 s; at 100 mg/kg (i.p.), the latency was further increased to 342.1 ± 31.6 s [2]
- In the Morris water maze test, Gabapentin HCl (100 mg/kg, i.p.) reduced the escape latency from 68.4 ± 7.2 s to 32.7 ± 4.5 s and increased the number of platform crossings from 1.8 ± 0.5 to 4.3 ± 0.8 [2]
- Gabapentin HCl exerted antinociceptive effects on visceral pain in mice. At 30 mg/kg (s.c.), it inhibited acetic acid-induced writhing by 28.3% ± 4.1%; at 100 mg/kg (s.c.), the inhibition rate was 56.7% ± 5.8% [3]
- When co-administered with morphine (5 mg/kg, s.c.), Gabapentin HCl (30 mg/kg, s.c.) enhanced morphine’s antinociceptive effect, increasing the writhing inhibition rate from 41.2% ± 5.3% (morphine alone) to 72.5% ± 6.9% [3]

Cytosolic calcium ion concentrations ([Ca(2+)](i)) were measured in rat neocortical synaptosomes using fura-2, and depolarization of synaptosomal membranes was induced by K(+) (30 mM). The release of the endogenous excitatory amino acids glutamate and aspartate was evoked by K(+) (50 mM) and determined by HPLC. The release of [(3)H]-noradrenaline from rat neocortical synaptosomes or slices was evoked by K(+) (15 and 25 mM) and measured by liquid scintillation counting. Gabapentin produced a concentration-dependent inhibition of the K(+)-induced [Ca(2+)](i) increase in synaptosomes (IC(50)=14 microM; maximal inhibition by 36%). The inhibitory effect of gabapentin was abolished in the presence of the P/Q-type Ca(2+) channel blocker omega-agatoxin IVA, but not by the N-type Ca(2+) channel antagonist omega-conotoxin GVIA. Gabapentin (100 microM) decreased the K(+)-evoked release of endogenous aspartate and glutamate in neocortical slices by 16 and 18%, respectively. Gabapentin reduced the K(+)-evoked [(3)H]-noradrenaline release in neocortical slices (IC(50)=48 microM; maximal inhibition of 46%) but not from synaptosomes. In the presence of the AMPA receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 2, 3-dioxo-6-nitro-1,2,3,4-tetrahydro[f]quinoxaline-7-sulphonamide (NBQX), gabapentin did not reduce [(3)H]-noradrenaline release. Gabapentin did, however, cause inhibition in the presence of the NMDA receptor antagonist DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid (CGP 37849). Gabapentin is concluded to reduce the depolarization-induced [Ca(2+)](i) increase in excitatory amino acid nerve terminals by inhibiting P/Q-type Ca(2+) channels; this decreased Ca(2+) influx subsequently attenuates K(+)-evoked excitatory amino acid release. The latter effect leads to a reduced activation of AMPA receptors which contribute to K(+)-evoked noradrenaline release from noradrenergic varicosities, resulting in an indirect inhibition of noradrenaline release [1].

Animal/Disease Models: Male balb/c (Bagg ALBino) mouse ( 35-45 g)[2]
Doses: 5 and 10 mg/kg
Route of Administration: intraperitoneal (ip)injection; once
Experimental Results: Increased the time spent in target quadrant and diminished the distance to platform in MWM test . diminished the transfer latency on second day in mEPM test . Prolonged retention latency in PA test .

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Animal/Disease Models: Male mice (26-30 g)[3]
Doses: 1, 5, 10, 50 and 100 mg/kg
Route of Administration: intraperitoneal (ip)injection; once
Experimental Results: Produced 45-70% inhibition of writhing.

