DHEC mesylate attenuates pathologies and aberrant bisecting N-glycosylation in Alzheimer's disease models.

Tremendous progress has been made to develop the therapy of Alzheimer's disease (AD). Existing several anti-AD remedies, with certain limitations, are far from adequate. Evidence suggests that dihydroergocristine (DHEC) mesylate, one of the main components of Ergoloid mesylates, can reduce the production of amyloid-ß in vitro. However, the therapeutic effect of DHEC mesylate in AD and its underlying mechanism are still largely unknown. Herein, we characterized the pharmacological effect of DHEC mesylate in AD and found that the spatial memory disorders and Alzheimer-type pathologies were alleviated by DHEC mesylate administration. Moreover, we demonstrated that DHEC mesylate improved aberrant bisecting N-glycosylation, which was identified as a potential biomarker of AD. We further explored the underlying mechanism and confirmed that DHEC mesylate protected against AD via AMPK and ERK signaling, in which, AMPK was the dominant down-stream molecule of DHEC mesylate. In summary, our findings provide foundations for development of DHEC mesylate as a therapeutic approach for AD.

Proteostasis Regulators Restore Function of Epilepsy-Associated GABAA Receptors.

Proteostasis deficiency in mutated ion channels leads to a variety of ion channel diseases that are caused by excessive endoplasmic reticulum-associated degradation (ERAD) and inefficient membrane trafficking. We investigated proteostasis maintenance of γ-aminobutyric acid type A (GABAA) receptors, the primary mediators of neuronal inhibition in the mammalian central nervous system. We screened a structurally diverse, Food and Drug Administration-approved drug library and identified dinoprost (DNP) and dihydroergocristine (DHEC) as highly efficacious enhancers of surface expression of four epilepsy-causing trafficking-deficient mutant receptors. Furthermore, DNP and DHEC restore whole-cell and synaptic currents by incorporating mutated subunits into functional receptors. Mechanistic studies revealed that both drugs reduce subunit degradation by attenuating the Grp94/Hrd1/Sel1L/VCP-mediated ERAD pathway and enhance the subunit folding by promoting subunit interactions with major GABAA receptors-interacting chaperones, BiP and calnexin. In summary, we report that DNP and DHEC remodel the endoplasmic reticulum proteostasis network to restore the functional surface expression of mutant GABAA receptors.

In Vitro Effect and Mechanism of Action of Ergot Alkaloid Dihydroergocristine in Chemoresistant Prostate Cancer Cells.

BACKGROUND/AIM: Chemoresistance is a major obstacle in the treatment of prostate cancer (PCa). It is imperative to develop novel strategies for overcoming chemoresistance and improving clinical outcomes. We evaluated the in vitro activity and mechanism of action of dihydroergocristine (DHECS), an ergot alkaloid approved for the treatment of dementia, in PCa cells. MATERIALS AND METHODS: The in vitro effects of DHECS on PCa cell cycle and viability were determined by flow cytometry and colorimetric assay. The effects of DHECS on PCa cell signaling were evaluated by quantitative PCR, western blot analysis and reporter assay. RESULTS: DHECS was effective in inducing cell cycle arrest and apoptosis in human PCa cells. Of particular interest, DHECS demonstrated high potency against chemoresistant PCa cells. At the molecular level, DHECS affected multiple factors implicated in the regulation of cancer cell cycle and programmed cell death, including p53, mouse double minute 2 homolog (MDM2), retinoblastoma protein (RB), p21, E2F transcription factor 1 (E2F1), survivin, myeloid cell leukemia 1 (Mcl-1) and poly ADP ribose polymerase (PARP). Furthermore, DHECS may function through dopamine receptor-mediated effects on 5'-AMP-activated protein kinase (AMPK) and nuclear factor kappa B (NF-ĸB). CONCLUSION: DHECS has the potential to be repurposed as a novel anticancer agent for the management of chemoresistant PCa.

Associations between fruits, vegetables, vitamin A, ß-carotene and flavonol dietary intake, and age-related macular degeneration in elderly women in Korea: the Fifth Korea National Health and Nutrition Examination Survey.

