Effect of NMDA receptor blocker in relieving HIV-1/gp120 induced learning and memory disorder in rats and its mechanism / 中国药理学通报

Aim: To investigate the alleviating effect of NMDA receptor blocking on learning and memory impairment induced by gp120 in rats and its mechanism. Methods: (1 ) Thirty-two SD rats were randomly divided into control group, sham operation group, gpl20 group, and gp120 + Memantine group. Except for the control group, the other groups underwent a bilateral hippocampal injection to establish the model of learning and memory impairment in rats. Memantine (10 mg • kg

Receptores NMDA: fundamentos e implicaciones terapéuticas en el manejo del dolor / NMDA receptors: foundations and therapeutic implications in the management of pain

The NMDA receptors has been described in the development of acute pain and maintenance of chronic pain; the knowledge of physiological processes has led to the growing interest in NMDA receptors antagonists, demonstrating optimal analgesic results. Inhibition of NMDA receptors is an effective therapeutic alternative in the management of pain; with beneficial results in the management of acute postoperative pain, chronic and neuropathic pain. The current scientific challenge is to identify antagonists that perform a selective inhibition of receptor subunits, achieving optimal analgesic results. For this non-systemic review, a search of the available scientific evidence was made in databases (Pubmed/Medline, Science Direct, OVID, SciELO) through the use of keywords (Pain, NMDA receptors, antagonists, ketamine).

Los receptores NMDA han sido descritos en el desarrollo del dolor agudo y mantenimiento del dolor crónico; el conocimiento de los procesos fisiológicos ha llevado al creciente interés en los antagonistas de los receptores NMDA, demostrando resultados analgésicos óptimos. La inhibición de los receptores NMDA es una alternativa terapéutica eficaz en el manejo del dolor; con resultados benéficos en el manejo del dolor agudo postoperatorio, dolor crónico y neuropático. El reto científico actual es identificar antagonistas que realicen una inhibición selectiva de las subunidades del receptor, logrando óptimos resultados analgésicos. Para esta revisión no sistemática se realizó una búsqueda de la evidencia científica disponible en bases de datos (Pubmed/Medline, Science Direct, OVID, SciELO) mediante el uso de palabras clave (dolor, receptores NMDA, antagonistas, ketamina).

NMDA-induced increases in intracellular Ca2+ concentrations in osteoblasts / 中华内分泌代谢杂志

Objective To study the effect of N-Methyl-D-asparticacid ( NMDA ) on the intracellular free calcium concentration ( [ Ca2+] i ) in primary cultured rat calvaria osteoblasts. Methods A calcium imaging technique was applied to observe [ Ca2+] i changes in primary cultured rat calvaria osteoblasts after stimulating by NMDA with various concentrations or pretreated with NMDA receptor noncompetitive antagonism MK801 ( Dizocilpin) . Results Different concentrations of NMDA caused [ Ca2+] i increases in varying degrees and by different ways. NMDA could evoke transient increase and secondary change in [ Ca2+] i including calcium oscillation or steady increase. MK801 inhibited NMDA-induced [ Ca2+] i increase in varying degrees. Conclusion These results indicated that there are abundant functional NMDA receptors expressed in primary cultured rat calvaria osteoblasts, showing different forms and varying degrees of [ Ca2+] i increases in response to different concentrations of NMDA. The characters of the blocking effect of MK801 to NMDA-induced [ Ca2+] i increasing, indicated that the NMDA receptors expressed in primary cultured rat calvaria osteoblasts differ in channel properties from those in central nervous system.

Functional Investigation of a GRIN2A Variant Associated with Rolandic Epilepsy / 神经科学通报·英文版