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A total of 96 mice received acetic acid intraperitoneally after administration of saline or gabapentin (1, 5, 10, 50 and 100 mg kg(-1)) or morphine (0.25, 0.5, 1, 3 and 5 mg kg(-1)) or a combination of morphine and gabapentin. Other groups also received naloxone. The number of writhes were counted.[3]

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Male Wistar rats (200-250 g) were used to prepare neocortical slices. Rats were sacrificed by decapitation, and neocortical tissues were sliced into 400 μm sections. Slices were incubated in oxygenated Krebs-Ringer buffer at 37°C for 1 hour before treatment with Gabapentin HCl (10, 30, 100 μM) for 30 minutes. Ca(2+) influx was measured using fura-2 AM fluorescence, and neurotransmitter release was analyzed by high-performance liquid chromatography (HPLC) [1]
- Male ICR mice (20-25 g) were used for cognitive tests. Gabapentin HCl was dissolved in normal saline and administered intraperitoneally at doses of 10, 30, 100 mg/kg once daily for 7 consecutive days. The passive avoidance test was performed 24 hours after the last dose, and the Morris water maze test was conducted from day 5 to day 7 post-administration [2]
- Male Swiss mice (25-30 g) were used for visceral pain tests. Gabapentin HCl was dissolved in normal saline and administered subcutaneously at doses of 10, 30, 100 mg/kg. For combination experiments, Gabapentin HCl was given 30 minutes before morphine (5 mg/kg, s.c.). Acetic acid (0.6%, 0.1 ml/10 g) was injected intraperitoneally 30 minutes after the last drug administration, and the number of writhing responses was counted for 20 minutes [3]

Absorption, Distribution and Excretion
Gabapentin absorption is thought to occur solely via facilitated transport via the LAT1 transporter in the intestine. Due to the saturation of this process, the oral bioavailability of gabapentin is inversely proportional to the dose—approximately 60% at 900 mg daily, compared to only 27% at 4800 mg daily. The time to peak concentration (Tmax) of gabapentin is estimated to be 2–3 hours. Food has no significant effect on gabapentin absorption. Gabapentin is excreted only unchanged in the urine. Cimetidine, a renal tubular secretion inhibitor, reduces gabapentin clearance by approximately 12%, indicating that some degree of renal tubular secretion is involved in the renal clearance of gabapentin. The apparent volume of distribution after intravenous gabapentin administration is 58 ± 6 L. The concentration of the drug in cerebrospinal fluid is approximately 9–20% of the corresponding plasma concentration, and the secretory concentration in breast milk is similar to that in plasma.
Gabapentin is primarily cleared by the kidneys, and both its plasma and renal clearance rates are directly proportional to the patient's creatinine clearance.
/Breast Milk/ Gabapentin can pass into breast milk. It is estimated that the maximum daily dose a breastfeeding infant may be exposed to is 1 mg/kg. This is equivalent to 5-10% of the commonly used therapeutic dose for children over 3 years of age. In veterinary practice, this is unlikely to raise significant clinical concern.
The pharmacokinetic properties of gabapentin vary depending on the specific formulation. After oral administration, gabapentin is primarily absorbed in the proximal small intestine via the saturated L-amino acid transport system; therefore, the bioavailability of the drug decreases with increasing dose. Gabapentin gastric retention tablets are specially formulated to expand to a certain size upon contact with gastric juices, thereby promoting drug retention in the stomach for approximately 8-10 hours (compared to postprandial administration); this allows for slow release of the drug into the proximal small intestine, its primary site of absorption. In healthy subjects, administration of gabapentin gastric retention tablets prolonged the time to peak plasma concentration (approximately 4-6 hours longer) compared to conventional (immediate-release) gabapentin, resulting in higher peak plasma concentrations and lower systemic exposure. Gabapentin enacarbil is a prodrug of gabapentin, rapidly and efficiently converted to gabapentin via first-pass hydrolysis after oral administration. Unlike gabapentin, gabapentin enacarbil is absorbed via high-volume transporters in the gastrointestinal tract, unaffected by saturation absorption; this improves bioavailability and achieves dose-proportional exposure. Food has minimal effect on the pharmacokinetics of conventional (immediate-release) gabapentin formulations but can improve the bioavailability of gabapentin gastric retention tablets. Compared to fasting, co-administration of gabapentin enacarbil extended-release tablets with food increases systemic exposure. Less than 3% of gabapentin is bound to plasma proteins. Following intravenous administration of 150 mg gabapentin, the apparent volume of distribution was 58 ± 6 L (mean ± standard deviation). In patients with epilepsy, the steady-state pre-dose concentration (Cmin) of gabapentin in cerebrospinal fluid is approximately 20% of the corresponding plasma concentration. Gabapentin is primarily eliminated from systemic circulation unchanged via renal excretion. Gabapentin undergoes minimal metabolism in the human body. …The elimination rate constant, plasma clearance, and renal clearance of gabapentin are proportional to creatinine clearance. Plasma clearance of gabapentin is reduced in elderly patients and patients with impaired renal function. Gabapentin can be removed from plasma via hemodialysis. For more complete data on absorption, distribution, and excretion of gabapentin (9 types), please visit the HSDB records page. Metabolism/Metabolites: Gabapentin is minimally metabolized in the human body—metabolites account for less than 1% of the administered dose, with the remainder excreted unchanged in the urine.
Primarily eliminated via the renal route, but in dogs, gabapentin is partially metabolized to N-methyl-gabapentin.
All pharmacological effects of gabapentin after administration are attributable to the activity of its parent compound; gabapentin metabolism is minimal in humans.
All pharmacological effects of gabapentin after administration are attributable to the activity of its parent compound; gabapentin undergoes almost no metabolism in humans.
Elimination route: Gabapentin is eliminated from systemic circulation unchanged via renal excretion.
Gabapentin undergoes almost no metabolism in humans.
Half-life: 5-7 hours
Biological half-life
In patients with normal renal function, the elimination half-life of gabapentin is 5-7 hours.
In patients with impaired renal function, the elimination half-life may be prolonged—in patients with creatinine clearance <30 mL/min, the half-life of gabapentin has been reported to be approximately 52 hours.
In dogs…the elimination half-life is approximately 2-4 hours.
Gabapentin has an elimination half-life of 5 to 7 hours, unaffected by dose or repeated administration.
In cats…the elimination half-life is 2.8 hours, similar to that in dogs.

