P/Q type Ca2+ channel

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)[1]. In neocortical slices, gabapentin (100 μM) reduces endogenous aspartate and glutamate's K+-evoked release by 16 and 18%, respectively[1]. In neocortical slices, gabapentin (0-1000 μM) decreases the release of [3H]-noradrenaline evoked by K+ (IC50=48 μM; maximal inhibition of 46%), but not from synaptosomes[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 (5 and 10 mg/kg; ip; once; male BALB/c mice)[2]. ?In male mice, gabapentin (1–100 mg/kg; intraperitoneally; once) exerts analgesic effect and dose-dependently lowers 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].

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]

Absorption, Distribution and Excretion
Absorption of gabapentin is thought to occur solely via facilitated transport by the LAT1 transporter within the intestines. As this process is saturable, the oral bioavailability of gabapentin is inversely proportional to the administered dose - the oral bioavailability of a 900mg/day regimen is approximately 60%, whereas a 4800mg/day regimen results in only 27% bioavailability. The Tmax of gabapentin has been estimated to be 2-3 hours. Food has no appreciable effect on gabapentin absorption.
Gabapentin is eliminated solely in the urine as unchanged drug. Cimetidine, an inhibitor of renal tubular secretion, reduces clearance by approximately 12%, suggesting that some degree of tubular secretion is involved in the renal elimination of gabapentin.
The apparent volume of distribution of gabapentin after IV administration is 58±6 L. The drug is found in the CSF in concentrations approximately 9-20% of the corresponding plasma concentrations and is secreted into breast milk in concentrations similar to that seen in plasma.
Both the plasma clearance and renal clearance of gabapentin are directly proportional to the patient's creatinine clearance due to its primarily renal elimination.
/MILK/ Gabapentin enters maternal milk. It has been calculated that a nursing human infant could be exposed to a maximum dosage of 1 mg/kg/day. This is 5-10% of the usual pediatric (>3 years old) therapeutic dose. In veterinary patients, this appears unlikely to be of significant clinical concern.
The pharmacokinetic properties of gabapentin vary based on the specific formulation of the drug. Following oral administration, gabapentin is absorbed principally in the proximal small intestine via a saturable L-amino acid transport system; as a result, the bioavailability of the drug decreases with increasing doses. Gabapentin gastroretentive tablets are specifically formulated to swell upon contact with gastric fluid to a size that promotes gastric retention for approximately 8-10 hours when taken with a meal; this allows for gradual and slow release of the drug to the proximal small intestine, its principal site of absorption. Following administration of gabapentin gastroretentive tablets in healthy individuals, time to peak plasma concentrations of the drug was increased (about 4-6 hours longer), peak plasma concentrations were increased, and systemic exposure was decreased relative to conventional (immediate-release) gabapentin. Gabapentin enacarbil, a prodrug of gabapentin, is rapidly and efficiently converted to gabapentin by first-pass hydrolysis following oral administration. Unlike gabapentin, gabapentin enacarbil is absorbed via high-capacity transporters throughout the GI tract and is not affected by saturable absorption; this improves bioavailability of the drug and allows for dose-proportional exposure. Food has only a minimal effect on the pharmacokinetics of conventional (immediate-release) formulations of gabapentin, but increases the bioavailability of gabapentin gastroretentive tablets. Administration of gabapentin enacarbil extended-release tablets with food also increases systemic exposure of the drug compared with exposure under fasted conditions.
Less than 3% of gabapentin circulates bound to plasma protein. The apparent volume of distribution of gabapentin after 150 mg intravenous administration is 58 +/- 6 L (mean +/- SD). In patients with epilepsy, steady-state predose (Cmin) concentrations of gabapentin in cerebrospinal fluid were approximately 20% of the corresponding plasma concentrations.
Gabapentin is eliminated from the systemic circulation by renal excretion as unchanged drug. Gabapentin is not appreciably metabolized in humans. ... Gabapentin elimination rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance. In elderly patients, and in patients with impaired renal function, gabapentin plasma clearance is reduced. Gabapentin can be removed from plasma by hemodialysis.
For more Absorption, Distribution and Excretion (Complete) data for GABAPENTIN (9 total), please visit the HSDB record page.