N-methyl-D-aspartate receptors (NMDARs), a subtype of glutamate-gated ion channels, play a central role in epileptogenesis. Recent studies have identified an increasing number of GRIN2A (a gene encoding the NMDAR GluN2A subunit) mutations in patients with epilepsy. Phenotypes of GRIN2A mutations include epilepsy-aphasia disorders and other epileptic encephalopathies, which pose challenges in clinical treatment. Here we identified a heterozygous GRIN2A mutation (c.1341T>A, p.N447K) from a boy with Rolandic epilepsy by whole-exome sequencing. The patient became seizure-free with a combination of valproate and lamotrigine. Functional investigation was carried out using recombinant NMDARs containing a GluN2A-N447K mutant that is located in the ligand-binding domain of the GluN2A subunit. Whole-cell current recordings in HEK 293T cells revealed that the N447K mutation increased the NMDAR current density by ~1.2-fold, enhanced the glutamate potency by 2-fold, and reduced the sensitivity to Mg inhibition. These results indicated that N447K is a gain-of-function mutation. Interestingly, alternative substitutions by alanine and glutamic acid at the same residue (N447A and N447E) did not change NMDAR function, suggesting a residual dependence of this mutation in altering NMDAR function. Taken together, this study identified human GluN2A N447K as a novel mutation associated with epilepsy and validated its functional consequences in vitro. Identification of this mutation is also helpful for advancing our understanding of the role of NMDARs in epilepsy and provides new insights for precision therapeutics in epilepsy.

Mutations of N-Methyl-D-Aspartate Receptor Subunits in Epilepsy / 神经科学通报·英文版

Epilepsy is one of the most common neurological diseases. Of all cases, 70%-80% are considered to be due to genetic factors. In recent years, a large number of genes have been identified as being involved in epilepsy. Among them, N-methyl-D-aspartate receptor (NMDAR) subunit-encoding genes represent a large proportion, suggesting an important role for NMDARs in epilepsy. In this review, we summarize and analyze the genotypes, functional alterations, and clinical aspects of NMDAR subunit mutations/variants identified from patients with epilepsy. These data will help to throw light upon the pathogenicity of these NMDAR mutations and advance our understanding of the subtle and complicated role of NMDARs in epilepsy. It will also offer new insights into precision therapy for this disorder.

Altered expression of AMPAR and NMDAR subunits in hippocampal CA1 area with contextual fear memory generalization in mice / 中华行为医学与脑科学杂志

Objective To investigate the alteration of subunit expression of AMPAR and NMDAR in hippocampal CA1 area of mice with contextual fear memory generalization.Methods 35 male C57BL/6 mice,aged 8 weeks,were involved in the experiment.Seven mice were randomly selected as the naive group, which didn't receive the behavioral training.28 mice experienced the context fear conditioning and contextual shift task were divided into generalization group and non generalization group according to the result.Then Western blot was used to measure the expression of AMPAR and NMDAR subunits in CA1 in the naive group,non generalization group and generalization group.Results (1)Seven mice(discrimination ratio:0.52±0.08)showed contextual generalization when undergoing the same stress level,while the other 21 mice (discrimination ratio:0.75±0.07)didn't(P<0.01),however,these two group showed similar freezing(%) in the memory acquisition process.(2)The subunit composition of AMPA receptors had no significant differ-ence in CA1 area among the Naive group,non generalization group and generalization group(P>0.05).(3) NR1 subunit was similar in the three groups(P>0.05).NR2A expression was significantly increased in the non generalization group(1.11±0.20)and generalization group(1.09±0.20)compared with that in the na-ive group(0.95±0.17)(both P<0.05).The expression of NR2B was significantly increased in generalization group(1.05±0.17)compared with that in the naive group(0.83±0.19)and non generalization group(0.80± 0.14)(both P<0.05).The ratio of NR2A/NR2B was significantly increased in non generalization group (1.23±0.25)compared with that in the naive group(0.89±0.31)and generalization group(0.86±0.17) (both P<0.05).Conclusion (1)Only part of the individuals show contextual fear memory generalization after the same stress,and this contextual generalization progress is not related to the acquisition of context fear memory.(2)There is no significant change in expression of AMPAR subunits in CA1 of mice with the contextual generalization.The rise of NR2B and the decline of ratio of NR2A/NR2B are the main changes, suggesting that consequently the alternation of synaptic plasticity maybe one of the mechanisms of contextual fear memory generalization.