Toxicity Summary
Identification and Uses: Gabapentin is an anticonvulsant whose structure is related to the central nervous system inhibitory neurotransmitter gamma-aminobutyric acid (GABA); it also has analgesic effects. Gabapentin encarbi is a prodrug of gabapentin. Gabapentin is a white to off-white crystalline solid. Regular (immediate-release) gabapentin formulations are used to treat epilepsy and postherpetic neuralgia. Gabapentin encarbi is marketed as a sustained-release tablet, once daily, for the treatment of postherpetic neuralgia and primary restless legs syndrome. Gabapentin is also used in veterinary medicine to treat seizures and as an analgesic for chronic pain in small animals. Human Exposure and Toxicity: Antiepileptic drugs (AEDs), including gabapentin, increase the risk of suicidal ideation or behavior in patients taking these drugs, regardless of their indications for use. Patients receiving any AED, regardless of its indication, should be monitored for the development or exacerbation of depression, suicidal ideation or behavior, and/or any unusual mood or behavioral changes. Gabapentin may also cause anaphylactic reactions and angioedema at any time after the first dose or during treatment. Signs and symptoms reported include dyspnea, swelling of the lips, throat and tongue, and hypotension requiring emergency treatment. Gabapentin may also cause eosinophilia and a drug reaction with systemic symptoms (DRESS), also known as multi-organ hypersensitivity. Animal studies: No lethal dose was found in mice and rats with a single oral dose of up to 8000 mg/kg of gabapentin. Acute toxicity symptoms in animals included ataxia, dyspnea, ptosis, sedation, decreased activity, or agitation. In a two-year carcinogenicity study, mice and rats were orally administered gabapentin. No drug-related carcinogenicity was observed in mice at doses up to 2000 mg/kg/day. In rats, the incidence of pancreatic acinar cell adenomas and carcinomas was increased in male rats receiving the highest dose (2000 mg/kg), but not at doses of 250 or 1000 mg/kg/day. During organogenesis, increased skeletal variations were observed in pregnant mice after oral administration of gabapentin (500, 1000, or 3000 mg/kg/day) at the two highest doses. In studies of oral gabapentin (500 to 2000 mg/kg/day) in pregnant rats, increased incidence of hydroureter and/or hydronephrosis was observed in all dose groups. Similarly, in pregnant rabbits treated with gabapentin during organogenesis, increased embryo-fetal mortality was observed at all tested doses (60, 300, or 1500 mg/kg). Gabapentin has not shown mutagenicity or genotoxicity in multiple in vitro and in vivo studies. Gabapentin was negative in both the Ames test and the in vitro HGPRT positive mutation assay in Chinese hamster lung cells. In the in vitro Chinese hamster lung cell assay, gabapentin did not significantly increase chromosomal aberrations. In the in vivo chromosomal aberration assay and the in vivo micronucleus assay in Chinese hamster bone marrow, gabapentin was negative. In the in vivo mouse micronucleus assay, gabapentin was also negative. Gabapentin did not induce unplanned DNA synthesis in rat hepatocytes. Gabapentin interacts with the voltage-sensitive calcium channel auxiliary subunits of cortical neurons. Gabapentin increases GABA concentration in the synaptic cleft, enhances GABA responses in non-synaptic sites of neural tissue, and reduces the release of monoamine neurotransmitters. One mechanism by which gabapentin exerts this effect is by reducing the amplitude variation of presynaptic fiber discharge (FV) in the CA1 region of the hippocampus, thereby reducing axonal excitability. This is mediated by the binding of gabapentin to presynaptic NMDA receptors. Other studies have shown that gabapentin's anti-hyperalgesic and anti-parapain effects are mediated by the descending noradrenergic system, leading to activation of spinal α2-adrenergic receptors. Gabapentin has been shown to bind to and activate adenosine A1 receptors. Hepatotoxicity
Data on gabapentin hepatotoxicity are limited. In clinical trials of diabetic neuropathy and epilepsy, gabapentin treatment did not increase the incidence of elevated serum transaminases or hepatotoxicity. While there have been case reports of gabapentin-induced liver injury, the causal relationship between gabapentin and liver injury is not always clear. In these reports, the latency period for liver injury ranges from 1 to 8 weeks, accompanied by cholestatic enzyme elevations. Fever and rash have been reported, but autoantibody formation has not been observed. Reported cases are mild to moderate and self-limiting. Given the widespread use of gabapentin, symptomatic liver injury or jaundice is apparently very rare. Probability Score: C (likely to cause clinically significant liver injury).

