dizocilpine-maleate has been researched along with Chronic-Disease* in 30 studies
1 review(s) available for dizocilpine-maleate and Chronic-Disease
1 trial(s) available for dizocilpine-maleate and Chronic-Disease
29 other study(ies) available for dizocilpine-maleate and Chronic-Disease
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The glial phosphorylase of glycogen isoform is reduced in the dorsolateral prefrontal cortex in chronic schizophrenia.
Reduced glutamatergic activity and energy metabolism in the dorsolateral prefrontal cortex (DLPFC) have been described in schizophrenia. Glycogenolysis in astrocytes is responsible for providing neurons with lactate as a transient energy supply helping to couple glutamatergic neurotransmission and glucose utilization in the brain. This mechanism could be disrupted in schizophrenia. The aim of this study was to explore whether the protein levels of the astrocyte isoform of glycogen phosphorylase (PYGM), key enzyme of glycogenolysis, and the isoform A of Ras-related C3 botulinum toxin substrate 1 (RAC1), a kinase that regulates PYGM activity, are altered in the postmortem DLPFC of chronic schizophrenia patients (n=23) and matched controls (n=23). We also aimed to test NMDAR blockade effect on these proteins in the mouse cortex and cortical astrocytes and antipsychotic treatments in rats. Here we report a reduction in PYGM and RAC1 protein levels in the DLPFC in schizophrenia. We found that treatment with the NMDAR antagonist dizocilpine in mice as a model of psychosis increased PYGM and reduced RAC1 protein levels. The same result was observed in rat cortical astroglial-enriched cultures. 21-day haloperidol treatment increased PYGM levels in rats. These results show that PYGM and RAC1 are altered in the DLPFC in chronic schizophrenia and are controlled by NMDA signalling in the rodent cortex and cortical astrocytes suggesting an altered NMDA-dependent glycogenolysis in astrocytes in schizophrenia. Together, this study provides evidence of a NMDA-dependent transient local energy deficit in neuron-glia crosstalk in schizophrenia, contributing to energy deficits of the disorder. Topics: Aged; Animals; Antipsychotic Agents; Astrocytes; Cells, Cultured; Chronic Disease; Cohort Studies; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Glycogen Phosphorylase; Haloperidol; Humans; Isoenzymes; Male; Mice, Inbred C57BL; Prefrontal Cortex; rac1 GTP-Binding Protein; Random Allocation; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Schizophrenia | 2016 |
Dopamine D(2)/D(3) receptor binding of [(123)I]epidepride in risperidone-treatment chronic MK-801-induced rat schizophrenia model using nanoSPECT/CT neuroimaging.
Epidepride is a compound with an affinity in picomolar range for D2/D3 receptors. The aim of this work was designed to investigate the diagnostic possibility of [(123)I]epidepride imaging platform for risperidone-treatment chronic MK-801-induced rat schizophrenia model.. Rats received repeated administration of MK-801 (dissolved in saline, i.p., 0.3 mg/kg/day) or saline for 4 weeks. After 1-week administration of MK-801, rats in MK-801+risperidone group received risperidone (0.5 mg/kg/day) intraperitoneally 15 min prior to MK-801 administration for the rest of 3-week treatment. We obtained serial [(123)I]epidepride neuroimages from nanoSPECT/CT and evaluated the alteration of specific binding in striatum and midbrain.. Risperidone reversed chronic MK-801-induced decrease in social interaction duration. IHC and ELISA analysis showed consistent results that chronic MK-801 treatment significantly decreased striatal and midbrain D2R expression but repeated risperidone administration reversed the effect of MK-801 treatment. In addition, [(123)I]epidepride nanoSPECT/CT neuroimaging revealed that low specific [(123)I]epidepride binding ratios caused by MK-801 in striatum and midbrain were statistically alleviated after 1- and 2-week risperidone administration, respectively.. We established a rat schizophrenia model by chronic MK-801 administration for 4 weeks. [(123)I]Epidepride nanoSPECT neuroimaging can trace the progressive alteration of D2R expression in striatum and midbrain caused by long-lasting MK-801 treatment. Besides diagnosing illness stage of disease, [(123)I]epidepride can be a useful tool to evaluate therapeutic effects of antipsychotic drug in chronic MK-801-induced rat schizophrenia model. Topics: Animals; Benzamides; Chronic Disease; Disease Models, Animal; Dizocilpine Maleate; Male; Multimodal Imaging; Neuroimaging; Protein Binding; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Dopamine D3; Risperidone; Schizophrenia; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; Tyrosine 3-Monooxygenase | 2014 |
[123I]Epidepride neuroimaging of dopamine D2/D3 receptor in chronic MK-801-induced rat schizophrenia model.
[(123)I]Epidepride is a radio-tracer with very high affinity for dopamine D(2)/D(3) receptors in brain. The importance of alteration in dopamine D(2)/D(3) receptor binding condition has been wildly verified in schizophrenia. In the present study we set up a rat schizophrenia model by chronic injection of a non-competitive NMDA receptor antagonist, MK-801, to examine if [(123)I]epidepride could be used to evaluate the alterations of dopamine D(2)/D(3) receptor binding condition in specific brain regions.. Rats were given repeated injection of MK-801 (dissolved in saline, 0.3mg/kg) or saline for 1month. Afterwards, total distance traveled (cm) and social interaction changes were recorded. Radiochemical purity of [(123)I]epidepride was analyzed by Radio-Thin-Layer Chromatography (chloroform: methanol, 9:1, v/v) and [(123)I]epidepride neuroimages were obtained by ex vivo autoradiography and small animal SPECT/CT. Data obtained were then analyzed to determine the changes of specific binding ratio.. Chronic MK-801 treatment for a month caused significantly increased local motor activity and induced an inhibition of social interaction. As shown in [(123)I]epidepride ex vivo autoradiographs, MK-801 induced a decrease of specific binding ratio in the striatum (24.01%), hypothalamus (35.43%), midbrain (41.73%) and substantia nigra (37.93%). In addition, [(123)I]epidepride small animal SPECT/CT neuroimaging was performed in the striatum and midbrain. There were statistically significant decreases in specific binding ratio in both the striatum (P<.01) and midbrain (P<.05) between the saline and MK-801 group.. These results suggest that [(123)I]epidepride is a useful radio-tracer to reveal the alterations of dopamine D(2)/D(3) receptor binding in a rat schizophrenia model and is also helpful to evaluate therapeutic effects of schizophrenia in the future. Topics: Animals; Behavior, Animal; Benzamides; Chronic Disease; Disease Models, Animal; Dizocilpine Maleate; Iodine Radioisotopes; Male; Multimodal Imaging; Neostriatum; Neuroimaging; Positron-Emission Tomography; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia; Tomography, X-Ray Computed; Tyrosine 3-Monooxygenase | 2012 |
Glossopharyngeal long-term facilitation requires serotonin 5-HT2 and NMDA receptors in rats.