Role of Pre-Synaptic NMDA Receptors in the Modulation of Inhibitory Synaptic Transmission in Sensory-Motor and Visual Cortical Pyramidal Neurons in Brain Slices of Young Epileptic Mice

Background: Previous studies from animal models have shown that pre-synapticNMDA receptors (preNMDARs) are present in the cortex, but the role of inhibition mediated bypreNMDARs during epileptogenesis remains unclear. In this study, we wanted to observe thechanges in GABAergic inhibition through preNMDARs in sensory-motor and visual corticalpyramidal neurons after pilocarpine-induced status epilepticus.Methods: Using a pilocarpine-induced epileptic mouse model, sensory-motor and visualcortical slices were prepared, and the whole-cell patch clamp technique was used to recordspontaneous inhibitory post-synaptic currents (sIPSCs).Results: The primary finding was that the mean amplitude of sIPSC from the sensorymotorcortex increased significantly in epileptic mice when the recording pipette contained MK-801 compared to control mice, whereas the mean sIPSC frequency was not significantly different,indicating that post-synaptic mechanisms are involved. However, there was no significant presynapticinhibition through preNMDARs in the acute brain slices from pilocarpine-inducedepileptic mice.Conclusion: In the acute case of epilepsy, a compensatory mechanism of post-synapticinhibition, possibly from ambient GABA, was observed through changes in the amplitude withoutsignificant changes in the frequency of sIPSC compared to control mice. The role of preNMDARmediatedinhibition in epileptogenesis during the chronic condition or in the juvenile stagewarrants further investigation.

Chronic Ca²⁺ influx through voltage-dependent Ca²⁺ channels enhance delayed rectifier K⁺ currents via activating Src family tyrosine kinase in rat hippocampal neurons

Excessive influx and the subsequent rapid cytosolic elevation of Ca²⁺ in neurons is the major cause to induce hyperexcitability and irreversible cell damage although it is an essential ion for cellular signalings. Therefore, most neurons exhibit several cellular mechanisms to homeostatically regulate cytosolic Ca²⁺ level in normal as well as pathological conditions. Delayed rectifier K⁺ channels (I(DR) channels) play a role to suppress membrane excitability by inducing K⁺ outflow in various conditions, indicating their potential role in preventing pathogenic conditions and cell damage under Ca²⁺-mediated excitotoxic conditions. In the present study, we electrophysiologically evaluated the response of IDR channels to hyperexcitable conditions induced by high Ca²⁺ pretreatment (3.6 mM, for 24 hours) in cultured hippocampal neurons. In results, high Ca²⁺-treatment significantly increased the amplitude of IDR without changes of gating kinetics. Nimodipine but not APV blocked Ca²⁺-induced IDR enhancement, confirming that the change of I(DR) might be targeted by Ca²⁺ influx through voltage-dependent Ca²⁺ channels (VDCCs) rather than NMDA receptors (NMDARs). The VDCC-mediated I(DR) enhancement was not affected by either Ca²⁺-induced Ca²⁺ release (CICR) or small conductance Ca²⁺-activated K⁺ channels (SK channels). Furthermore, PP2 but not H89 completely abolished I(DR) enhancement under high Ca²⁺ condition, indicating that the activation of Src family tyrosine kinases (SFKs) is required for Ca²⁺-mediated I(DR) enhancement. Thus, SFKs may be sensitive to excessive Ca²⁺ influx through VDCCs and enhance I(DR) to activate a neuroprotective mechanism against Ca²⁺-mediated hyperexcitability in neurons.

Parishin C's prevention of Aβ 1-42-induced inhibition of long-term potentiation is related to NMDA receptors

The rhizome of Gastrodia elata (GE), a herb medicine, has been used for treatment of neuronal disorders in Eastern Asia for hundreds of years. Parishin C is a major ingredient of GE. In this study, the i.c.v. injection of soluble Aβ 1-42 oligomers model of LTP injury was used. We investigated the effects of parishin C on the improvement of LTP in soluble Aβ 1-42 oligomer-injected rats and the underlying electrophysiological mechanisms. Parishin C (i.p. or i.c.v.) significantly ameliorated LTP impairment induced by i.c.v. injection of soluble Aβ 1-42 oligomers. In cultured hippocampal neurons, soluble Aβ 1-42 oligomers significantly inhibited NMDAR currents while not affecting AMPAR currents and voltage-dependent currents. Pretreatment with parishin C protected NMDA receptor currents from the damage induced by Aβ. In summary, parishin C improved LTP deficits induced by soluble Aβ 1-42 oligomers. The protection by parishin C against Aβ-induced LTP damage might be related to NMDA receptors.