BACKGROUND/OBJECTIVES: Age-related macular degeneration (AMD) is one of the principal causes of blindness. This study investigated the association between diet and the prevalence of AMD in elderly Korean women. SUBJECTS/METHODS: Study subjects were women aged ⩾65 years (n=1008) from the Korea National Health and Nutrition Examination Survey (2010-2012). The presence of early- and late-onset AMD was determined on the basis of a fundus photograph from a health examination survey. Food intake was estimated using 24 h recall. RESULTS: The prevalence of AMD was 18.8% in elderly women in Korea. Multiple logistic regression analysis showed a significant negative association between vegetable intake and AMD (odds ratio (OR) 0.44, 95% confidence interval (CI) 0.25, 0.77, P for trend=0.002) after adjusting for age, body mass index, postmenopausal period, duration of hormone replacement therapy, residential area, education level, family income, smoking status, alcohol consumption, dietary supplement use and total energy intake. After adjusting for potential confounders, the ORs between extreme quartiles were 0.55 (95% CI 0.29, 1.05, P for trend=0.070) for fruit and vegetable intake, 0.38 (95% CI 0.21, 0.68, P for trend=0.001) for vitamin A, 0.36 (95% CI 0.19, 0.67, P for trend<0.001) for ß-carotene and 0.45 (95% CI 0.25, 0.82, P for trend=0.008) for flavonols. CONCLUSIONS: These results suggest that higher consumption of fruits and vegetables containing antioxidant nutrients and phytochemicals may provide some protection against AMD.

Electrochemical simulation of biotransformation reactions of citrinin and dihydroergocristine compared to UV irradiation and Fenton-like reaction.

Mycotoxins occur widely in foodstuffs and cause a variety of mold-related health risks to humans and animals. Elucidation of the metabolic fate of mycotoxins and the growing number of newly discovered mycotoxins have enhanced the demand for fast and reliable simulation methods. The viability of electrochemistry coupled with mass spectrometry (EC/ESI-MS), Fenton-like oxidation, and UV irradiation for the simulation of oxidative phase I metabolism of the mycotoxins citrinin (CIT) and dihydroergocristine (DHEC) was investigated. The specific reaction products are compared with metabolites produced by human and rat liver microsomes in vitro. Depending on the applied potential between 0 and 2000 mV vs. Pd/H2 by using a flow-through cell, CIT and DHEC are oxidized to various products. Besides dehydrogenation and dealkylation reactions, several hydroxylated DHEC and CIT species are produced by EC and Fenton-like reaction, separated and analyzed by LC-MS/MS and ESI-HRMS. Compared to reaction products from performed microsomal incubations, several mono- and dihydroxylated DHEC species were found to be similar to the reaction products of EC, Fenton-like reaction, and UV-induced oxidation. Consequentially, nonmicrosomal efficient and economic simulation techniques can be useful in early-stage metabolic studies, even if one-to-one simulation is not always feasible.

The FDA-approved natural product dihydroergocristine reduces the production of the Alzheimer's disease amyloid-ß peptides.

Known γ-secretase inhibitors or modulators display an undesirable pharmacokinetic profile and toxicity and have therefore not been successful in clinical trials for Alzheimer's disease (AD). So far, no compounds from natural products have been identified as direct inhibitors of γ-secretase. To search for bioactive molecules that can reduce the amount of amyloid-beta peptides (Aß) and that have better pharmacokinetics and an improved safety profile, we completed a screen of ~400 natural products by using cell-based and cell-free γ-secretase activity assays. We identified dihydroergocristine (DHEC), a component of an FDA- (Food and Drug Administration)-approved drug, to be a direct inhibitor of γ-secretase. Micromolar concentrations of DHEC substantially reduced Aß levels in different cell types, including a cell line derived from an AD patient. Structure-activity relationship studies implied that the key moiety for inhibiting γ-secretase is the cyclized tripeptide moiety of DHEC. A Surface Plasmon Resonance assay showed that DHEC binds directly to γ-secretase and Nicastrin, with equilibrium dissociation constants (Kd) of 25.7 nM and 9.8 µM, respectively. This study offers DHEC not only as a new chemical moiety for selectively modulating the activity of γ-secretase but also a candidate for drug repositioning in Alzheimer's disease.

The Effects of Anti-Dementia and Nootropic Treatments on the Mortality of Patients with Dementia: A Population-Based Cohort Study in Taiwan.