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Metabolism / Metabolites
Gabapentin is not appreciably metabolized in humans - in humans, metabolites account for less than 1% of an administered dose, with the remainder being excreted as unchanged parent drug in the urine.
Elimination is primarily via renal routes, but gabapentin is partially metabolized bo N-methyl-gabapentin in dogs.
All pharmacological actions following gabapentin administration are due to the activity of the parent compound; gabapentin is not appreciably metabolized in humans.
All pharmacological actions following gabapentin administration are due to the activity of the parent compound; gabapentin is not appreciably metabolized in humans.
Route of Elimination: Gabapentin is eliminated from the systemic circulation by renal excretion as unchanged drug.
Gabapentin is not appreciably metabolized in humans.
Half Life: 5-7 hours

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Biological Half-Life
The elimination t_1/2 of gabapentin in patients with normal renal function is 5-7 hours. In patients with reduced renal function, the elimination t_1/2 may be prolonged - in patients with a creatinine clearance of <30 mL/min, the reported half-life of gabapentin was approximately 52 hours.
In dogs ... elimination half life is approximately 2-4 hours.
Gabapentin elimination half-life is 5 to 7 hours and is unaltered by dose or following multiple dosing.
In cats ... elimination half life of 2.8 hours is similar to dogs.

Toxicity Summary
IDENTIFICATION AND USE: Gabapentin is an anticonvulsant structurally related to the inhibitory CNS neurotransmitter gamma-aminobutyric acid (GABA); the drug also possesses analgesic activity. Gabapentin enacarbil is a prodrug of gabapentin. Gabapentin is a white to off-white crystalline solid. Conventional (immediate-release) preparations of gabapentin are used in the management of seizure disorders and in the treatment of postherpetic neuralgia. Gabapentin enacarbil is commercially available as an extended-release tablet formulation for once-daily administration in the treatment of postherpetic neuralgia and primary restless legs syndrome. Gabapentin is also used in veterinary medicine in the treatment of seizures and as an analgesic for treating chronic pain in small animals. HUMAN EXPOSURE AND TOXICITY: Antiepileptic drugs (AEDs), including gabapentin increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Gabapentin can also cause anaphylaxis and angioedema after the first dose or at any time during treatment. Signs and symptoms in reported cases have included difficulty breathing, swelling of the lips, throat, and tongue, and hypotension requiring emergency treatment. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has occurred with gabapentin. ANIMAL STUDIES: A lethal dose of gabapentin was not identified in mice and rats receiving single oral doses as high as 8000 mg/kg. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, sedation, hypoactivity, or excitation. Gabapentin was administered orally to mice and rats in 2-year carcinogenicity studies. No evidence of drug-related carcinogenicity was observed in mice treated at doses up to 2000 mg/kg/day. In rats, increases in the incidence of pancreatic acinar cell adenoma and carcinoma were found in male rats receiving the highest dose (2000 mg/kg), but not at doses of 250 or 1000 mg/kg/day. When pregnant mice received oral doses of gabapentin (500, 1000, or 3000 mg/kg/day) during the period of organogenesis, increased incidences of skeletal variations were observed at the two highest doses. In studies in which rats received oral doses of gabapentin (500 to 2000 mg/kg/day), during pregnancy, increased incidences of hydroureter and/or hydronephrosis were observed at all doses. Likewise, when pregnant rabbits were treated with gabapentin during the period of organogenesis, an increase in embryo-fetal mortality was observed at all doses tested (60, 300, or 1500 mg/kg). Gabapentin did not demonstrate mutagenic or genotoxic potential in several in vitro and in vivo assays. It was negative in the Ames test and the in vitro HGPRT forward mutation assay in Chinese hamster lung cells; it did not produce significant increases in chromosomal aberrations in the in vitro Chinese hamster lung cell assay; it was negative in the in vivo chromosomal aberration assay and in the in vivo micronucleus test in Chinese hamster bone marrow; it was negative in the in vivo mouse micronucleus assay; and it did not induce unscheduled DNA synthesis in hepatocytes from rats given gabapentin.
Gabapentin interacts with cortical neurons at auxillary subunits of voltage-sensitive calcium channels. Gabapentin increases the synaptic concentration of GABA, enhances GABA responses at non-synaptic sites in neuronal tissues, and reduces the release of mono-amine neurotransmitters. One of the mechanisms implicated in this effect of gabapentin is the reduction of the axon excitability measured as an amplitude change of the presynaptic fibre volley (FV) in the CA1 area of the hippocampus. This is mediated through its binding to presynaptic NMDA receptors. Other studies have shown that the antihyperalgesic and antiallodynic effects of gabapentin are mediated by the descending noradrenergic system, resulting in the activation of spinal alpha2-adrenergic receptors. Gabapentin has also been shown to bind and activate the adenosine A1 receptor. Hepatotoxicity
Limited data are available on the hepatotoxicity of gabapentin. In clinical trials in diabetic neuropathy and epilepsy, therapy with gabapentin was not associated with an increased frequency of serum aminotransferase elevations or liver toxicity. Rare individual case reports of liver injury from gabapentin have been published, although the causal relationship of gabapentin with the liver injury was not always clear. The latency to onset in these reports was 1 to 8 weeks and associated with cholestatic pattern of enzyme elevations. Fever and rash have been described but not autoantibody formation. Reported cases have been mild to moderate in severity and self-limited in course. In view of the wide-scale use of gabapentin, liver injury with symptoms or jaundice is clearly quite rare.