Facilitation of AMPA receptor-mediated steady-state current by extrasynaptic NMDA receptors in supraoptic magnocellular neurosecretory cells

In addition to classical synaptic transmission, information is transmitted between cells via the activation of extrasynaptic receptors that generate persistent tonic current in the brain. While growing evidence supports the presence of tonic NMDA current (INMDA) generated by extrasynaptic NMDA receptors (eNMDARs), the functional significance of tonic I(NMDA) in various brain regions remains poorly understood. Here, we demonstrate that activation of eNMDARs that generate I(NMDA) facilitates the α-amino-3-hydroxy-5-methylisoxazole-4-proprionate receptor (AMPAR)-mediated steady-state current in supraoptic nucleus (SON) magnocellular neurosecretory cells (MNCs). In low-Mg2+ artificial cerebrospinal fluid (aCSF), glutamate induced an inward shift in I(holding) (I(GLU)) at a holding potential (V(holding)) of -70 mV which was partly blocked by an AMPAR antagonist, NBQX. NBQX-sensitive I(GLU) was observed even in normal aCSF at V(holding) of -40 mV or -20 mV. I(GLU) was completely abolished by pretreatment with an NMDAR blocker, AP5, under all tested conditions. AMPA induced a reproducible inward shift in I(holding) (I(AMPA)) in SON MNCs. Pretreatment with AP5 attenuated I(AMPA) amplitudes to ~60% of the control levels in low-Mg2+ aCSF, but not in normal aCSF at V(holding) of -70 mV. I(AMPA) attenuation by AP5 was also prominent in normal aCSF at depolarized holding potentials. Memantine, an eNMDAR blocker, mimicked the AP5-induced I(AMPA) attenuation in SON MNCs. Finally, chronic dehydration did not affect I(AMPA) attenuation by AP5 in the neurons. These results suggest that tonic I(NMDA), mediated by eNMDAR, facilitates AMPAR function, changing the postsynaptic response to its agonists in normal and osmotically challenged SON MNCs.

Antidepressant Effects of Ketamine on Depression-like Behavior in Juvenile Mice after Neonatal Dexamethasone Exposure

OBJECTIVE: Pediatric depression is associated with significant functional impairment at school and at work. Recently, we reported on depression-like behavior in juvenile mice neonatally exposed to dexamethasone (DEX) as a potential animal model for pediatric depression. The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has promoted rapid and long-lasting antidepressant effects in patients with treatment-resistant major depression. This study was conducted to examine whether ketamine had antidepressant effects in juvenile mice after neonatal DEX exposure. METHODS: A single dose (10 mg/kg) of ketamine or vehicle was injected into juvenile mice at days 29-32 after neonatal DEX (or saline) exposure (days 1-3). The sucrose preference test, tail suspension test, and forced swimming test were performed 24, 40, and 46 hours, respectively, after injection of ketamine. RESULTS: Ketamine (10 mg/kg) significantly improved depression-like behavior in DEX-treated juvenile mice. CONCLUSION: This finding suggests that ketamine confers antidepressant effects in an animal model of pediatric depression.

The Downregulation of Somatic A-Type K+ Channels Requires the Activation of Synaptic NMDA Receptors in Young Hippocampal Neurons of Rats

The downregulation of A-type K+ channels (IA channels) accompanying enhanced somatic excitability can mediate epileptogenic conditions in mammalian central nervous system. As IA channels are dominantly targeted by dendritic and postsynaptic processings during synaptic plasticity, it is presumable that they may act as cellular linkers between synaptic responses and somatic processings under various excitable conditions. In the present study, we electrophysiologically tested if the downregulation of somatic IA channels was sensitive to synaptic activities in young hippocampal neurons. In primarily cultured hippocampal neurons (DIV 6~9), the peak of IA recorded by a whole-cell patch was significantly reduced by high KCl or exogenous glutamate treatment to enhance synaptic activities. However, the pretreatment of MK801 to block synaptic NMDA receptors abolished the glutamate-induced reduction of the IA peak, indicating the necessity of synaptic activation for the reduction of somatic IA. This was again confirmed by glycine treatment, showing a significant reduction of the somatic IA peak. Additionally, the gating property of IA channels was also sensitive to the activation of synaptic NMDA receptors, showing the hyperpolarizing shift in inactivation kinetics. These results suggest that synaptic LTP possibly potentiates somatic excitability via downregulating IA channels in expression and gating kinetics. The consequential changes of somatic excitability following the activity-dependent modulation of synaptic responses may be a series of processings for neuronal functions to determine outputs in memory mechanisms or pathogenic conditions.