BACKGROUND: Few studies have examined the contribution of treatment on the mortality of dementia based on a population-based study. OBJECTIVE: To investigate the effects of anti-dementia and nootropic treatments on the mortality of dementia using a population-based cohort study. METHODS: 12,193 incident dementia patients were found from 2000 to 2010. Their data were compared with 12,193 age- and sex-matched non-dementia controls that were randomly selected from the same database. Dementia was classified into vascular (VaD) and degenerative dementia. Mortality incidence and hazard ratios (HRs) were calculated. RESULTS: The median survival time was 3.39 years (95% confidence interval [CI]: 2.88-3.79) for VaD without medication, 6.62 years (95% CI: 6.24-7.21) for VaD with nootropics, 3.01 years (95% CI: 2.85-3.21) for degenerative dementia without medication, 8.11 years (95% CI: 6.30-8.55) for degenerative dementia with anti-dementia medication, 6.00 years (95% CI: 5.73-6.17) for degenerative dementia with nootropics, and 9.03 years (95% CI: 8.02-9.87) for degenerative dementia with both anti-dementia and nootropic medications. Compared to the non-dementia group, the HRs among individuals with degenerative dementia were 2.69 (95% CI: 2.55-2.83) without medication, 1.46 (95% CI: 1.39-1.54) with nootropics, 1.05 (95% CI: 0.82-1.34) with anti-dementia medication, and 0.92 (95% CI: 0.80-1.05) with both nootropic and anti-dementia medications. VaD with nootropics had a lower mortality (HR: 1.25, 95% CI: 1.15-1.37) than VaD without medication (HR: 2.46, 95% CI: 2.22-2.72). CONCLUSION: Pharmacological treatments have beneficial effects for patients with dementia in prolonging their survival.

Antiallodynic effects of intrathecal tianeptine in a neuropathic pain rat

BACKGROUND: Tianeptine is an antidepressant drug which is used for treating depression. Interestingly, the tianeptine has shown antinociceptive effects within a variety of nociceptions. The aim of this study is to investigate the antiallodynic effects of tianeptine in neuropathic pain rats and also determine the involvements of serotonergic, alpha-2 adrenergic and adenosine receptors at the spinal level. METHODS: Neuropathic pain was induced by ligation of left lumbar at 5th and 6th spinal nerves in male Sprague-Dawley rats. PE-10 catheters were placed into the thoracolumbar subarachnoid space for drug injections. Mechanical allodynia was evaluated by measuring the withdrawal threshold to von Frey filament when applying on the plantar surface of rats. The effects of intrathecal tianeptine were observed at 15, 30, 60, 90, 120, 150, 180 minutes after delivery. Antagonists for serotonergic (dihydroergocristine), alpha-2 adrenergic (yohimbine) and adenosine (CGS 15943) receptors were intrathecally administered 10 minutes prior to tianeptine in order to evaluate the involvement of both receptors. RESULTS: Intrathecal tianeptine increased dose-dependently at the withdrawal threshold in the ligated paw. Pretreatment with intrathecal dihydroergocristine, yohimbine and CGS 15943 antagonized the antiallodynic effects of tianeptine. CONCLUSIONS: These results suggested that intrathecal tianeptine attenuates the spinal nerve ligation induced tactile allodynia. Serotonergic, alpha-2 adrenergic and adenosine receptors are all involved in the antiallodynic effects of tianeptine at the spinal level.

Roles of Serotonergic and Adrenergic Receptors in the Antinociception of Selective Cyclooxygenase-2 Inhibitor in the Rat Spinal Cord

BACKGROUND: The analgesic mechanisms of cyclooxygenase (COX)-2 inhibitors have been explained mainly on the basis of the inhibition of prostaglandin biosynthesis. However, several lines of evidence suggest that their analgesic effects are mediated through serotonergic or adrenergic transmissions. We investigated the roles of these neurotransmitters in the antinociception of a selective COX-2 inhibitor at the spinal level. METHODS: DUP-697, a selective COX-2 inhibitor, was delivered through an intrathecal catheter to male Sprague-Dawley rats to examine its effect on the flinching responses evoked by formalin injection into the hindpaw. Subsequently, the effects of intrathecal pretreatment with dihydroergocristine, prazosin, and yohimbine, which are serotonergic, alpha1 adrenergic and alpha2 adrenergic receptor antagonists, respectively, on the analgesia induced by DUP-697 were assessed. RESULTS: Intrathecal DUP-697 reduced the flinching response evoked by formalin injection during phase 1 and 2. But, intrathecal dihydroergocristine, prazosin, and yohimbine had little effect on the antinociception of intrathecal DUP-697 during both phases of the formalin test. CONCLUSIONS: Intrathecal DUP-697, a selective COX-2 inhibitor, effectively relieved inflammatory pain in rats. Either the serotonergic or adrenergic transmissions might not be involved in the analgesic activity of COX-2 inhibitors at the spinal level.

