Bilateral blockade of NMDA receptors in anterior thalamus by dizocilpine (MK-801) injures pyramidal neurons in rat retrosplenial cortex

Abstract Background Earlier studies show that endogenous sphingolipids can induce pain hypersensitivity, activation of spinal astrocytes, release of proinflammatory cytokines and activation of TRPM3 channel. Here we studied whether the development of pain hypersensitivity induced by sphingolipids in the spinal cord can be prevented by pharmacological inhibition of potential downstream mechanisms that we hypothesized to include TRPM3, σ1 and NMDA receptors, gap junctions and D-amino acid oxidase. Methods Experiments were performed in adult male rats with a chronic intrathecal catheter for spinal drug administrations. Mechanical nociception was assessed with monofilaments and heat nociception with radiant heat. N,N-dimethylsphingosine (DMS) was administered to induce pain hypersensitivity. Ononetin, isosakuranetin, naringenin (TRPM3 antagonists), BD-1047 (σ1 receptor antagonist), carbenoxolone (a gap junction decoupler), MK-801 (NMDA receptor antagonist) and AS-057278 (inhibitor of D-amino acid oxidase, DAAO) were used to prevent the DMS-induced hypersensitivity, and pregnenolone sulphate (TRPM3 agonist) to recapitulate hypersensitivity. Results DMS alone produced within 15 min a dose-related mechanical hypersensitivity that lasted at least 24 h, without effect on heat nociception. Preemptive treatments with ononetin, isosakuranetin, naringenin, BD-1047, carbenoxolone, MK-801 or AS-057278 attenuated the development of the DMS-induced hypersensitivity, but had no effects when administered alone. Pregnenolone sulphate (TRPM3 agonist) alone induced a dose-related mechanical hypersensitivity that was prevented by ononetin, isosakuranetin and naringenin. Conclusions Among spinal pronociceptive mechanisms activated by DMS are TRPM3, gap junction coupling, the σ1 and NMDA receptors, and DAAO.

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Isoflurane and Propofol Block Neurotoxicity Caused by MK-801 in the Rat Posterior Cingulate/Retrosplenial Cortex

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199702000-00006 ◽

1997 ◽

Vol 17 (2) ◽

pp. 168-174 ◽

Cited By ~ 38

Author(s):

Vesna Jevtović-Todorović ◽

Charity O. Kirby ◽

John W. Olney

Keyword(s):

Brain Injury ◽

Neuronal Degeneration ◽

Nmda Antagonist ◽

Retrosplenial Cortex ◽

Acute Brain Injury ◽

Nmda Antagonists ◽

General Anesthetics ◽

General Anesthetic ◽

Mk 801 ◽

Anesthetic Agents

In acute brain injury syndromes, the potent N-methyl-D-aspartate (NMDA) antagonist, MK-801, can prevent neuronal degeneration, and the general anesthetics, isoflurane and propofol, may also provide neuroprotective benefits. An obstacle to the use of NMDA antagonists for neuroprotective purposes is that they can cause a neurotoxic vacuole reaction in cerebrocortical neurons. This study demonstrates the ability of isoflurane and propofol to prevent the neurotoxic vacuole reaction induced by MK-801. Low sedative doses of inhaled isoflurane (1%) or intravenous (i.v.) propofol (7.5 mg/kg/h) were as effective as higher general anesthetic doses. Thus, in the clinical management of acute brain injury conditions such as stroke and brain trauma, administration of one of these anesthetic agents together with an NMDA antagonist may be an excellent formula for obtaining optimal neuroprotection while eliminating serious side effects.

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Role of N-methyl-D-aspartate receptors in the pontine pneumotaxic mechanism in the cat

Journal of Applied Physiology ◽

10.1152/jappl.1994.76.3.1138 ◽

1994 ◽

Vol 76 (3) ◽

pp. 1138-1143 ◽

Cited By ~ 45

Author(s):

L. Ling ◽

D. R. Karius ◽

D. F. Speck

Keyword(s):

Nmda Receptor ◽

Nmda Receptors ◽

Partial Recovery ◽

Inspiratory Time ◽

Systemic Injection ◽

Lung Inflation ◽

Mk 801 ◽

Efferent Limb ◽

Adult Cats

Systemic injection of MK-801, an N-methyl-D-aspartate (NMDA) receptor-associated channel blocker, induces an apneusis in vagotomized cats similar to that produced by pontine respiratory group (PRG) lesions, suggesting the possible involvement of NMDA receptors in the pontine pneumotaxic mechanism. Previous results from our laboratory indicate that the efferent limb of the pontine pneumotaxic mechanism is unlikely to require NMDA receptor-mediated neurotransmission. Therefore, the present study examined the potential involvement of PRG NMDA receptors in the pontine pneumotaxic mechanism. Experiments were conducted in decerebrate, paralyzed, and ventilated adult cats. The effects on inspiratory time (TI) of MK-801 microinjection into PRG were tested in 12 cats. Pressure microinjection of MK-801 (15 mM, 80–3,000 nl) significantly prolonged TI in all animals when lung inflation was withheld. TI progressively increased in most animals for > or = 30 min. After this period, partial recovery of the effect occurred in eight cats as TI shortened toward predrug levels. In three animals, microinjection of MK-801 induced a complete apneusis in the absence of lung inflation from which there was no detectable recovery. Microinjections into regions approximately 2 mm distant from PRG produced little or no effect. These results provide evidence that NMDA receptors located in the region of PRG play an important functional role in the control of the breathing cycle.