Likelihood score: C (probable cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited information indicates that maternal doses of gabapentin up to 2.1 grams daily produce relatively low levels in infant serum. Monitor the infant for drowsiness, adequate weight gain, and developmental milestones, especially in younger, exclusively breastfed infants and when using combinations of anticonvulsant or psychotropic drugs. A single oral dose of either 300 mg or 600 mg given to the mother before cesarean section appeared to have no effect on breastfeeding initiation. An expert consensus guideline indicates that gabapentin is an acceptable choice for refractory restless leg syndrome during lactation.
◉ Effects in Breastfed Infants
Three infants who were 2 to 3 weeks of age and one who was 14 weeks of age were breastfed during maternal use of gabapentin in an average daily dosages of 1575 mg (range 600 mg to 2.1 grams daily). One infant's mother was also taking topiramate and lorazepam and another infant's mother was taking clonazepam. No adverse effects were noted in any of the infants. A follow-up publication by the same authors found no adverse reactions among 3 additional breastfed infants whose mothers were taking gabapentin during pregnancy and lactation.
An exclusively breastfed 5-day-old infant whose mother was taking gabapentin 1.2 grams and levetiracetam 2.5 grams daily during pregnancy and lactation appeared healthy to the investigators throughout the 6- to 8-week study period.
An infant whose mother was taking gabapentin 36.7 mg/kg daily breastfed her infant 6 to 7 times daily for most of the first 1.6 months of life with some additional artificial feeding at night. The mother was also taking amitriptyline 2.5 mg daily. At 1.6 months of age, the infant was found to be healthy with a weight between the 10th and 25th percentiles, having been at the 50th percentile at birth. His age on the Denver developmental test was the same as his chronological age.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.
◈ What is gabapentin?
Gabapentin is a medication that has been used to prevent and control partial seizures, treat some forms of nerve pain, and treat moderate-to-severe restless legs syndrome. Some brand names are Horizant®, Gralise® and Neurontin®.Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take your medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy.
◈ I take gabapentin. Can it make it harder for me to get pregnant?
It is not known if gabapentin can make it harder to get pregnant. Sexual dysfunction (including loss of desire to have sex and loss of ability to have an orgasm) has been reported among people who take gabapentin.
◈ Does taking gabapentin increase the chance of miscarriage?
Miscarriage is common and can occur in any pregnancy for many different reasons. Studies have not been done to see if gabapentin can increase the chance of miscarriage in humans. Animal studies reported an increased chance for miscarriage.
◈ Does taking gabapentin increase the chance of birth defects?
Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Small, controlled studies on gabapentin have not suggested an increased chance of birth defects. There is also no known pattern of birth defects associated with the use of gabapentin in pregnancy.One study looked at the pregnancy outcomes of people who received prescriptions for gabapentin. When looking at the outcomes of all the study participants, gabapentin exposure during early pregnancy does not appear to increase the chance of birth defects above the background risk. When the authors only looked at the data from participants who filled at least two prescriptions for gabapentin in the first trimester, an increased chance of heart defects was seen. Studies based on prescriptions cannot tell if a person took the medication, so it is hard to know if the outcomes are related to the medication being studied or other factors.Gabapentin might lower levels of folic acid in people who take this medication. Some professional organizations recommend that people on this type of medication take a higher dose of folic acid, while other groups do not. Talk with your healthcare provider about how much folic acid is right for you. Please see our MotherToBaby fact sheet and baby blog on folic acid/folate at https://mothertobaby.org/fact-sheets/folic-acid/ and https://mothertobaby.org/baby-blog/folic-acid-is-more-really-better/.
◈ Does taking gabapentin in pregnancy increase the chance of other pregnancy-related problems?
Pregnancy-related problems, such as preterm delivery (birth before week 37) or low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth) have been reported in some studies looking at the use of gabapentin during pregnancy. However, is hard to know if these problems are from the gabapentin, from the underlying health condition(s) being treated, or other factors.
◈ I need to take gabapentin throughout my entire pregnancy. Will it cause withdrawal symptoms in my baby after birth?
Studies have not been done to see if gabapentin use alone can cause withdrawal in a newborn. One study found that when gabapentin is combined with opioids late in pregnancy, withdrawal can occur. It is not known how often withdrawal occurs in babies exposed to this combination. It is important that your healthcare providers know you are taking gabapentin so that if symptoms occur your baby can get the care that is best for them. The baby can be monitored for symptoms such as unusual eye, tongue, and/or muscle movements, restlessness of the arms and legs, and arching of the back after birth.
◈ Does taking gabapentin in pregnancy affect future behavior or learning for the child?
One study that looked at 378 children exposed to gabapentin during pregnancy did not find an increased chance of conditions that affect how the brain works (neurodevelopmental disorders), conditions that cause problems with social and communication skills (pervasive developmental disorders), intellectual disability, or communication-related disorders.
◈ Breastfeeding while taking gabapentin:
Gabapentin enters breastmilk in low levels. Blood tests on breastfed infants found low levels or levels too low to be detected. There are reports of infants exposed to gabapentin through breastmilk; no side effects were noted.If you suspect the baby has any symptoms (such as drowsiness or trouble gaining weight gain), contact the child’s healthcare provider. Be sure to talk to your healthcare provider about all your breastfeeding questions.
◈ If a male takes gabapentin, could it affect fertility or increase the chance of birth defects?
Sexual dysfunction, such as loss of desire to have sex and loss of ability to have an erection, ejaculate, and/or have an orgasm, has been reported in people using gabapentin. In general, exposures that fathers or sperm donors have are unlikely to increase risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