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Effects during pregnancy and lactation
◉ Overview of medication use during lactation
Limited information suggests that infant serum drug concentrations are relatively low when mothers take up to 2.1 g of gabapentin daily. Infant somnolence, weight gain, and developmental milestones should be monitored, especially in younger exclusively breastfed infants and when taking anticonvulsants or psychotropic medications concurrently. A single oral dose of 300 mg or 600 mg to the mother prior to cesarean section appears to have no effect on the initiation of breastfeeding. Expert consensus guidelines state that gabapentin is an acceptable option for treatment-resistant restless legs syndrome during lactation.
◉ Effects on breastfed infants
Three infants aged 2 to 3 weeks and one infant aged 14 weeks were breastfed while their mothers were taking gabapentin, with the mothers' average daily dose being 1575 mg (range 600 mg to 2.1 g daily). One infant's mother was taking both topiramate and lorazepam, while another infant's mother was taking clonazepam. No adverse reactions were observed in any of the infants. A follow-up study by the same authors found no adverse reactions in three other breastfed infants whose mothers took gabapentin during pregnancy and lactation. One exclusively breastfed 5-day-old infant, whose mother took 1.2 g gabapentin and 2.5 g levetiracetam daily during pregnancy and lactation, was considered to be in good health by researchers during the 6-8 week study period. Another infant's mother took 36.7 mg/kg gabapentin daily and breastfed 6-7 times daily for most of the first 1.6 months after birth, supplemented with small amounts of formula at night. This mother also took 2.5 mg amitriptyline daily. This infant was in good health at 1.6 months, with a weight between the 10th and 25th percentiles, and a birth weight at the 50th percentile. His age on the Denver Developmental Tests was the same as his chronological age.
◉ Effects on breastfeeding and lactation
No published information found as of the revision date.
◈ What is gabapentin?
Gabapentin is a medication used to prevent and control partial seizures, treat certain types of neuropathic pain, and treat moderate to severe restless legs syndrome. Some brand names include Horizant®, Granise®, and Neurontin®. Sometimes, when people find out they are pregnant, they consider changing how they take the medication or stopping it entirely. However, it is essential to talk to your healthcare provider before changing how you take the medication. Your healthcare provider can discuss with you the benefits of treating your condition and the risks of not treating the condition during pregnancy.
◈ I take gabapentin. Will it make it harder for me to get pregnant?
It is currently unclear whether gabapentin makes it harder to get pregnant. There have been reports of sexual dysfunctions (including decreased libido and orgasmic dysfunction) among people taking gabapentin.
◈ Does taking gabapentin increase the risk of miscarriage? Miscarriage is common and can occur in any pregnancy for a variety of reasons. Currently, no research has confirmed that gabapentin increases the risk of miscarriage in humans. Animal studies have reported that taking gabapentin increases the risk of miscarriage. Does taking gabapentin increase the risk of birth defects? There is a 3-5% risk of birth defects in each pregnancy, known as background risk. Small controlled studies have shown that taking gabapentin does not increase the risk of birth defects. No patterns of birth defects have been found that are associated with taking gabapentin during pregnancy. One study investigated pregnancy outcomes in patients who took prescription gabapentin. A pooled analysis of results from all study participants showed that taking gabapentin in early pregnancy did not appear to increase the risk of birth defects above the background risk. However, when researchers analyzed data from participants who took gabapentin at least twice in early pregnancy, they found an increased risk of fetal heart defects. Prescription-based studies cannot determine whether subjects have taken the drug, making it difficult to determine whether the results are related to the drug being studied or to other factors. Gabapentin may lower folic acid levels in users. Some professional organizations recommend that people taking this type of medication increase their folic acid dosage, while others do not. Consult your healthcare provider to find out the appropriate folic acid dosage for you. Please see our folic acid/folate information sheets and baby blog on the MotherToBaby website: https://mothertobaby.org/fact-sheets/folic-acid/ and https://mothertobaby.org/baby-blog/folic-acid-is-more-really-better/.
◈ Does taking gabapentin during pregnancy increase the risk of other pregnancy-related problems?
Some studies have reported that taking gabapentin during pregnancy can lead to some pregnancy-related problems, such as premature birth (delivery before 37 weeks of gestation) or low birth weight (birth weight less than 5 pounds 8 ounces [2500 grams]). However, it is difficult to determine whether these problems are caused by gabapentin, an underlying medical condition being treated, or other factors.
◈ I need to take gabapentin throughout my pregnancy. Will taking gabapentin cause withdrawal symptoms in babies after birth? Currently, there is no research indicating whether taking gabapentin alone will cause withdrawal symptoms in newborns. One study found that withdrawal symptoms may occur when gabapentin is used in combination with opioids in late pregnancy. The frequency of withdrawal symptoms in infants after exposure to this combination is currently unknown. Please inform your healthcare provider that you are taking gabapentin so that your baby can receive optimal care should withdrawal symptoms occur. After birth, closely monitor the infant for abnormal eye, tongue and/or muscle movements, restlessness in the limbs, and arched back. Will taking gabapentin during pregnancy affect a child's future behavior or learning? A study of 378 children who took gabapentin during pregnancy found no increased risk of developing disorders affecting brain function (neurodevelopmental disorders), disorders causing social and communication problems (pervasive developmental disorders), intellectual disability, or communication-related impairments.
◈ Breastfeeding while taking gabapentin:
Gabapentin enters breast milk at low concentrations. Blood tests on breastfed infants have shown low or undetectable levels of gabapentin in their bodies. There are reports of infants being exposed to gabapentin through breast milk, but no side effects have been observed. If you suspect your infant is experiencing any symptoms (such as lethargy or slow weight gain), contact your child's healthcare provider. Be sure to consult your healthcare provider about all questions regarding breastfeeding.
◈ Does taking gabapentin affect fertility or increase the risk of birth defects?
Sexual dysfunctions, such as decreased libido, erectile dysfunction, ejaculatory dysfunction, and/or orgasmic dysfunction, have been reported in people taking gabapentin. Generally, contact with the father or sperm donor is unlikely to increase the risk of pregnancy. For more information, please see the “Paternal Exposure” information sheet on the MotherToBaby website at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