Although the glossopharyngeal nerve (IX) is mainly a sensory nerve, it innervates stylopharyngeus and some other pharyngeal muscles, whose excitations would likely improve upper airway patency since electrical IX stimulation increases pharyngeal airway size. As acute intermittent hypoxia (AIH) induces hypoglossal and genioglossal long-term facilitation (LTF), we hypothesized that AIH induces glossopharyngeal LTF, which requires serotonin 5-HT(2) and NMDA receptors. Integrated IX activity was recorded in anesthetized, vagotomized, paralyzed and ventilated rats before, during and after 5 episodes of 3-min isocapnic 12% O(2) with 3-min intervals of 50% O(2). Either saline, ketanserin (5-HT(2) antagonist, 2mg/kg) or MK-801 (NMDA antagonist, 0.2mg/kg) was (i.v.) injected 30-60 min before AIH. Both phasic and tonic IX activities were persistently increased (both P<0.05) after AIH in vehicle, but not ketanserin or MK-801, rats. Hypoxic glossopharyngeal responses were minimally changed after either drug. These data suggest that AIH induces both phasic and tonic glossopharyngeal LTF, which requires activation of 5-HT(2) and NMDA receptors. Topics: Anesthesia; Animals; Blood Gas Analysis; Chronic Disease; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glossopharyngeal Nerve; Hypoxia; Injections, Intravenous; Ketanserin; Long-Term Potentiation; Male; Oxygen; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, Serotonin, 5-HT2; Serotonin Antagonists; Time Factors; Vagotomy | 2010 |
Effect of analgesic standards on persistent postoperative pain evoked by skin/muscle incision and retraction (SMIR).
Various common surgeries such as thoracotomy and inguinal hernia repair involve essential prolonged tissue retraction, often causing persistent postoperative pain. A new model was developed to mimic this clinical scenario, whereby skin/muscle incision and retraction (SMIR) in the medial thigh evoked persistent postoperative pain (Flatters (2008) [Pain 135:119-130]). This study examines the response of SMIR-evoked mechanical hypersensitivity to analgesic standards commonly used as positive controls in behavioural pain studies. Rats were anaesthetised, the skin and superficial muscle of the medial thigh was then incised and retracted for 1h. In separate experiments, morphine, gabapentin and MK-801 were intraperitoneally administered to SMIR-operated rats, at maximally tolerated doses, on postoperative day 9-13. Mechanical hypersensitivity was measured by withdrawal responses to von Frey stimulation of the plantar hindpaws. Morphine (6mg/kg) and gabapentin (100mg/kg) elicited an almost complete reversal of SMIR-evoked mechanical hypersensitivity. In contrast, MK-801 (0.1mg/kg) did not affect SMIR-evoked mechanical hypersensitivity. Contralateral hindpaw responses to von Frey stimulation were unaffected by SMIR surgery or any drug treatment. In conclusion, the SMIR model displays persistent mechanical hypersensitivity that is reversible by morphine or gabapentin treatment. As previously demonstrated, SMIR-evoked pain is not driven by neuronal damage and these data show that NMDA receptor activation does not play a role in the maintenance of SMIR-evoked pain. This study further demonstrates the value of the SMIR model as a tool to understand persistent postoperative/postsurgical pain mechanisms and evaluate potential treatments. Topics: Amines; Analgesics; Animals; Chronic Disease; Cyclohexanecarboxylic Acids; Dermatologic Surgical Procedures; Disease Models, Animal; Dizocilpine Maleate; Gabapentin; gamma-Aminobutyric Acid; Hindlimb; Hyperalgesia; Male; Morphine; Muscle, Skeletal; Pain Measurement; Pain, Postoperative; Rats; Rats, Sprague-Dawley; Touch | 2010 |
Effects of chronic hypoxia on MK-801-induced changes in the acute hypoxic ventilatory response.
Chronic hypoxia increases the sensitivity of the central nervous system to afferent input from carotid body chemoreceptors. We hypothesized that this process involves N-methyl-D-aspartate (NMDA) receptor-mediated mechanisms and predicted that chronic hypoxia would change the effect of the NMDA receptor blocker dizocilpine (MK-801) on the poikilocapnic hypoxic ventilatory response (HVR). Male Sprague-Dawley rats were studied before and after acclimatization to hypoxia (70 Torr inspiratory Po(2) for 9 days). We measured ventilation (VI) and the HVR before and after systemic MK-801 treatment (3 mg/kg ip). MK-801 resulted in a constant respiratory frequency (approximately 175 min(-1)) during acute exposure to 10% and 30% O(2) before and after acclimatization. MK-801 had no effect on tidal volume (VT) before acclimatization, but it significantly decreased Vt when the animals were breathing 10% O(2) after acclimatization. The net effect of MK-801 was to eliminate the O(2) sensitivity of Vi before (via changes in respiratory frequency) and after (via changes in VT) acclimatization. Hence, chronic hypoxia altered the effect of MK-801 on the acute HVR, primarily because of increased effects on Vt. This indicates that changes in NMDA receptor-mediated neurotransmission may be involved in ventilatory acclimatization to hypoxia. However, further experiments are necessary to determine the precise location of such plasticity in the central nervous system. Topics: Acetamides; Adaptation, Physiological; Animals; Chronic Disease; Dizocilpine Maleate; Glycine; Hypoxia; Male; Pulmonary Gas Exchange; Pulmonary Ventilation; Rats; Rats, Sprague-Dawley; Respiration; Tidal Volume | 2005 |
Effects of low-affinity NMDA receptor channel blockers in two rat models of chronic pain.
In contrast to conventional opioid analgesics, antagonists acting at the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors are capable of suppressing pain-related phenomena in chronic pain models while having little or no effect on acute nociception. One of the few clinically used NMDA receptor antagonists, memantine, differs from prototypic antagonists with psychotomimetic activity such as phencyclidine and (+)MK-801, in showing lower receptor affinity, faster unblocking kinetics and stronger voltage-dependency. Recently, a series of novel amino-alkyl-cyclohexanes was reported to interact with NMDA receptors in a manner similar to that of memantine. The present study aimed to evaluate the effects of these compounds as well as (+)MK-801 and memantine in two rat models of chronic pain and the rotarod test. Unlike (+)MK-801 and memantine, most of the tested compounds were inactive against tactile allodynia induced by sciatic nerve ligation. On the other hand, all tested drugs were found to inhibit formalin-induced grooming behavior-a model of chronic pain induction. In agreement with previous reports on the effects of NMDA receptor antagonists in similar assays, the late phase seemed to be inhibited to a greater extent than the early phase. For all tested compounds, inhibition of formalin-induced behaviors occurred at dose levels that were also producing significant motor deficits (rotarod test). These results confirm low efficacy of acute administration of NMDA receptor antagonists in the models of established pain states. Thus, studies on the prevention and management of chronic pain should focus on preemptive or long-term administration of NMDA receptor antagonists. Topics: Animals; Chronic Disease; Dizocilpine Maleate; Electrophysiology; Excitatory Amino Acid Antagonists; Formaldehyde; Grooming; Ligation; Male; Memantine; Oocytes; Pain; Pain Measurement; Postural Balance; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; RNA, Complementary; Sciatic Nerve; Sciatic Neuropathy; Xenopus | 2004 |
MK-801 inhibits the micturition reflex in chronic bladder irritation caused by crystalluria in the rat.