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Protein Binding
Less than 3% of an orally administered dose of gabapentin is bound 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 gamma-amino acid that is cyclohexane substituted at position 1 by aminomethyl and carboxymethyl groups. Used for treatment of neuropathic pain and restless legs syndrome. It has a role as an anticonvulsant, a calcium channel blocker, an environmental contaminant and a xenobiotic. It is functionally related to a gamma-aminobutyric acid.
Gabapentin is a structural analogue of the inhibitory neurotransmitter gamma-aminobutyric acid ([GABA]) that was first approved for use in the United States in 1993. It was originally developed as a novel anti-epileptic for the treatment of certain types of seizures - today it is also widely used to treat neuropathic pain. Gabapentin has some stark advantages as compared with other anti-epileptics, such as a relatively benign adverse effect profile, wide therapeutic index, and lack of appreciable metabolism making it unlikely to participate in pharmacokinetic drug interactions.. It is structurally and functionally related to another GABA derivative, [pregabalin].
The physiologic effect of gabapentin is by means of Decreased Central Nervous System Disorganized Electrical Activity.
Gabapentin is a unique anticonvulsant that is used as adjunctive therapy in management of epilepsy and for neuropathic pain syndromes. Therapy with gabapentin is not associated with serum aminotransferase elevations, but several cases of clinically apparent liver injury from gabapentin have been reported.
Gabapentin is a synthetic analogue of the neurotransmitter gamma-aminobutyric acid with anticonvulsant activity. Although its exact mechanism of action is unknown, gabapentin appears to inhibit excitatory neuron activity. This agent also exhibits analgesic properties. (NCI04)
Gabapentin was originally developed as a chemical analogue of gamma-aminobutyric acid (GABA) to reduce the spinal reflex for the treatment of spasticity and was found to have anticonvulsant activity in various seizure models. In addition, it also displays antinociceptive activity in various animal pain models. Clinically, gabapentin is indicated as an add-on medication for the treatment of partial seizures, and neuropathic pain. It was also claimed to be beneficial in several other clinical disorders such as anxiety, bipolar disorder, and hot flashes. The possible mechanisms or targets involved in the multiple therapeutic actions of gabapentin have been actively studied. Since gabapentin was developed, several hypotheses had been proposed for its action mechanisms. They include selectively activating the heterodimeric GABA(B) receptors consisting of GABA(B1a) and GABA(B2) subunits, selectively enhancing the NMDA current at GABAergic interneurons, or blocking AMPA-receptor-mediated transmission in the spinal cord, binding to the L-alpha-amino acid transporter, activating ATP-sensitive K(+) channels, activating hyperpolarization-activated cation channels, and modulating Ca(2+) current by selectively binding to the specific binding site of [(3)H]gabapentin, the alpha(2)delta subunit of voltage-dependent Ca(2+) channels. Different mechanisms might be involved in different therapeutic actions of gabapentin. In this review, we summarized the recent progress in the findings proposed for the antinociceptive action mechanisms of gabapentin and suggest that the alpha(2)delta subunit of spinal N-type Ca(2+) channels is very likely the analgesic action target of gabapentin. (A7831).
A cyclohexane-gamma-aminobutyric acid derivative that is used for the treatment of PARTIAL SEIZURES; NEURALGIA; and RESTLESS LEGS SYNDROME.
See also: Gabapentin Enacarbil (active moiety of).