Involvement of AMPA receptors for Mesobuthus tamulus Pocock venom-induced depression of monosynaptic reflex in neonatal rat spinal cord in vitro.

Glutamate is a putative neurotransmitter at Ia-α motoneuron synapse in the spinal cord and mediate the action via N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors. Since NMDA receptors are not involved in M. tamulus Pocock (MBT) venom-induced depression of spinal monosynaptic reflex (MSR), the present study was undertaken to evaluate the role of AMPA receptors in mediating the depression of MSR by MBT venom. The experiments were performed on isolated hemisected spinal cord from 4-6 day old rats. Stimulation of a dorsal root with supramaximal voltage evoked MSR and polysynaptic reflex (PSR) potentials in the corresponding segmental ventral root. Superfusion of MBT venom (0.3 µg/ml) depressed the spinal reflexes in a time-dependent manner. The maximum depression of MSR(~ 66%) was seen at 10 min  and it was 25 min for PSR (~ 75%). The time to produce 50% depression of MSR and PSR was 6.7 ± 1.5 and 10.8 ± 2.6 min, respectively. Pretreatment of the cords with 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX, 0.1 μM), an AMPA receptor antagonist, blocked the venom-induced depression of MSR but not PSR. The results indicate that venom-induced depression of MSR is mediated via AMPA receptors.

Effects of cyclin dependent kinase 5 inhibitor Roscovitine on remifentanil-induced hyperalgesia / 中华行为医学与脑科学杂志

ObjectiveTo study the effects of intrathecal injection of cyclin dependent kinase 5 inhibitor Roscovitine on the hyperalgesia induced by remifentanil in a rat model of incisional pain.MethodsForty-five SD rats were randomly divided into 5 groups ( n =9 in each group):control group ( C ),incisional pain group ( Ⅰ ),Roscovitine group(ROS),remifentanil group(R) and Roscovitine + remifentanil group ( ROS + R).Roscovitine (50μg/10μl) was injected intrathecally at 30 min before plantar incision in groups ROS and ROS + R,other groups were injected with 20％ DMSO(10μl).All groups except for C group needed to be made the model of incisional pain.In group R and ROS + R,remifentanil(0.04 mg/kg) was infused subcutaneously with a pump for 30min at the moment of surgical incision.The paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency(PWTL) were used to evaluate the behavioral changes and measured at 24 h before incision and at 2 h,6 h,24 h and 48 h after incision.ResultsCompared with group C,the PWMT and PWTL of group Ⅰ were significantly decreased after incision (P＜0.01).Compared with group Ⅰ,the PWMT and PWTL of group R were significantly decreased after incision (P ＜ 0.01 ) ; however,the PWTL was significantly increased (2h:( 20.26 ± 1.33)s,(17.97 ±0.47)s;48h:(22.15 ±0.660)s,(19.89 ±1.27) s),P＜0.05)in ROS group.Compared with group R,at 2h after incision,the significant increase of PWTL ( ( 19.13 ± 1.72)s,( 14.41 ± 2.30) s) and PWMT ( ( 10.4 ± 1.95 ) g,(6.38 ± 0.91 ) g) were observed,then lasted up to 48 h ( ( 19.24 ± 2.8 ) s,( 14.87 ± 1.95 ) s )and 24h ( (8.88 ± 1.41 ) g,( 6.83 ± 0.80) g) respectively in group ROS + R (P ＜ 0.05 ).ConclusionIn a rat model of postoperative pain,Roseovitine could reduce the thermal hyperalgesia purely induced by incision,and also could prevent the development of hyperalgesia induced by remifentanil.