Urodynamic and pharmacological studies were performed to investigate the effect of crystalluria on the micturition reflex and the involvement of glutamatergic transmission. The rats, which were given LP-805 (100 mg/kg/day) orally for 12 days, voided crystalluria. The pH of these crystalluria (LP-805 urine) was the same as normal urine. The amount of crystals was 70-100/division magnified 400 x. The end of the crystals was sharp. Intravesical administration of LP-805 urine induced hyperreflexia of the micturition reflex in normal rats. When the infusion solution was changed to LP-805 urine from saline, the latency was reduced to 57.6+/-2.1% of control in single cystometrogram (CMG) or was reduced to 51.4+/-0.9% of control in continuous CMG. The voiding volume was reduced to 52.1+/-3.6% of control in single CMG or was reduced to 62.5+/-0.8% of control in continuous CMG. These parameters were recovered after LP-805 urine was removed. Intravesical administration of acetic acid did not induce hyperreflexia of the micturition reflex in LP-805-treated rats. These data suggest that the chronic irritation by aculeate crystals might induce hyperreflexia of the micturition reflex, which increase afferent neuronal activity. Intravenous administration of MK-801 (0.001 to 1 mg/kg) inhibited the micturition reflex in a dose-dependent manner. The ID50 in LP-805-treated rats (0.03 mg/kg i.v.) was lower than that in normal rats (0.56 mg/kg i.v.). After chronic irritation of the bladder epithelium, MK-801 sensitivity was enhanced for the micturition reflex. These data suggested that crystalluria elicit hyperreflexia in the micturition reflex that mediated with NMDA glutamatergic receptors. Topics: Animals; Chronic Disease; Crystallization; Cystitis, Interstitial; Dizocilpine Maleate; Dose-Response Relationship, Drug; Female; Pyrazoles; Pyrimidines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Reflex; Urinary Bladder Diseases; Urination | 2003 |
Influence of acute or repeated restraint stress on morphine-induced locomotion: involvement of dopamine, opioid and glutamate receptors.
The development of restraint stress-induced sensitization to the locomotor stimulating effect of morphine (2 mg/kg i.p.) was investigated. In experiment 1, both a single restraint session (2 h) and a repeated restraint stress (2 h per day for 7 days), similarly enhanced the effects of morphine on motor activity. In experiment 2, we observed that this sensitization was prevented by administration of both D(1) and D(2) dopaminergic antagonist [SCH-23390 (0.5 mg/kg i.p.) and (+/-)-sulpiride (60 mg/kg i.p.)] 10 min prior to the stress session. In experiment 3, we showed that an opioid antagonist pretreatment [naltrexone (1 mg/kg i.p.) 10 min prior to stress session, suppressed the stress-induced sensitization after morphine administration. In experiment 4, pretreatment with a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) type of glutamate receptors [(+)-MK-801 (0.1 mg/kg i.p.)], 30 min prior to the acute restraint session, prevented the development of sensitization to morphine. All these results suggest that: (1) sensitization to morphine on stimulating locomotor effect does not depend on the length of exposure to stress (acute vs. repeated); (2) stimulation of both D(1) and D(2) dopaminergic receptors is necessary for the development of restraint stress-induced sensitization to morphine; (3) an opioid system is also involved in this sensitization process; and (4) the stimulation of glutamatergic NMDA receptors is involved in this acute restraint-induced effect. Topics: Acute Disease; Animals; Benzazepines; Chronic Disease; Dizocilpine Maleate; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Excitatory Amino Acid Antagonists; Male; Morphine; Motor Activity; Naltrexone; Narcotic Antagonists; Narcotics; Rats; Rats, Wistar; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Restraint, Physical; Stress, Psychological; Sulpiride | 2002 |
Phenobarbital and MK-801, but not phenytoin, improve the long-term outcome of status epilepticus.
To examine the effect of therapy on status epilepticus (SE) acutely and on long-term outcome, we compared three drugs with three different mechanisms. Phenobarbital, MK-801, and phenytoin were administered at 1, 2, and 4 hours after initiation of limbic status epilepticus by "continuous" hippocampal stimulation in rats. We evaluated the effects of these drugs on the course of SE and the subsequent development of chronic epilepsy. Phenobarbital and MK-801 were superior to phenytoin in suppressing SE and in preventing chronic epilepsy. There was no benefit if treatment was given 2 hours after the initiation of SE. Phenobarbital was most effective in suppressing electrographic seizure activity, but MK-801 had a slightly wider window for the prevention of chronic epilepsy. Early treatment, rather than electrographic suppression of SE, correlated with prevention of chronic epilepsy. This study shows that the drugs administered, which have different mechanisms of action, have clear differences in altering the outcomes. The findings suggest that studies of SE treatment should examine the effect of therapy on SE itself, as well as the long-term benefits of each treatment. The use of N-methyl-D-aspartate receptor antagonists should be considered early in the treatment of SE. Topics: Animals; Anticonvulsants; Behavior, Animal; Chronic Disease; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Phenobarbital; Phenytoin; Rats; Rats, Sprague-Dawley; Status Epilepticus | 2002 |
Pronociceptive actions of dynorphin maintain chronic neuropathic pain.