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Drug Indication
In the United States, gabapentin is officially indicated for the treatment of postherpetic neuralgia in adults and for the adjunctive treatment of partial-onset seizures, with or without secondary generalization, in patients 3 years of age and older. In Europe, gabapentin is indicated for adjunctive therapy in the treatment of partial-onset seizures, with or without secondary generalization, in patients 6 years of age and older and as monotherapy in patients 12 years of age and older. It is also used in adults for the treatment of various types of peripheral neuropathic pain, such as painful diabetic neuropathy.
Treatment of chronic pain
Treatment of postherpetic neuralgia

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Mechanism of Action
The precise mechanism through which gabapentin exerts its therapeutic effects is unclear. The primary mode of action appears to be at the auxillary α2δ-1 subunit of voltage-gated calcium channels (though a low affinity for the α2δ-2 subunit has also been reported). The major function of these subunits is to facilitate the movement of pore-forming α1 subunits of calcium channels from the endoplasmic reticulum to the cell membrane of pre-synaptic neurons. There is evidence that chronic pain states can cause an increase in the expression of α2δ subunits and that these changes correlate with hyperalgesia. Gabapentin appears to inhibit the action of α2δ-1 subunits, thus decreasing the density of pre-synaptic voltage-gated calcium channels and subsequent release of excitatory neurotransmitters. It is likely that this inhibition is also responsible for the anti-epileptic action of gabapentin. There is some evidence that gabapentin also acts on adenosine receptors and voltage-gated potassium channels, though the clinical relevance of its action at these sites is unclear.
Although the exact mechanism by which gabapentin exerts its analgesic effects is not known, the drug has been shown to prevent allodynia (pain-related behavior in response to normally innocuous stimuli) and hyperalgesia (exaggerated response to painful stimuli) in several models of neuropathic pain. Gabapentin also has been shown to decrease pain-related responses after peripheral inflammation in animals; however, the drug has not altered immediate pain-related behaviors. The clinical relevance of these findings is not known. In vitro studies demonstrate that gabapentin binds to the alpha2delta subunit of voltage-activated calcium channels; however, the clinical importance of this effect is not known.
Gabapentin is an anticonvulsant agent structurally related to the inhibitory CNS neurotransmitter gamma-aminobutyric acid (GABA). Gabapentin enacarbil is a prodrug of gabapentin that is rapidly converted to gabapentin following oral administration; the therapeutic effects of gabapentin enacarbil are attributed to gabapentin. Although gabapentin was developed as a structural analog of GABA that would penetrate the blood-brain barrier (unlike GABA) and mimic the action of GABA at inhibitory neuronal synapses, the drug has no direct GABA-mimetic action and its precise mechanism of action has not been elucidated.
Results of some studies in animals indicate that gabapentin protects against seizure and/or tonic extensions induced by the GABA antagonists picrotoxin and bicuculline or by GABA synthesis inhibitors (e.g., 3-mercaptopropionic acid, isonicotinic acid, semicarbazide). However, gabapentin does not appear to bind to GABA receptors nor affect GABA reuptake or metabolism and does not act as a precursor of GABA or of other substances active at GABA receptors. Gabapentin also has no affinity for binding sites on common neuroreceptors (e.g., benzodiazepine; glutamate; quisqualate; kainate; strychnine-insensitive or -sensitive glycine; alpha1-, alpha2-, or beta-adrenergic; adenosine A1 or A2; cholinergic [muscarinic or nicotinic]; dopamine D1 or D2; histamine H1; type 1 or 2 serotonergic [5-HT1 or 5-HT2]; opiate mc, delta, or k) or ion channels (e.g., voltage-sensitive calcium channel sites labeled with nitrendipine or diltiazem, voltage-sensitive sodium channel sites labeled with batrachotoxinin A 20alpha-benzoate). Conflicting results have been reported in studies of gabapentin affinity for and activity at N-methyl-d-aspartic acid (NMDA) receptors.