Role of nitric oxide in the periaqueductal gray in defensive behavior in mice: influence of prior local N-methyl-D-aspartate receptor activation and aversive condition

Glutamate N-methyl-D-aspartate (NMDA) receptor activation within the dorsal column of the periaqueductal gray (dPAG) leads to antinociceptive, autonomic, and behavioral responses characterized as the fear reaction. Activation of NMDA receptors in the brain increases nitric oxide (NO) synthesis, and NO has been proposed to be a mediator of the aversive action of glutamate. This paper reviews a series of studies investigating the effects of neuronal NO synthase (nNOS) inhibition in the dPAG of mice in different aversive conditions. nNOS inhibition by infusion of Nω-propyl-L-arginine (NPLA) prevents fear-like reactions (e.g., jumping, running, freezing) induced by NMDA receptor stimulation within the dPAG and produces anti-aversive effects when injected into the same midbrain site in mice confronted with a predator. Interestingly, nNOS inhibition within the dPAG does not change anxiety-like behavior in mice exposed to the elevated plus maze (EPM), but it reverses the effect of an anxiogenic dose of NMDA injected into the same site in animals subjected to the EPM. Altogether, the results support a role for glutamate NMDA receptors and NO in the dPAG in the regulation of defensive behaviors in mice. However, dPAG nitrergic modulation of anxiety-like behavior appears to depend on the magnitude of the aversive stimulus.

Peripheral N-methyl-D-aspartate Receptors Involved in Long-term Hyperalgesia Induced by Peripheral Injection of Formalin in Rats / 中国康复理论与实践

@#Objective To investigate the role of peripheral N-methyl-D-aspartate (NMDA) receptors in the long-term hyperalgesia induced by peripheral injection of formalin in rats. Methods Formalin was injected in the paws of the SD rats with or without the MK-801 pre-injection. OX-42 expressions in the dorsal horn were observed, and the paw withdrawal thermal latency was measured. Results The OX-42 expression decreased and the paw withdrawal thermal latency prolonged in rats with MK-801 pre-injection. Conclusion Peripheral NMDA receptors may be involved in the long-term hyperalgesia.

Influence of NMDA and non-NMDA antagonists on acute and inflammatory pain in the trigeminal territory: a placebo control study / Influência dos antagonistas dos receptores NMDA e não-NMDA sobre a dor aguda e inflamatória ao nível do território do trigêmeo: um estudo placebo controlado

NMDA and non-NMDA receptors are involved in spinal transmission of nociceptive information in physiological and pathological conditions. Our objective was to study the influence of NMDA and non-NMDA receptor antagonists on pain control in the trigeminal system using a formalin-induced orofacial pain model. Motor performance was also evaluated. Male Rattus norvegicus were pre-treated with topiramate (T) (n=8), memantine (M) (n=8), divalproex (D) (n=8) or isotonic saline solution (ISS) (n=10) intraperitoneally 30 minutes before the formalin test. Formalin 2.5 percent was injected into the right upper lip (V2 branch) and induced two phases: phase I (early or neurogenic) (0-3 min) and phase II (late or inflammatory) (12-30 min). For motor behavior performance we used the open-field test and measured latency to movement onset, locomotion and rearing frequencies, and immobility time. Pre-treatment of animals with M and D only attenuated nociceptive formalin behavior for phase II. T increased locomotion and rearing frequencies and reduced immobility time. Treatment with M increased immobility time and with D reduced locomotion frequency. Our results showed that the NMDA antagonist (M) is more potent than the non-NMDA antagonists (D and T) in the control of pain in the inflammatory phase. The non-NMDA topiramate improved motor performance more than did D and M, probably because T has more anxiolytic properties.