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Exposure to cyclic intermittent hypoxia increases expression of functional NMDA receptors in the rat carotid body

Journal of Applied Physiology ◽

10.1152/japplphysiol.90626.2008 ◽

2009 ◽

Vol 106 (1) ◽

pp. 259-267 ◽

Cited By ~ 22

Author(s):

Yuzhen Liu ◽

En-Sheng Ji ◽

Shuanglin Xiang ◽

Renaud Tamisier ◽

Jingli Tong ◽

...

Keyword(s):

Nmda Receptors ◽

Carotid Body ◽

Intermittent Hypoxia ◽

Acute Hypoxia ◽

Sprague Dawley ◽

Excitatory Neurotransmitter ◽

Mk 801 ◽

Baseline Activity ◽

Nmda Receptor Blocker

Although large quantities of glutamate are found in the carotid body, to date this excitatory neurotransmitter has not been assigned a role in chemoreception. To examine the possibility that glutamate and its N-methyl-d-aspartate (NMDA) receptors play a role in acclimatization after exposure to cyclic intermittent hypoxia (CIH), we exposed male Sprague-Dawley rats to cyclic hypoxia or to room air sham (Sham) for 8 h/day for 3 wk. Using RT-PCR, Western blot analysis, and immunohistochemistry, we found that ionotropic NMDA receptors, including NMDAR1, NMDAR2A, NMDAR2A/2B, are strongly expressed in the carotid body and colocalize with tyrosine hydroxylase in glomus cells. CIH exposure enhanced the expression of NMDAR1 and NMDAR2A/2B but did not substantially change the level of NMDAR2A. We assessed in vivo carotid sinus nerve activity (CSNA) at baseline, in response to acute hypoxia, in response to infused NMDA, and in response to infused endothelin-1 (ET-1) with and without MK-801, an NMDA receptor blocker. Infusion of NMDA augmented CSNA in CIH rats (124.61 ± 2.64% of baseline) but not in sham-exposed rats. Administration of MK-801 did not alter baseline activity or response to acute hypoxia, in either CIH or sham animals but did reduce the effect of ET-1 infusion on CSNA (CSNA after ET-1 = 160.96 ± 8.05% of baseline; ET-1 after MK-801 = 118.56 ± 9.12%). We conclude that 3-wk CIH exposure increases expression of NMDA functional receptors in rats, suggesting glutamate and its receptors may play a role in hypoxic acclimatization to CIH.

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NMDA receptors mediate peripheral chemoreceptor afferent input in the conscious rat

Journal of Applied Physiology ◽

10.1152/jappl.1998.84.3.853 ◽

1998 ◽

Vol 84 (3) ◽

pp. 853-861 ◽

Cited By ~ 100

Author(s):

Patricia J. Ohtake ◽

José E. Torres ◽

Yair M. Gozal ◽

Gavin R. Graff ◽

David Gozal

Keyword(s):

Nmda Receptor ◽

Nmda Receptors ◽

Receptor Activation ◽

Sodium Cyanide ◽

Respiratory Drive ◽

Peripheral Chemoreceptor ◽

Cardiorespiratory Control ◽

Mk 801 ◽

Ventilatory Responses ◽

Before And After

N-methyl-d-aspartate (NMDA) glutamate receptors mediate critical components of cardiorespiratory control in anesthetized animals. The role of NMDA receptors in the ventilatory responses to peripheral and central chemoreceptor stimulation was investigated in conscious, freely behaving rats. Minute ventilation (V˙e) responses to 10% O2, 5% CO2, and increasing intravenous doses of sodium cyanide were measured in intact rats before and after intravenous administration of the NMDA receptor antagonist MK-801 (3 mg/kg). After MK-801, eupcapnic tidal volume (Vt) decreased while frequency increased, resulting in a modest reduction inV˙e. Inspiratory time (Ti) decreased, whereas expiratory time remained unchanged. TheV˙e responses to hypercapnia were qualitatively similar in control and MK-801 conditions, with slight reductions in respiratory drive (Vt/Ti) after MK-801. In contrast, responses to hypoxia were markedly attenuated after MK-801 and were primarily due to reduced frequency changes, whereas Vt was unaffected. Sodium cyanide doses associated with significantV˙eincreases were 5 and 50 μg/kg before and after MK-801, respectively. Thus 1-log shift to the right of individual dose-response curves occurred with MK-801. Selective carotid body denervation reducedV˙e during hypoxia by 70%, and residual hypoxic ventilatory responses were abolished after MK-801. These findings suggest that, in conscious rats, carotid and other peripheral chemoreceptor-mediated hypoxic ventilatory responses are critically dependent on NMDA receptor activation and that NMDA receptor mechanisms are only modestly involved during hypercapnia.

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