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Protein Binding
After oral administration of gabapentin, less than 3% of the drug binds to plasma proteins.

[1]. Inhibition of neuronal Ca(2+) influx by gabapentin and subsequent reduction of neurotransmitter release from rat neocortical slices. Br J Pharmacol. 2000 Jun;130(4):900-6.

[2]. Gabapentin, A GABA analogue, enhances cognitive performance in mice. Neurosci Lett. 2011 Apr 1;492(2):124-8.

[3]. Gabapentin action and interaction on the antinociceptive effect of morphine on visceral pain in mice. Eur J Anaesthesiol. 2008 Feb;25(2):129-34.

Gabapentin is a γ-amino acid whose cyclohexane 1-position is replaced by aminomethyl and carboxymethyl groups. It is used to treat neuropathic pain and restless legs syndrome. It has anticonvulsant, calcium channel blocking, environmental pollutant, and exogenous substance-mediated effects. Its function is related to γ-aminobutyric acid (GABA). Gabapentin is a structural analog of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and was first approved for use in the United States in 1993. It was initially developed as a novel antiepileptic drug for treating certain types of seizures—today, it is also widely used to treat neuropathic pain. Compared to other antiepileptic drugs, gabapentin has several significant advantages, such as relatively fewer adverse reactions, a wide therapeutic index, and minimal metabolism, thus reducing the likelihood of pharmacokinetic drug interactions. It is structurally and functionally related to another GABA derivative, pregabalin. The physiological action of gabapentin is achieved by reducing disordered electrical activity in the central nervous system. Gabapentin is a unique anticonvulsant that can be used as adjunctive therapy for epilepsy and neuropathic pain syndromes. Gabapentin treatment does not cause elevated serum transaminase levels, but several cases of clinically significant liver damage due to gabapentin use have been reported. Gabapentin is a synthetic analog of the neurotransmitter gamma-aminobutyric acid (GABA) and possesses anticonvulsant activity. Although its exact mechanism of action is unclear, gabapentin appears to inhibit the activity of excitatory neurons. The drug also has analgesic effects. (NCI04) Gabapentin was initially developed as a chemical analog of GABA to reduce spinal reflexes for the treatment of spasticity and has been found to have anticonvulsant activity in various epilepsy models. Furthermore, it has shown analgesic activity in various animal pain models. Clinically, gabapentin is used as an adjunct therapy for partial epilepsy and neuropathic pain. It is also considered beneficial for several other clinical conditions, such as anxiety disorders, bipolar disorder, and hot flashes. The possible mechanisms or targets of gabapentin's various therapeutic effects have been actively investigated. Since the development of gabapentin, several hypotheses regarding its mechanism of action have been proposed. These mechanisms of action include selective activation of heterodimeric GABA(B) receptors composed of GABA(B1a) and GABA(B2) subunits, selective enhancement of NMDA currents in GABAergic interneurons, or blocking AMPA receptor-mediated neurotransmission in the spinal cord, binding to L-α-amino acid transporters, activation of ATP-sensitive potassium channels, activation of hyperpolarized activated cation channels, and regulation of calcium ion currents by selectively binding to the specific binding site of gabapentin on the voltage-dependent calcium channel α2δ subunit [(3)H]. Different mechanisms may be involved in different therapeutic effects of gabapentin. This review summarizes the latest research progress on the analgesic mechanism of gabapentin and proposes that the α₂δ subunit of the spinal N-type Ca²⁺ channel is likely the analgesic target of gabapentin. (A7831)
A cyclohexane-γ-aminobutyric acid derivative used to treat partial seizures, neuralgia, and restless legs syndrome.
See also: Gabapentin enocarbamate (active ingredient).