Whereas tissue injury increases spinal dynorphin expression, the functional relevance of this upregulation to persistent pain is unknown. Here, mice lacking the prodynorphin gene were studied for sensitivity to non-noxious and noxious stimuli, before and after induction of experimental neuropathic pain. Prodynorphin knock-out (KO) mice had normal responses to acute non-noxious stimuli and a mild increased sensitivity to some noxious stimuli. After spinal nerve ligation (SNL), both wild-type (WT) and KO mice demonstrated decreased thresholds to innocuous mechanical and to noxious thermal stimuli, indicating that dynorphin is not required for initiation of neuropathic pain. However, whereas neuropathic pain was sustained in WT mice, KO mice showed a return to baselines by post-SNL day 10. In WT mice, SNL upregulated lumbar dynorphin content on day 10, but not day 2, after injury. Intrathecal dynorphin antiserum reversed neuropathic pain in WT mice at post-SNL day 10 (when dynorphin was upregulated) but not on post-SNL day 2; intrathecal MK-801 reversed SNL-pain at both times. Opioid (mu, delta, and kappa) receptor density and G-protein activation were not different between WT and KO mice and were unchanged by SNL injury. The observations suggest (1) an early, dynorphin-independent phase of neuropathic pain and a later dynorphin-dependent stage, (2) that upregulated spinal dynorphin is pronociceptive and required for the maintenance of persistent neuropathic pain, and (3) that processes required for the initiation and the maintenance of the neuropathic pain state are distinct. Identification of mechanisms that maintain neuropathic pain appears important for strategies to treat neuropathic pain. Topics: Animals; Chronic Disease; Disease Models, Animal; Dizocilpine Maleate; Dynorphins; Excitatory Amino Acid Antagonists; Hyperesthesia; Immune Sera; Injections, Spinal; Ligation; Lumbosacral Region; Male; Mice; Mice, Knockout; Neuralgia; Pain Measurement; Pain Threshold; Physical Stimulation; Reaction Time; Receptors, Opioid; Spinal Cord; Spinal Nerves | 2001 |
The influence of NMDA receptor-mediated processes on breathing pattern in ground squirrels.
The effects of blockade of N-methyl-D-aspartate (NMDA) type glutamate receptors by a non-competitive antagonist (MK-801) on cortical arousal, breathing pattern and ventilatory responses to hypoxia (10% O2 in N2) and hypercapnia (5% CO2 in air) were assessed in anesthetized (urethane) and unanesthetized golden-mantled ground squirrels (Spermophilus lateralis). Intra-cerebroventricular administration of MK-801 did not alter ventilation during wakefulness, although it did alter the pattern (breathing frequency and tidal volume components) of the hypercapnic ventilatory response, and suppressed the ventilatory response to hypoxia. Animals did not sleep following treatment with MK-801, and intravenous administration of MK-801 prevented expression of the sleep-like state normally observed in anesthetized animals. In anesthetized animals MK-801 elevated breathing frequency to levels observed without anesthesia, and suppressed the hypoxic ventilatory response. These data suggest that NMDA-type glutamatergic receptor-mediated processes influence cortical arousal and facilitate depression of breathing frequency during anesthesia and the hypoxic ventilatory response. Such processes are not essential for the hypercapnic ventilatory response. Topics: Acute Disease; Animals; Arousal; Chronic Disease; Dizocilpine Maleate; Electroencephalography; Excitatory Amino Acid Antagonists; Female; Hypercapnia; Hypoxia; Male; Receptors, N-Methyl-D-Aspartate; Respiratory Mechanics; Sciuridae | 2001 |
MK-801 reduces non-noxious stimulus-evoked Fos-like immunoreactivity in the spinal cord of rats with chronic constriction nerve injury.
We investigated the role of N-methyl-D-aspartate (NMDA) receptors on non-noxious stimulus-induced pain by examining the effect of MK-801, a non-competitive NMDA receptor antagonist, on Fos-like immunoreactivity (FLI) in the spinal dorsal horn by non-noxious stimulation to rats with chronic constriction injury (CCI) of the sciatic nerve. In CCI rats that did not receive the non-noxious stimulus, FLI was significantly increased in laminae V/VI of the dorsal horn at the 7th and 14th days after surgery relative to sham rats. When CCI rats received non-noxious stimuli, rubbing the plantar of the hind paw, FLI in laminae I/II at the 14th day was significantly increased relative to CCI rats that did not receive the stimulation. In sham rats, the same stimulus significantly decreased FLI in laminae III/IV and V/VI at the 7th and 14th day. When MK-801 was administered intraperitoneally prior to non-noxious stimulation in CCI rats at the 14th day after surgery, the stimulus-induced FLI in laminae I/II in CCI rats was significantly reduced. This study indicates that NMDA receptor is involved in upregulating FLI in response to non-noxious stimulation of CCI rats. Topics: Animals; Cell Count; Chronic Disease; Disease Models, Animal; Dizocilpine Maleate; Down-Regulation; Excitatory Amino Acid Antagonists; Immunohistochemistry; Male; Mechanoreceptors; Nerve Compression Syndromes; Neuronal Plasticity; Pain Threshold; Peripheral Nervous System Diseases; Physical Stimulation; Posterior Horn Cells; Proto-Oncogene Proteins c-fos; Rats; Receptors, N-Methyl-D-Aspartate; Touch | 2001 |
Two kinds of mitogen-activated protein kinase phosphatases, MKP-1 and MKP-3, are differentially activated by acute and chronic methamphetamine treatment in the rat brain.
Two functionally different MAP kinase phosphatases (MKPs) were investigated to clarify their roles in behavioral sensitization to methamphetamine (METH). MKP-1 mRNA levels increased substantially by about 60-300% in a range of brain regions, including several cortices, the striatum and thalamus 0.5-1 h after acute METH administration. After chronic METH administration its increase was less pronounced, but a more than 50% increase was still seen in the frontal cortex. MKP-1 protein levels also increased 3 h after acute or chronic METH administration. MKP-3 mRNA levels increased by about 30-50% in several cortices, the striatum and hippocampus 1 h after acute METH administration, but only in the hippocampus CA1 after chronic METH administration. Pre-treatment with the D(1) dopamine receptor antagonist, SCH23390, attenuated the METH-induced increase of MKP-1 and MKP-3 mRNA in every brain region, while pre-treatment with the NMDA receptor antagonist, MK-801, attenuated it in some regions. These findings suggest that in METH-induced sensitization, MKP-1 and MKP-3 play important roles in the neural plastic modification in widespread brain regions in the earlier induction process, but in the later maintenance process, they do so only in restricted brain regions such as MKP-1 in the frontal cortices and MKP-3 in the hippocampus. Topics: Acute Disease; Amphetamine-Related Disorders; Animals; Autoradiography; Behavior, Animal; Benzazepines; Brain; Cell Cycle Proteins; Central Nervous System Stimulants; Chronic Disease; Dizocilpine Maleate; Dopamine Antagonists; Dual Specificity Phosphatase 1; Dual Specificity Phosphatase 6; Enzyme Activation; Excitatory Amino Acid Antagonists; Gene Expression Regulation, Enzymologic; Immediate-Early Proteins; Male; Methamphetamine; Mitogen-Activated Protein Kinases; Neuronal Plasticity; Phosphoprotein Phosphatases; Protein Phosphatase 1; Protein Tyrosine Phosphatases; Rats; Rats, Sprague-Dawley; RNA, Messenger | 2001 |
Hypoxia influences somatostatin release in rats.