Currently, the clinical management of visceral pain remains unsatisfactory for many patients suffering from this disease. While preliminary animal studies have suggested the effectiveness of gabapentin in successfully treating visceral pain, the mechanism underlying its analgesic effect remains unclear. Evidence from other studies has demonstrated the involvement of protein kinase C (PKC) and extracellular signal-regulated kinase1/2 (ERK1/2) in the pathogenesis of visceral inflammatory pain. In this study, we tested the hypothesis that gabapentin produces analgesia for visceral inflammatory pain through its inhibitory effect on the PKC-ERK1/2 signaling pathway. Intracolonic injections of formalin were performed in rats to produce colitis pain. Our results showed that visceral pain behaviors in these rats decreased after intraperitoneal injection of gabapentin. These behaviors were also reduced by intrathecal injections of the PKC inhibitor, H-7, and the ERK1/2 inhibitor, PD98059. Neuronal firing of wide dynamic range neurons in L6-S1 of the rat spinal cord dorsal horn were significantly increased after intracolonic injection of formalin. This increased firing rate was inhibited by intraperitoneal injection of gabapentin and both the individual and combined intrathecal application of H-7 and PD98059. Western blot analysis also revealed that PKC membrane translocation and ERK1/2 phosphorylation increased significantly following formalin injection, confirming the recruitment of PKC and ERK1/2 during visceral inflammatory pain. These effects were also significantly reduced by intraperitoneal injection of gabapentin. Therefore, we concluded that the analgesic effect of gabapentin on visceral inflammatory pain is mediated through suppression of PKC and ERK1/2 signaling pathways. Furthermore, we found that the PKC inhibitor, H-7, significantly diminished ERK1/2 phosphorylation levels, implicating the involvement of PKC and ERK1/2 in the same signaling pathway. Thus, our results suggest a novel mechanism of gabapentin-mediated analgesia for visceral inflammatory pain through a PKC-ERK1/2 signaling pathway that may be a future therapeutic target for the treatment of visceral inflammatory pain.
The gabapentinoids (pregabalin and gabapentin) are first line treatments for neuropathic pain. They exert their actions by binding to the alpha2delta (a2d) accessory subunits of voltage-gated Ca2+ channels. Because these subunits interact with critical aspects of the neurotransmitter release process, gabapentinoid binding prevents transmission in nociceptive pathways. Gabapentinoids also reduce plasma membrane expression of voltage-gated Ca2+ channels but this may have little direct bearing on their therapeutic actions. In animal models of neuropathic pain, gabapentinoids exert an anti-allodynic action within 30 minutes but most of their in vitro effects are 30-fold slower, taking at least 17 hours to develop. This difference may relate to increased levels of a2d expression in the injured nervous system. Thus, in situations where a2d is experimentally upregulated in vitro, gabapentinoids act within minutes to interrupt trafficking of a2d subunits to the plasma membrane within nerve terminals. When a2d is not up-regulated, gabapentinoids act slowly to interrupt trafficking of a2d protein from cell bodies to nerve terminals. This improved understanding of the mechanism of gabapentinoid action is related to their slowly developing actions in neuropathic pain patients, to the concept that different processes underlie the onset and maintenance of neuropathic pain and to the use of gabapentinoids in management of postsurgical pain.

C9H17NO2

171.24

171.125

C, 63.13; H, 10.01; N, 8.18; O, 18.69

60142-96-3

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

3446

White to off-white solid powder

1.1±0.1 g/cm3

314.4±15.0 °C at 760 mmHg

162°C

144.0±20.4 °C

0.0±1.4 mmHg at 25°C

1.489

1.19

2

3

3

12

162

0

UGJMXCAKCUNAIE-UHFFFAOYSA-N

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

2-[1-(aminomethyl)cyclohexyl]acetic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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: 25 mg/mL (145.99 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication (<60°C).

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