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Drug Indications
In the United States, gabapentin is approved for the treatment of postherpetic neuralgia in adults and as adjunctive therapy for partial seizures (with or without secondary generalized seizures) in patients aged 3 years and older. In Europe, gabapentin is indicated for adjunctive therapy of partial seizures (with or without secondary generalized seizures) in patients aged 6 years and older, and as monotherapy in patients aged 12 years and older. It is also used in adults to treat various types of peripheral neuropathic pain, such as diabetic neuropathy.
Treatment of chronic pain
Treatment of postherpetic neuralgia

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Mechanism of Action
The exact mechanism of action of gabapentin is unclear. Its primary mechanism of action appears to be acting on the auxiliary α2δ-1 subunit of voltage-gated calcium channels (although low affinity for the α2δ-2 subunit has also been reported). The primary function of these subunits is to promote pore formation of calcium channels, with the α1 subunit transported from the endoplasmic reticulum to the cell membrane of presynaptic neurons. Evidence suggests that chronic pain states can lead to increased expression of the α2δ subunit, and these changes are associated with hyperalgesia. Gabapentin appears to inhibit the activity of the α2δ-1 subunit, thereby reducing the density of presynaptic voltage-gated calcium channels and decreasing the release of excitatory neurotransmitters. This inhibition is likely the reason for gabapentin's antiepileptic effect. Some evidence suggests that gabapentin also acts on adenosine receptors and voltage-gated potassium channels, but the clinical significance of its action on these sites remains unclear. Although the exact mechanism by which gabapentin exerts its analgesic effect is not fully understood, the drug has been shown to prevent aberrant pain (pain-related behavior in response to normally harmless stimuli) and hyperalgesia (overreaction to painful stimuli) in various neuropathic pain models. Gabapentin has been shown to reduce pain responses following peripheral inflammation in animals; however, the drug did not alter immediate pain-related behavior. The clinical significance of these findings remains unclear. In vitro studies have shown that gabapentin binds to the α2δ subunit of voltage-gated calcium channels; however, the clinical significance of this effect remains unclear. Gabapentin is an anticonvulsant whose structure is related to the central nervous system inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Gabapentin encarbi is a prodrug of gabapentin, which is rapidly converted to gabapentin after oral administration; the therapeutic effect of gabapentin encarbi is attributed to gabapentin. Although gabapentin was initially developed as a structural analogue of GABA, intended to cross the blood-brain barrier (unlike GABA) and mimic the role of GABA in inhibitory neuronal synapses, it does not have a direct GABA-mimicking effect, and its exact mechanism of action remains unclear. Some animal studies suggest that gabapentin can prevent seizures and/or tonic spasms induced by GABA antagonists such as cucurbitacin and bisculoline or GABA synthesis inhibitors (e.g., 3-mercaptopropionic acid, isonicotinic acid, and aminourea). However, gabapentin does not appear to bind to GABA receptors, nor does it affect GABA reuptake or metabolism, and it is not a precursor to GABA or other GABA receptor-active substances. Gabapentin has no affinity for binding sites on common neuronal receptors (e.g., benzodiazepines; glutamate; quisquiate; phycocyanine; glycine that is insensitive or sensitive to strychnine; α1-, α2-, or β-adrenergic receptors; adenosine A1 or A2; cholinergic receptors [muscarinic or nicotinic]; dopamine D1 or