The impact of hypoxia on somatostatin (SS) secretion from the median eminence (ME) of the hypothalamus and the possible glucocorticosteroid involvement in modulating secretion, were investigated in adult male rats exposed to hypoxia. SS levels were measured by specific radioimmunoassay during acute and prolonged hypoxia as well as after bilateral adrenalectomy (ADX) with or without a replacement with dexamethasone (DEX). The results were as follows: (a) acute hypoxia (5 km altitude, 10.8% O(2)) for 2 and 24 h markedly increased SS content in ME, but acute severe hypoxia (7 km, 8.2% O(2) for 24 h) markedly decreased SS level in ME. (b) Chronic hypoxia (10.8% O(2)) from 5 to 25 days exposure did not significantly affect SS content of ME. (c) ADX alone increased SS content of ME and this increase was further enhanced after 2 h exposure to hypoxia. (d) The increased SS in ME of ADX rats was blocked by replacement with DEX (500 microg/rat i.p.). The data presented suggest that acute hypoxia stress may increase or decrease SS content of ME in rats, depending on the severity and duration of the hypoxia and that the stimulatory action of hypoxia on SS content of ME be may in part mediated by the increased corticosterone levels during hypoxia. Topics: Acute Disease; Adrenal Glands; Adrenalectomy; Altitude; Animals; Chronic Disease; Dexamethasone; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hypoxia; Male; Median Eminence; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Somatostatin; Stress, Physiological; Time Factors | 2000 |
Actions of the anticonvulsant remacemide metabolite AR-R12495AA on afferent-evoked spinal synaptic transmission in vitro and on models of acute and chronic inflammation in the rat.
The effects of the anticonvulsant remacemide [(+/-)-2-amino-N-(1-methyl-1,2-diphenylethyl)-acetamide hydrochloride] and its metabolite AR-R12495AA [(+/-)-1-methyl-1, 2-diphenylethylamine-monohydrochloride] on primary afferent synaptic transmission were assessed in the young rat spinal cord in vitro. Stimulation of dorsal roots at A- and C-afferent intensity elicited a dorsal root-evoked ventral root potential (DR-VRP) with a slowly decaying phase. Repetitive stimuli (2 Hz) produced summation of slow potentials and a cumulative ventral root depolarization (CVRD), a form of wind-up. Remacemide and AR-R12495AA antagonized the DR-VRP slow peak t(1/2) decay and slow phase total duration at drug concentration of > or =25 microM. AR-R12495AA was approximately 2-fold more potent than remacemide. The most potent action was against the slow phase duration with IC(50) values of 157 and 60 microM for remacemide and AR-R12495AA, respectively. Both drugs at concentrations of > or =100 microM attenuated the DR-VRP fast peak amplitude (IC(50) = 253 and 142 microM, respectively). The amplitude of CVRD was reduced by remacemide and AR-R12495AA (IC(50) = 195 and 111 microM, respectively). MK-801 reduced DR-VRP fast peak amplitude (IC(50) = 58 microM), slow peak t(1/2) decay (IC(50) = 60 microM), slow phase duration (IC(50) = 50 microM), and CVRD amplitude (IC(50) = 91 microM). In behavioral studies, AR-R12495AA (i.p.) reduced the mechanical hyperalgesia and paw swelling that followed hind paw injection of carrageenan or Freund's complete adjuvant. These electrophysiological and behavioral data indicate further studies should be conducted on the efficacy of remacemide and AR-R12495AA as putative analgesics. Topics: Acetamides; Acute Disease; Afferent Pathways; Animals; Animals, Newborn; Anticonvulsants; Chronic Disease; Dizocilpine Maleate; Electric Stimulation; Electrophysiology; Excitatory Amino Acid Antagonists; Hyperalgesia; In Vitro Techniques; Inflammation; Phenethylamines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Spinal Nerve Roots; Synaptic Transmission | 2000 |
Effects of methylprednisolone and MK-801 on functional recovery after experimental chronic spinal cord injury.
An experimental study was conducted to evaluate the effects of methylprednisolone and MK-801 after the compressive injury of spinal cord in rats.. To investigate the effect of methylprednisolone and non-competitive NMDA antagonist MK-801 in long-term functional outcome after spinal cord injury (SCI).. A randomized group A of Sprague-Dawley rats were treated with MK-801 (1.0 mg/kg, n=10; Group A) after a compression injury. A group of methylprednisolone (MP)-treated (30 mg/kg, n=10; Group B) and non-treated animals (n=9; Group C) were included for comparison. The functional motor outcome such as inclined plane (IP), toe spreading reflex (TSR), and modified Tarlov scale (TS) were measured in each animal at regular time points up to 8 weeks post-treatment. Histologically the injury site was scored in four groups and immunohistochemically Wallerian Degeneration (WD), astrocytosis and expression of beta-amyloid protein was identified.. In examining the IP data, no significant difference was recognized between the group means (P-value>0.5). For the TSR, there were no differences in the group responses. For the TS, the differences were not statistically significant. Only group B showed significance in cavitation scores compared to group A (P>0.0094), WD was significantly different than group C (P>0.03), astrocytosis was significantly higher than group A (P>0.001) and modest presence of beta-amyloid protein.. Our data indicate that one time bolus administration of MK-801 lacks any significant effect on axonal function in chronically injured rats. Daily bolus administration of MP at 30 mg/kg also did not ensure a better functional outcome. Immunohistochemically we have been able to show significant differences in WD, astrocytosis and small insignificant changes in beta-amyloid protein. Topics: Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents; Axons; Chronic Disease; Dizocilpine Maleate; Drug Therapy, Combination; Gliosis; Male; Methylprednisolone; Nerve Degeneration; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Recovery of Function; Spinal Cord; Spinal Cord Injuries | 2000 |
Effect of pre-emptive NMDA antagonist treatment on long-term Fos expression and hyperalgesia in a model of chronic neuropathic pain.