Roles of adenosine and serotonin receptors on the antinociception of sildenafil in the spinal cord of rats.

PURPOSE: The phosphodiesterase 5 inhibitor sildenafil has antinociceptive effects, mediated by an increase in cGMP. This study examined the role of spinal adenosine and serotonin receptors played in the antinociceptive effects of intrathecal sildenafil. MATERIALS AND METHODS: Intrathecal catheters were inserted into the subarachnoid space of Sprague-Dawley male rats as a drug delivery device. Pain was induced by injecting formalin into the plantar surface of rats and observing nociceptive behavior (flinching response) for 60 minutes. Then, the effects of intrathecal adenosine and serotonin receptor antagonists on the antinociceptive activity of intrathecal sildenafil were examined. RESULTS: Intrathecal sildenafil suppressed the flinching response in a dose-dependent manner during phases 1 and 2 in the formalin test. Both CGS 15943 and dihydroergocristine decreased the antinociceptive effects of sildenafil during phases 1 and 2 in the formalin test. CONCLUSION: Intrathecal sildenafil effectively attenuated the pain evoked by formalin injection. Both adenosine and serotonin receptors may be involved in the antinociceptive action of sildenafil at the spinal level.

High-performance liquid chromatographic determination of dihydroergocristine in a pharmaceutical formulation with fluorescence detection.

A rapid procedure based on a direct extraction and HPLC determination of dihydroergocristine in a pharmaceutical preparation with fluorescence detection has been developed and validated. The optimized chromatographic conditions included a Purospher RP18e column, 5 microm particle size, 250 x 4.0 mm, and 25 mM potassium dihydrogen phosphate buffer (pH 2.8)-acetonitrile (60 + 40, v/v) mobile phase at a flow rate of 1 ml/min. The separation was carried out at 50 degrees C, and the injection volume was 5 microL. Fluorescence detection was performed at an excitation and emission wavelength of 224 and 344 nm, respectively. The mobile phase parameters such as organic solvent composition, temperature, and pH were studied. The proposed method has the advantages of a very simple sample pretreatment and fast HPLC determination.

Roles of Adenosine and Serotonin Receptors on the Antinociception of Sildenafil in the Spinal Cord of Rats

PURPOSE: The phosphodiesterase 5 inhibitor sildenafil has antinociceptive effects, mediated by an increase in cGMP. This study examined the role of spinal adenosine and serotonin receptors played in the antinociceptive effects of intrathecal sildenafil. MATERIALS AND METHODS: Intrathecal catheters were inserted into the subarachnoid space of Sprague-Dawley male rats as a drug delivery device. Pain was induced by injecting formalin into the plantar surface of rats and observing nociceptive behavior (flinching response) for 60 mininutes. Then, the effects of intrathecal adenosine and serotonin receptor antagonists on the antinociceptive activity of intrathecal sildenafil were examined. RESULTS: Intrathecal sildenafil suppressed the flinching response in a dose-dependent manner during phases 1 and 2 in the formalin test. Both CGS 15943 and dihydroergocristine decreased the antinociceptive effects of sildenafil during phases 1 and 2 in the formalin test. CONCLUSION: Intrathecal sildenafil effectively attenuated the pain evoked by formalin injection. Both adenosine and serotonin receptors may be involved in the antinociceptive action of sildenafil at the spinal level.

Estudo do metabolismo, quimica e farmacocinetica do principal metabolito da diidroergocristina / Metabolic, chemical and pharmacokinetics of the main diidroergocristine metabolite