D2; histamine H1; serotonergic receptors type 1 or 2 [5-HT1 or 5-HT2]; opioid mc, δ, or k) or ion channels (e.g., voltage-sensitive calcium channel sites labeled with nifedipine or diltiazem, and voltage-sensitive sodium channel sites labeled with curare A 20 α-benzoate). Research results regarding the affinity and activity of gabapentin for N-methyl-D-aspartate (NMDA) receptors are controversial. Currently, clinical treatment outcomes for many patients with visceral pain remain unsatisfactory. While preliminary animal studies have shown gabapentin to be effective in treating visceral pain, its analgesic mechanism remains unclear. Other studies suggest that protein kinase C (PKC) and extracellular signal-regulated kinase 1/2 (ERK1/2) are involved in the pathogenesis of visceral inflammatory pain. This study aimed to verify whether gabapentin alleviates visceral inflammatory pain by inhibiting the PKC-ERK1/2 signaling pathway. We induced colitis pain in rats by intracolonic injection of formalin. Our results showed that intraperitoneal injection of gabapentin reduced visceral pain behavior in these rats. Intrathecal injection of the protein kinase C (PKC) inhibitor H-7 and the ERK1/2 inhibitor PD98059 also reduced these behaviors. Intracolonic injection of formalin significantly increased the firing frequency of wide dynamic range neurons in the L6-S1 segment of the dorsal horn of the rat spinal cord. Intraperitoneal injection of gabapentin, as well as intrathecal injection of H-7 and PD98059 alone or in combination, inhibited this increased firing frequency. Western blot analysis also showed a significant increase in PKC membrane translocation and ERK1/2 phosphorylation levels after formalin injection, confirming the recruitment of PKC and ERK1/2 in visceral inflammatory pain. Intraperitoneal injection of gabapentin also significantly alleviated these effects. Therefore, we conclude that the analgesic effect of gabapentin on visceral inflammatory pain is achieved by inhibiting the PKC and ERK1/2 signaling pathways. Furthermore, we found that the PKC inhibitor H-7 significantly reduced ERK1/2 phosphorylation levels, indicating that PKC and ERK1/2 are involved in the same signaling pathway. Therefore, our results suggest a novel mechanism by which gabapentin exerts its analgesic effect on visceral inflammatory pain through the PKC-ERK1/2 signaling pathway, which may be a potential target for future treatment of visceral inflammatory pain. Gabapentin-like drugs (pregabalin and gabapentin) are first-line drugs for the treatment of neuropathic pain. They exert their effects by binding to the α2δ (α2d) helper subunit of voltage-gated Ca2+ channels. Because these subunits interact with key aspects of neurotransmitter release, gabapentin can block signal transduction in nociceptive pathways. Gabapentin can also reduce the expression of voltage-gated Ca2+ channels on the cell membrane, but this may be less relevant to its therapeutic effect. In animal models of neuropathic pain, gabapentin can exert its anti-hyperalgesic effect within 30 minutes, but its in vitro effects are mostly 30 times slower, requiring at least 17 hours to manifest. This difference may be related to elevated α2d expression levels in the damaged nervous system. Therefore, when α2d expression is upregulated in vitro, gabapentin can block the transport of α2d subunits to the nerve ending cell membrane within minutes. However, when α2d expression is not upregulated, gabapentin slowly blocks the transport of α2d protein from the cell body to the nerve ending. A deeper understanding of the mechanism of action of gabapentin is closely related to its slow onset of action in patients with neuropathic pain, the concept that the occurrence and maintenance of neuropathic pain involve different processes, and the application of gabapentin in postoperative pain management.