The unilateral sciatic nerve chronic constriction injury (CCI) model of Bennett and Xie [G.J. Bennett, Y.-K. Xie, A peripheral neuropathy in rat that produces disorders of pain sensation like those seen in man, Pain, 33 (1988) 87-108] shows features of a neuropathic pain state. We examined mechanical hyperalgesia and Fos protein staining in the lumbar spinal cord 1, 7, 14 and 28 days after unilateral CCI to the sciatic nerve or sham operation. In addition, we examined the effect of the NMDA antagonist MK-801 (0.3 mg/kg s.c. administered 30 min prior to and 6 h following operation) on Fos expression and hyperalgesia at 28 days. CCI animals were hyperalgesic compared to the sham operated animals at 14 and 28 days post injury. MK-801 reduced hyperalgesia by 68% in CCI animals on day 28 (p=0.0001). In the spinal cord, Fos positive cells were present bilaterally in deeper laminae in both sham and CCI animals at all time points examined. Relatively few Fos positive cells were present in laminae 1-2 at any time point examined. At days 1 and 7, there were increased numbers of Fos positive cells ipsilaterally in the deeper laminae of the spinal cord in CCI animals compared to sham animals, but by 14 and 28 days Fos counts were similar in sham and CCI despite the obvious behavioural differences between the two groups. Fos counts ipsilateral to the injury in laminae 3-10 correlated with hyperalgesia scores in the CCI but not sham animals. Analysis at the 28-day time point showed that MK-801 differentially affected Fos expression: MK-801 significantly reduced the Fos count bilaterally in laminae 3-10 in the CCI but not in the sham group animals. These results indicate that Fos expression is initiated by different peripheral and central mechanisms following nerve injury or sham operation. Topics: Animals; Behavior, Animal; Chronic Disease; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hyperalgesia; Male; Nerve Compression Syndromes; Neuralgia; Peripheral Nerve Injuries; Proto-Oncogene Proteins c-fos; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Spinal Cord | 1999 |
Effect of post-injury NMDA antagonist treatment on long-term Fos expression and hyperalgesia in a model of chronic neuropathic pain.
Chronic constriction injury (CCI) of the sciatic nerve results in persistent mechanical hyperalgesia together with Fos protein expression in the lumbar spinal cord. We have examined the relationship between mechanical hyperalgesia and Fos expression within the lumbar spinal cord on days 14, 35 and 55 after either CCI or sham operation. To determine the role of NMDA receptor mechanisms in the maintenance of hyperalgesia and Fos expression, the NMDA antagonist MK-801 (0.3 mg kg-1 s.c.) was administered daily on days 28 to 34 after operation. CCI animals developed unilateral hind limb hyperalgesia that persisted unchanged from days 14 to 55 of the study. MK-801 treatment reduced hyperalgesia by 57% (p=0.02) on day 35 in CCI animals but did influence hyperalgesia at day 55. In the spinal cord, Fos positive cells were present bilaterally throughout laminae 3-10 at all time points examined in both CCI and sham group animals. Fos counts ipsilateral to the side of injury in laminae 3-10 correlated significantly with hyperalgesia scores in the CCI but not sham animals. MK-801 treatment resulted in a suppression of Fos expression in ipsilateral laminae 3-4 (p=0.0017) and laminae 5-10 (p=0.0026) of CCI animals on day 35. Fos expression in sham group animals was not inhibited by MK-801 treatment at day 35. These results indicate that Fos expression is maintained by differing mechanisms following nerve injury or sham operation. The functional consequences of Fos expression following nerve injury and sham operation are discussed. Topics: Animals; Behavior, Animal; Chronic Disease; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Genes, Immediate-Early; Hyperalgesia; Male; Nerve Compression Syndromes; Neuralgia; Peripheral Nerve Injuries; Proto-Oncogene Proteins c-fos; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Spinal Cord | 1999 |
Biphasic expression of TGF-beta1 mRNA in the rat brain following permanent occlusion of the middle cerebral artery.
Two patterns of transforming growth factor-beta1 (TGF-beta1) expression were identified in brains of normotensive rats following permanent occlusion of the middle cerebral artery (MCAO). First, a relative increase of TGF-beta1 mRNA by 37% was found at 12 h after MCAO in the ipsilateral cingulate cortex as compared to the homotopic contralateral region. The cingulate cortex is located distant from the ischemic territory. Treatment with the glutamate receptor antagonists MK-801 and NBQX did not reduce this expression (34% and 26% increase, respectively). Therefore, peri-infarct depolarization waves were probably not responsible for induction. Secondly, an increase of TGF-beta1 mRNA by 116% was found at 7 days after MCAO within infarcted tissue. This expression was not reduced by the glutamate receptor antagonists MK-801 (increase 140%) and NBQX (increase 137%), either. TGF-beta1 mRNA expression in the cingulate cortex at 12 h after MCAO is possibly mediated by neurons and astroglia and may support cell survival. Expression in the infarcted tissue at 7 days after MCAO is most likely related to the invasion of monocytes and may be involved in the downregulation of inflammatory events, in neoangiogenesis, and in formation of a glial scar around the infarct. Topics: Animals; Arterial Occlusive Diseases; Brain; Cerebral Arteries; Chronic Disease; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Quinoxalines; Rats; Rats, Inbred F344; RNA, Messenger; Transforming Growth Factor beta | 1999 |
Pre-emptive intrathecal Mk-801, a non-competitive N-methyl-D-aspartate receptor antagonist, inhibits the up-regulation of spinal dynorphin mRNA and hyperalgesia in a rat model of chronic inflammation.
The effects of N-methyl-D-aspartate(NMDA) receptor antagonist, Mk-801, on the expression of spinal dynorphin (DYN) mRNA and the hyperalgesia induced by peripheral inflammation were studied by Northern analysis and behavioral test. Following an unilateral injection of complete Freund's adjuvant (CFA) into the rat hindpaw, there appeared a significant hyperalgesia of inflamed hindpaw and up-regulation of ipsilateral spinal DYN mRNA; while the pre-emptive and continuous intrathecal administration of Mk-801 (10 microg/microl per h) could significantly suppress both the hyperalgesia and the up-regulation of spinal DYN mRNA induced by peripheral inflammation. The results suggest that NMDA receptor activation may contribute to the development and maintenance of the thermal hyperalgesia that is associated with the up-regulation of DYN expression in spinal dorsal horn. Topics: Animals; Binding, Competitive; Chronic Disease; Disease Models, Animal; Dizocilpine Maleate; Dynorphins; Freund's Adjuvant; Hindlimb; Hyperalgesia; Inflammation; Infusion Pumps, Implantable; Injections, Spinal; Male; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Spinal Cord; Up-Regulation | 1998 |
Effect of spinal cord transection on N-methyl-D-aspartate receptors in the cord.