Diidroergocristina (DHEC) é um fármaco semi-sintético, derivada do alcalóide do Ergot, principalmente utilizada para enxaqueca e estudada em distúrbios cognitivos relacionados ao envelhecimento. No presente estudo, o seu principal metabólito 8-hidroxidiidroergocristina (8'-OH-DHEC) foi produzido através de incubação de preparações enzimáticas de fígado de boi usando o Mesilato de Diidroergocristina como substrato. Foi feita uma avaliação de qual o melhor método de preparação enzimática a ser utilizado para produção do padrão do metabólito ativo em grande escala através da comparação de atividade enzimática entre microssomos e S12, ambos extraídos de heptócitos de fígado bovino. A purificação desse metabólito foi feita através da utilização de uma coluna cromatográfica clássica com sílica gel e cromatografia líquida de fase reversa. Sua identificação foi baseada em mensuração de sua massa molecular por espectro de fragmentação de massa e Ressonância Magnética (NMR - 1H/13C). Através da produção dessa substância in vitro, um método rápido, sensível e robusto de determinação da DHEC e seu principal metabólito foi desenvolvido e validado em LC-MS/MS a partir de análise de plasma humano. Bromocriptina foi utilizado com padrão interno e os limites de quantificação da DHEC e 8-OH-DHEC foram 10 pg/ml e 20 pg/ml, respectivamente. Os parâmetros farmacocinéticos foram investigados em 12 voluntários masculinos através da administração de uma dose única oral de 18mg...

Dihydroergocristine (DHEC) is a semi-synthetic drug mainly used for migraine and studied in age-related cognitive impairment. In this study, its major metabolite 8´-hydroxy-dihydroergocristine (8´-OH-DHEC) was produced in incubates of a bovine liver preparation using dihydroergocristine mesylate (DHECM) as substrate. An evaluation of the best enzymatic preparation method was done in order to verify the adequate process for massive production of the metabolite. A comparison between microssomes and S12 was performed, where both preparations were extracted from bovine hepatocytes. Purification was achieved by flash silica gel column and reverse phase liquid chromatographies, and identification was based on accurate molecular mass measurements, mass fragmentation spectra and NMR (1H/13C) chemical shifts. By using the substance produced in vitro, a fast, sensitive, specific and robust LC/MS/MS method for the simultaneous determination of DHEC and its major metabolite in human plasma was...

Erupción liquenoide inducida por olanzapina / Lichenoid drug eruption induced by olanzapine

Las erupciones liquenoides inducidas por fármacos pueden simular un liquen plano idiopático y otras dermatosis. La lista de fármacos que pueden inducirlas es amplia y se incrementa constantemente. Aunque los efectos secundarios cutáneos en relación con antipsicóticos son raros, se han descrito diversas manifestaciones cutáneas en relación con la olanzapina. Presentamos el caso de una paciente que desarrolló una erupción liquenoide atípica debida a olanzapina. En la revisión de la literatura que hemos realizado (Medline desde 1951 hasta 2007 e Índice Médico Español) no hemos encontrado ningún caso descrito de erupción liquenoide relacionado con este fármaco (AU)

Lichenoid drug eruptions can mimic idiopathic lichen planus and other dermatoses. The list of drugs that can cause them is long and growing steadily. Although cutaneous side effects of antipsychotics are rare, various cutaneous manifestations have been reported in association with olanzapine. We present the case of a patient who developed an atypical lichenoid eruption due to olanzapine. A review of the literature in Medline from 1951 to 2007 and in the Índice Médico Español (Spanish Medical Index) revealed no previous cases of lichenoid eruptions associated with the use of this drug (AU)

Identification and human pharmacokinetics of dihydroergotoxine metabolites in man: preliminary results.

Dihydroergotoxine is a mixture of semi-synthetic ergot alkaloids mainly used for age-related cognitive impairment. In this study, dihydroergotoxine (30 microM) was added to incubates of rat and bovine liver microsomes, and the resulting major metabolites were identified as hydroxy-dihydroergocornine, hydroxy-dihydroergocryptine and hydroxy-dihydroergocristine on the basis of molecular mass measurements, determined with a time-of-flight mass spectrometer. The relevance of these to humans was then investigated by simultaneously monitoring dihydroergotoxine and its hydroxy-metabolites in human plasma by LC-MS/MS after oral dosing of dihydroergotoxine mesylate (27 mg) to a healthy volunteer (male, age 45, height 1.93 m, weight 103 kg). In this preliminary approach, the peaks (C(max)) of dihydroergocornine, dihydroergocryptine and dihydroergocristine were about 0.04 microg/l. The peaks (C(max)) of their hydroxy-metabolites were 0.98, 0.53 and 0.30 microg/l, respectively. In conclusion, in this preliminary approach it was found that hydroxy-dihydroergocornine, hydroxy-dihydroergocryptine and hydroxy-dihydroergocristine were one order of magnitude higher in concentration than their parents in human plasma.