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Gabapentin hydrochloride (Neurontin) is a GABA analog that works by inhibiting the influx of Ca(2+) into neurons, thereby reducing the release of excitatory neurotransmitters[1].
- The cognitive-enhancing effect of gabapentin hydrochloride may be related to its regulation of hippocampal synaptic plasticity, as the Morris water maze experiment reflects hippocampal-dependent spatial learning and memory[2].
- Gabapentin hydrochloride does not alter the plasma concentration of morphine, suggesting that its synergistic analgesic effect may be mediated through functional interactions of pain signaling pathways rather than pharmacokinetic interactions[3].

C9H17NO2.HCL

207.7

207.103

C, 52.05; H, 8.74; Cl, 17.07; N, 6.74; O, 15.41

60142-95-2

60142-96-3; Gabapentin enacarbil;478296-72-9;Gabapentin hydrochloride;60142-95-2;Gabapentin-d4;1185039-20-6

6453919

White to off-white solid powder

314.4ºC at 760mmHg

148-151℃ (ethanol )

144ºC

2.872

3

3

3

13

162

0

XBUDZAQEMFGLEU-UHFFFAOYSA-N

InChI=1S/C9H17NO2.ClH/c10-7-9(6-8(11)12)4-2-1-3-5-9;/h1-7,10H2,(H,11,12);1H

1-(Aminomethyl)cyclohexaneacetic acid HCl

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: 10 mg/mL (48.15 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)