Spinal cord injury can lead to an exaggeration of transmission through spinal pathways, resulting in muscle spasticity, chronic pain, and abnormal control of blood pressure and bladder function. These conditions are mediated, in part, by N-methyl-D-aspartate (NMDA) receptors on spinal neurons, but the effects of cord injury on the expression or function of these receptors is unknown. Therefore, antibodies to the NMDA-R1 receptor subunit and binding of [3H]MK-801 were used to assess NMDA receptors in the spinal cord. Receptor density in rats with intact spinal cords was compared to that in rats 1 and 2 weeks after spinal cord transection (SCT) at the mid-thoracic level. At 1 and 2 weeks after SCT, [3H]MK-801 binding was reduced in most laminae in cord segments caudal to the injury, whereas no decrease in amount of R1 subunit immunoreactivity was observed. No significant changes in [3H]MK-801 binding and NMDA-R1 immunoreactivity could be seen rostral to the transection. Since [3H]MK-801 binding requires an open ion channel, the discrepancy between [3H]MK-801 binding and immunocytochemistry may indicate a loss of functional receptors without a consistent change in their total number. Therefore, the exaggerated reflexes that are well established in rats 2 weeks after cord injury must be mediated by a mechanism that withstands attenuation of NMDA receptor function. Topics: Animals; Autonomic Nervous System Diseases; Autoradiography; Chronic Disease; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Immunohistochemistry; Male; Muscle Spasticity; Nociceptors; Pain; Radioligand Assay; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Reflex, Abnormal; Spinal Cord; Spinal Cord Injuries; Tritium | 1998 |
The effect of NMDA antagonists on footshock-induced fighting behavior in chronically stressed rats.
In the present study we investigated the effect of two non-competitive antagonists of N-methyl-D-aspartate (NMDA) subtype of glutamate receptor: memantine (2.5 mg/kg) or MK-801 (0.1 mg/kg) on electric footshock-induced fighting behavior in normal (unstressed) and chronically (14 various stressors over 16 days) stressed rats. In rats submitted to chronic stress the number of fighting attacks was reduced by about 60%. Prolonged treatment with memantine or MK-801 counteracted the deficit of aggression induced by chronic stress (the same effect was observed after a single dose of MK-801 but not of memantine). The findings of our study demonstrate, that the non-competitive NMDA antagonists can reduce the behavioral deficits produced by chronic stress, the effect of which is similar to those of antidepressant drugs. Topics: Aggression; Animals; Chronic Disease; Dizocilpine Maleate; Electroshock; Excitatory Amino Acid Antagonists; Exploratory Behavior; Male; Memantine; N-Methylaspartate; Rats; Rats, Wistar; Stress, Psychological | 1997 |
The effects of LY293558, an AMPA receptor antagonist, on acute and chronic morphine dependence.
In rodents, noncompetitive and competitive NMDA receptor antagonists have been shown to attenuate and, in some cases, reverse tolerance to the analgesic effects of morphine. However, the ability of these same excitatory amino acid (EAA) receptor antagonists to modulate morphine dependence is controversial, and very little is known about the role of AMPA receptors in morphine dependence. LY293558, a novel, systemically active, competitive AMPA receptor antagonist and the NMDA receptor antagonists, MK-801 and/or LY235959, were evaluated in tolerant or dependent CD-1 mice. In mice rendered tolerant by morphine injection or pellet implantation, continuous s.c. infusion of LY293558 (60 mg/kg per 24 h) or MK-801 (1 mg/kg per 24 h) attenuated the development of tolerance. Neither LY293558 nor MK-801 produced analgesia or altered the ED50 value of morphine. Continuous s.c. infusion of LY293558 (60 mg/kg per 24 h), MK-801 (1 mg/kg per 24 h) or LY235959 (12 mg/kg per 24 h) attenuated the development of acute (3 h) morphine dependence (i.e., decreased naloxone-precipitated withdrawal jumping). In contrast, continuous s.c. infusion of LY293558 (60 mg/kg per 24 h) or LY235959 (12 mg/kg per 24 h) did not significantly attenuate the development of chronic dependence produced by morphine pellet implantation. These data indicate that the development of morphine tolerance is more sensitive to modulation by EAA receptor antagonists than is the development of morphine dependence as assessed by naloxone-precipitated withdrawal jumping. Topics: Acute Disease; Animals; Chronic Disease; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Tolerance; Excitatory Amino Acid Antagonists; Infusions, Parenteral; Isoquinolines; Male; Mice; Mice, Inbred Strains; Morphine Dependence; Naloxone; Narcotic Antagonists; Receptors, AMPA; Tetrazoles | 1997 |
Treatment of a chronic allodynia-like response in spinally injured rats: effects of systemically administered excitatory amino acid receptor antagonists.
A chronic allodynia-like response to mechanical stimulation was observed in rats after severe spinal cord ischemia. This allodynia-like response was not relieved by most conventional analgesics used for treating chronic neuropathic pain. The present experiments evaluated the effects of systemically administered excitatory amino acid receptor antagonists, including the non-competitive N-methyl-D-aspartate (NMDA) receptor/channel blockers MK-801 and dextromethorphan, the competitive NMDA receptor antagonist CGS 19755 and a competitive antagonist of the alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptor NBQX, on the chronic allodynia-like response in spinally injured rats. Systemic MK-801, dextromethorphan and CGS 19755 dose-dependently relieved the mechanical allodynia-like response. Systemic MK-801 and CGS 19755, but not dextromethorphan, also induced severe motor impairment at analgesic doses. All three NMDA antagonists increased spontaneous motor activity. Systemic NBQX reduced muscle tone and caused sedation. The mechanical allodynia was only relieved by NBQX at a sedative dose. It is concluded that systemic NMDA, but not AMPA, receptor antagonists may have an analgesic effect upon the chronic allodynia-like response. However, the analgesic effect of all NMDA antagonists was associated with side effects. Dextromethorphan, which is clinically tolerated and produced less side effects, may be useful for treating chronic pain associated with central nervous system injury. Topics: Animals; Behavior, Animal; Chronic Disease; Dextromethorphan; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Hyperalgesia; Ischemia; Motor Activity; Pipecolic Acids; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Regional Blood Flow; Spinal Cord; Spinal Cord Injuries | 1996 |
Single intrathecal injections of dynorphin A or des-Tyr-dynorphins produce long-lasting allodynia in rats: blockade by MK-801 but not naloxone.