Pharmacokinetics of dihydroergocristine and its major metabolite 8'-hydroxy-dihydroergocristine in human plasma.

Dihydroergocristine (DHEC) is a semi-synthetic drug mainly used for age-related cognitive impairment. In this study, its major metabolite 8'-hydroxy-dihydroergocristine (8'-OH-DHEC) was produced in incubates of a bovine liver preparation using dihydroergocristine mesylate (DHECM) as substrate. Purification was achieved by flash silica gel column and reverse phase liquid chromatographies, and identification was based on accurate molecular mass measurements, mass fragmentation spectra and NMR ((1)H/(13)C) chemical shifts. By using the substance produced in vitro, a fast, sensitive, specific and robust LC/MS/MS method for the simultaneous determination of DHEC and its major metabolite in human plasma was developed and validated. Bromocriptine was used as internal standard and limits of quantification for DHEC and 8'-OH-DHEC were 10 pg/ml and 20 pg/ml, respectively. Pharmacokinetic parameters were investigated on 12 male healthy volunteers to whom a single dose of 18 mg DHECM was administered in tablets (Iskevert). The peak of DHEC was 0.28 +/- 0.22 microg/l, the t(max) 0.46 +/- 0.26 h, the AUC(last) 0.39 +/- 0.41 microg/l.h and the terminal elimination half-life 3.50 +/- 2.27 h. The peak of 8'-OH-DHEC was 5.63 +/- 3.34 microg/l, the t(max) 1.04 +/- 0.66 h, the AUC(last) 13.36 +/- 5.82 microg/l.h and the terminal elimination half-life 3.90 +/- 1.07 h. Dosing of 18 mg DHECM was well tolerated, causing no adverse events.

Spinal gabapentin and antinociception: mechanisms of action.

Spinal gabapentin has been known to show the antinociceptive effect. Although several assumptions have been suggested, mechanisms of action of gabapentin have not been clearly established. The present study was undertaken to examine the action mechanisms of gabapentin at the spinal level. Male SD rats were prepared for intrathecal catheterization. The effect of gabapentin was assessed in the formalin test. After pretreatment with many classes of drugs, changes of effect of gabapentin were examined. General behaviors were also observed. Intrathecal gabapentin produced a suppression of the phase 2 flinching, but not phase 1 in the formalin test. The antinociceptive action of intrathecal gabapentin was reversed by intrathecal NMDA, AMPA, D-serine, CGS 15943, atropine, and naloxone. No antagonism was seen following administration of bicuculline, saclofen, prazosin, yohimbine, mecamylamine, L-leucine, dihydroergocristine, or thapsigargin. Taken together, intrathecal gabapentin attenuated only the facilitated state. At the spinal level, NMDA receptor, AMPA receptor, nonstrychnine site of NMDA receptor, adenosine receptor, muscarinic receptor, and opioid receptor may be involved in the antinociception of gabapentin, but GABA receptor, L-amino acid transporter, adrenergic receptor, nicotinic receptor, serotonin receptor, or calcium may not be involved.

Spinal Gabapentin and Antinociception: Mechanisms of Action

Spinal gabapentin has been known to show the antinociceptive effect. Although several assumptions have been suggested, mechanisms of action of gabapentin have not been clearly established. The present study was undertaken to examine the action mechanisms of gabapentin at the spinal level. Male SD rats were prepared for intrathecal catheterization. The effect of gabapentin was assessed in the formalin test. After pretreatment with many classes of drugs, changes of effect of gabapentin were examined. General behaviors were also observed. Intrathecal gabapentin produced a suppression of the phase 2 flinching, but not phase 1 in the formalin test. The antinociceptive action of intrathecal gabapentin was reversed by intrathecal NMDA, AMPA, D-serine, CGS 15943, atropine, and naloxone. No antagonism was seen following administration of bicuculline, saclofen, prazosin, yohimbine, mecamylamine, L-leucine, dihydroergocristine, or thapsigargin. Taken together, intrathecal gabapentin attenuated only the facilitated state. At the spinal level, NMDA receptor, AMPA receptor, nonstrychnine site of NMDA receptor, adenosine receptor, muscarinic receptor, and opioid receptor may be involved in the antinociception of gabapentin, but GABA receptor, L-amino acid transporter, adrenergic receptor, nicotinic receptor, serotonin receptor, or calcium may not be involved.