Receptores NMDA e não-NMDA estão envolvidos na transmissão das informações nociceptivas em condições fisiológicas e patológicas. Com o objetivo de estudar a influência dos antagonistas dos receptores NMDA e não-NMDA sobre o controle de dor no sistema trigeminal utilizamos modelo de dor orofacial induzida pela formalina. Testes de desempenho motor foram também avaliados. Ratos machos da espécie Rattus norvegicus foram tratados com topiramato (T) (n=8), memantina (M) (n=8), divalproato de sódio (D) (n=8) ou solução salina isotônica (SSI) (n=10), por via intraperitoneal, 30 minutos antes dos testes com a formalina. Formalina 2.5 por cento foram injetadas na região do lábio superior dos animais (segundo ramo do trigêmeo) induzindo comportamento em duas fases distintas: fase I (precoce ou neurogênica) (0-3 min ) e fase II (tardia ou inflamatória) (12-30 min). Para avaliação da atividade motora utilizou-se o teste do campo aberto mensurando-se a latência para o início dos movimentos, número de casas andadas, freqüência de levantamentos e tempo de imobilidade. Animais pré-tratados com M e D atenuaram a fase inflamatória do teste da formalina. O T aumenta o número de casas andadas, freqüência de levantamentos e reduz o tempo de imobilidade. Nossos resultados mostram que o antagonista NMDA é mais potente do que os antagonistas não-NMDA para o controle da fase inflamatória da dor. O topiramato entretanto aumenta a atividade motora provavelmente porque apresente propriedades ansiolíticas.

The Role of NMDA Receptor Antagonists in Nicotine Tolerance, Sensitization, and Physical Dependence: A Preclinical Review

Nicotine, the primary psychoactive component of tobacco products, produces diverse neurophysiological, motivational, and behavioral effects through several brain regions and neurochemical pathways. Various neurotransmitter systems have been explored to understand the mechanisms behind nicotine tolerance, dependence, and withdrawal. Recent evidence suggests that glutamate neurotransmission has an important role in this phenomenon. The aim of the present review is to discuss preclinical findings concerning the role of N-methyl-D-aspartate (NMDA) receptor neurotransmission in mediating the behavioral effects of nicotine, tolerance, sensitization, dependence, and withdrawal. Based on preclinical findings, it is hypothesized that NMDA receptors mediate the common adaptive processes that are involved in the development, maintenance, and expression of nicotine addiction. Modulation of glutamatergic neurotransmission with NMDA receptor antagonists may prove to be useful in alleviating the symptoms of nicotine abstinence and facilitate tobacco-smoking cessation.

N-methyl-D-aspartate (NMDA) and Non-NMDA Receptors are Involved in the Production and Maintenance of Nociceptive Responses by Intraplantar Injection of Bee Venom and Melittin in the Rat

Whole bee venom (WBV) and its major component, melittin, have been reported to induce long-lasting spontaneous flinchings and hyperalgesia. The current study was designed to elucidate the peripheral and spinal mechanisms of N-methyl-D-aspartate (NMDA) and non-NMDA receptors by which intraplantar (i.pl.) injection of WBV and melittin induced nociceptive responses. Changes in mechanical threshold and flinching behaviors were measured after the injection of WBV (0.04 mg or 0.1 mg/paw) and melittin (0.02 mg or 0.05 mg/paw) into the mid-plantar area of a rat hindpaw. MK-801 and CNQX (6-cyano-7-nitroquinoxaline-2, 3-dione disodium) were administered intrathecally (i.t. 10microgram) or i.pl. (15microgram) 15 min before or i.t. 60 min after i.pl. WBV and melittin injection. Intrathecal pre- and post- administration of MK-801 and CNQX significantly attenuated the ability of high dose WBV and melittin to reduce paw withdrawal threshold (PWT). In the rat injected with low dose, but not high dose, of WBV and melittin, i.pl. injection of MK-801 effectively suppressed the decrease of PWTs only at the later time-points, but the inhibitory effect of CNQX (i.pl.) was significant at all time-point after the injection of low dose melittin. High dose WBV- and melittin-induced spontaneous flinchings were significantly suppressed by i.t. administration of MK-801 and CNQX, and low dose WBV- and melittin-induced flinchings were significantly reduced only by intraplantarly administered CNQX, but not by MK-801. These experimental flinchings suggest that spinal, and partial peripheral mechanisms of NMDA and non-NMDA receptors are involved in the development and maintenance of WBV- and melittin-induced nociceptive responses.

Effects of intrathecal injection of NMDA on the analgesia of inhalation anesthetics / 中国药理学通报

0.05);in contrast, intrathecal NMDA 2.5,5,10 ng could significantly and dose dependently decrease the HPPT(P