Neuropathic pain states are accompanied by increased sensitivity to both noxious and non-noxious sensory stimuli, characterized as hyperalgesia and allodynia, respectively. In animal models of neuropathic pain, the presence of hyperalgesia and allodynia are accompanied by neuroplastic changes including increased spinal levels of substance P, cholecystokinin (CCK), and dynorphin. N-Methyl-D-aspartate (NMDA) receptors appear to be involved in maintaining the central sensitivity which contributes to neuropathic pain. In addition to its opioid activities, dynorphin has been suggested to act at the NMDA receptor complex. In an attempt to mimic the increased levels of spinal dynorphin seen in animal models of neuropathic pain, rats received a single intrathecal (i.t.) injection of dynorphin A(1-17), dynorphin A(1-13), dynorphin A(2-17) or dynorphin A(2-13) through indwelling catheters. Tactile allodynia was determined by measuring response threshold to probing with von Frey filaments. Dynorphin A(1-17) administration evoked significant and long-lasting tactile allodynia (i.e. > 60 days). Likewise, the i.t. administration of dynorphin A(1-13) or dynorphin A(2-17) or dynorphin A(2-13) also produced long-lasting tactile allodynia. Intrathecal pretreatment, but not post-treatment, with MK-801 prevented dynorphin A(1-17)-induced development of allodynia; i.t. administration of MK-801 alone had no effect on responses to tactile stimuli. In contrast, i.t. pretreatment with naloxone did not affect the development of tactile allodynia induced by dynorphin A(1-17) or alter sensory threshold when given alone. These results demonstrate that a single dose of dynorphin A, or its des-Tyr fragments, produces long-lasting allodynia which may be irreversible in the rat. Further, this effect appears to be mediated through activation of NMDA, rather than opioid, receptors. While the precise mechanisms underlying the development and maintenance of the allodynia is unclear, it seems possible that dynorphin may produce changes in the spinal cord, which may contribute to the development of signs reminiscent of a "neuropathic' state. Given that levels of dynorphin are elevated following nerve injury, it seems reasonable to speculate that dynorphin may have a pathologically relevant role in neuropathic pain states. Topics: Animals; Chronic Disease; Dizocilpine Maleate; Dynorphins; Excitatory Amino Acid Antagonists; Injections, Spinal; Male; Naloxone; Narcotic Antagonists; Pain; Peptide Fragments; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Sensory Thresholds | 1996 |
Conditioned place preference paradigm: a novel approach for analgesic drug assessment against chronic pain.
In response to concerns over the clinical relevance of analgesic testing paradigms which involve acute nociceptive stimuli, the present research examined the utility of the conditioned place preference (CPP) paradigm as a novel approach for determination of analgesic drug efficacy against chronic nociception. Rats display preferences for environments that have been previously paired with positively reinforcing drugs; whether place preference to the negatively reinforcing effects of analgesic drugs in an animal model of chronic pain occurs is yet unknown. The present research sought to determine whether animals experiencing chronic pain would display a place preference for an environment paired with analgesic drug treatment. Persistent inflammatory nociception was induced by unilateral injections of complete Freund's adjuvant (0.1 ml) into the rat hind paw. Place preference to the opiate agonist morphine, the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and the non-steroidal anti-inflammatory drug (NSAID) indomethacin was examined in 3 separate experiments. Rats received 8 counter-balanced conditioning trials (4 drug, 4 no-drug) of 60 min each with various drug doses (morphine: 3.0 and 10.0 mg/kg; indomethacin: 2.5 and 5.0 mg/kg; MK-801: 0.03, 0.1 and 0.3 mg/kg, i.p.) or vehicle serving as the reinforcing stimuli in a 3 compartment (2 stimuli, 1 neutral) place preference apparatus. In general, morphine place preference was observed in both inflamed and non-inflamed groups; inflamed groups exhibited enhanced morphine place preference than non-inflamed groups. MK-801 produced a low-dose place preference in inflamed animals; higher doses of MK-801 produced a place aversion in both inflamed and non-inflamed groups. Indomethacin failed to produced place preference in either inflamed or non-inflamed groups. These data demonstrate that the negatively reinforcing properties of analgesic drugs can be assessed via the CPP paradigm. In addition, this paradigm offers greater clinical relevance as animals determine drug efficacy without the involvement of high-intensity, phasic nociceptive stimulation. Topics: Analgesics; Animals; Chronic Disease; Conditioning, Operant; Dizocilpine Maleate; Edema; Hot Temperature; Indomethacin; Male; Morphine; Nociceptors; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Reinforcement, Psychology | 1994 |
Pre treatment with MK-801, a non-competitive NMDA antagonist, prevents development of mechanical hyperalgesia in a rat model of chronic neuropathy, but not in a model of chronic inflammation.
In the rat, loose ligation of the sciatic nerve results in behavioural signs of hyperalgesia reminiscent of neuropathy in man. A further rat model, of chronic inflammatory hyperalgesia, is produced by intraplantar administration of Freund's complete adjuvant (FCA). We report here that preemptive administration of a non-competitive antagonist of the glutamate N-methyl-D-aspartate (NMDA) receptor, MK-801 (0.3 mg kg-1, s.c.) 30 min prior to and twice daily for a further 8 days following loose ligation of the sciatic nerve, blocks the development of mechanical hyperalgesia measured 27 days later. In contrast, MK-801 administration using the same dosing regimen did not significantly inhibit the hyperalgesia apparent 15 days following i.pl. administration of FCA. Our results suggest that the mechanisms responsible for the development of mechanical hyperalgesia associated with chronic nerve injury and chronic inflammation differ. Topics: Animals; Chronic Disease; Dizocilpine Maleate; Freund's Adjuvant; Hyperalgesia; Inflammation; Male; N-Methylaspartate; Nervous System Diseases; Nociceptors; Physical Stimulation; Rats; Receptors, N-Methyl-D-Aspartate; Sciatic Nerve | 1994 |
Alterations in cortical [3H]kainate and alpha-[3H]amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid binding in a spontaneous canine model of chronic hepatic encephalopathy.
Excitatory amino acid receptor binding parameters were investigated in a spontaneous dog model of chronic hepatic encephalopathy. L-[3H]Glutamate, (+)-[3H]-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-im ine maleate ([3H]MK-801), [3H]kainate, and alpha-[3H]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ([3H]AMPA) binding experiments were performed using crude cerebrocortical synaptosomal membrane preparations from dogs with congenital portosystemic encephalopathy (PSE) and control dogs. There was no change in the affinity or density of L-[3H]-glutamate or [3H]MK-801 binding sites in dogs with congenital PSE compared with control dogs. However, in the PSE dogs there was a significant reduction in the density of [3H]kainate binding sites compared with control dogs and abolition of the low-affinity [3H]AMPA binding site. The relative binding capacity of PSE synaptosomal membranes for [3H]kainate and [3H]AMPA was expressed as the ratio Bmax/KD. There was a significant inverse correlation between the Bmax/KD ratio for [3H]AMPA binding and the worst grade of encephalopathy experienced by each dog. These results suggest that there is a significant perturbation of cerebrocortical non-N-methyl-D-aspartate receptor binding in dogs with congenital PSE which may have relevance to the pathogenesis of hepatic encephalopathy. Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Cerebral Cortex; Chronic Disease; Dizocilpine Maleate; Dogs; Glutamates; Glutamic Acid; Hepatic Encephalopathy; Ibotenic Acid; Kainic Acid; Ligands; Tritium | 1991 |