dizocilpine-maleate and Edema

Dizocilpine is a highly selective and potent non-competitive antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor. It is well known that dizocilpine has different neuroprotective effects in animal models of pain, epilepsy and oedema during trauma. The search for alternative antiinflammatory drugs is ongoing. We investigated the anti-oedematous effects of dizocilpine and the probable mechanism of action in a rat model that mimics local and persistent inflammation without tissue injury or damage. Male Wistar rats were injected with 100 μL of 0.5% carrageenan to the plantar surface of the hind paw. Anti-oedematous activity was assessed in the carrageenan-induced paw inflammatory oedema test with a plethysmometer. To assess possible mechanisms of dizocilpine action, we examined the effects of the selective inhibitor of neuronal [N-ω-propyl-L-arginine hydrochloride (L-NPA)] and inducible [S-methylisothiourea (SMT)] nitric oxide synthase (NOS). Dizocilpine after systemic (0.0005, 0.005 and 0.02 mg/kg, subcutaneous (s.c.)), but not after local peripheral administration, reduced the paw inflammatory oedema. The effect is not dose dependent, and the highest decrease by about 47% at the time of maximally developed oedema was achieved with 0.005 mg/kg. Intraperitoneally (i.p.) administered L-NPA (0.5, 1 and 2 mg/kg) or SMT (0.005, 0.01 and 0.015 mg/kg) before dizocilpine abolished or reduced the anti-oedematous effect of dizocilpine by about 70-85%. An acute single dose of dizocilpine administered before inducing oedema systemically reduced the development of inflammatory oedema. The mechanism of the anti-oedematous effect includes, at least partially, an increase in nitric oxide (NO) production.

Topics: Animals; Anti-Inflammatory Agents; Arginine; Carrageenan; Dizocilpine Maleate; Edema; Inflammation; Isothiuronium; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Pain; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate

The ionotropic glutamate receptorantagonists include two types: MK-801, antagonist of N-methyl-D-asparticacid (NMDA) receptor, and NBQX, antagonist of non-NMDA receptor.The above-mentioned ionotropic antagonists can block the glutamate and its corresponding receptor binding to produce analgesic effect. The objective of this research was to study two antagonists in analgesic effect on rat behavior,as well as to investigate the down-regulation and up-regulation of cyclooxygenase-2 (COX-2) and Janus-activated kinase (Jak3) in collagen-induced arthritis (CIA) rat serum and tissue fluid after the application of these antagonists, that is, the effect on molecular biology.. This study used the ionotropic glutamate receptors as the target and established CIA rat model. Vivo studies were used to observe changes in behavior and molecular biology of the CIA rat.Behavioral assessment includedmechanical allodynia and joint swelling in the CIA rat,where themechanical allodynia was measured using the paw-withdrawal threshold (PWT) with VonFrey filaments according to the "Up-Down" method,and the drainage volume was used to assess joint swelling. Then the blood samples taken from the heart of the rat and the tissue homogenate were collected to detect the down-regulation and up-regulation of COX-2 and Jak3 in the serum and tissue fluid after the antagonists wereused.. Using MK-801, NBQX alone or using the combination of these two antagonists,these three methods all could alleviate pain(P<0.01).The analgesic effect lasted more than 24 h.Both antagonists reached the peak of analgesia at the end of 4 hours post-injection. NBQX had stronger analgesic effect than MK-801 (P<0.05).Whether alone or combined use of these two antagonists,could not change the CIA rats' swelling of the joint (P>0.05). MK-801 could decrease the expression of COX-2 (P<0.01).At the same time, NBQX did not have this effect (P>0.05). Using MK-801, NBQX alone or combination of these two antagonists could not affect the increased expression of Jak3 caused by the CIA (P>0.05).. MK-801 and NBQX could both alleviate pain, NBQX was much better than MK-801. Neither MK-801 nor NBQX had the effect on the swelling of the joint. NMDA receptor and COX-2 inflammatory pathways had certain interactions. For Jak3, it could not be found to have cross-function with ionotropic glutamate signaling pathways by this experiment.

Topics: Analgesics; Animals; Arthritis, Experimental; Cyclooxygenase 2; Dizocilpine Maleate; Edema; Excitatory Amino Acid Antagonists; Gene Expression Regulation; Hyperalgesia; Janus Kinase 3; Male; Pain; Quinoxalines; Rats; Receptors, N-Methyl-D-Aspartate

Male Wistar rats were subjected to chronic restraint stress (CRS; 6 h/day for 21 days) alone or along with either hydroalcoholic extract of Ocimum sanctum (Os; 100 mg/kg; orally) or MK-801, an NMDA receptor antagonist (0.3 mg/kg; i.p.). In the rats subjected to only CRS, plasma cAMP level was significantly raised on day 21, with no significant change in plasma corticosterone level. There was a significant (p < 0.05) fall in myocardial glutathione level, along with a significant (p < 0.05) rise in myocardial superoxide dismutase (SOD) and catalase activities, while light microscopy showed evidence of myocardial edema. Both Os and MK-801 significantly prevented the CRS-induced rise in plasma cAMP level, myocardial SOD and catalase activities as well as the light microscopic changes in the myocardium. This study revealed that Ocimum sanctum protects rat heart from chronic restraint stress induced changes, through its central effect.

Topics: Administration, Oral; Animals; Body Weight; Catalase; Corticosterone; Cyclic AMP; Dizocilpine Maleate; Edema; Male; Myocardium; Ocimum; Plant Extracts; Rats; Rats, Wistar; Restraint, Physical; Superoxide Dismutase

Contribution of peripheral NMDA receptors in craniofacial muscle nociception and inflammation was examined. Nocifensive paw-shaking behavior following masseteric injection of mustard oil (MO) was quantified in lightly anesthetized rats. MK-801 (0.3 mg/kg) preadministered in the masseter muscle significantly reduced the peak and overall magnitude of the MO-induced noficensive behavior. The reduction was greater than that produced by the same dose of MK-801 given intravenously or in the biceps muscle. Rats were sacrificed 2 h later and masseter muscles dissected and weighed. The injected muscle was 27.29+/-6.7% heavier than the contralateral muscle. The weight difference was significantly less only in rats pretreated with masseteric MK-801. These data provide evidence that peripheral NMDA receptors play an important role in craniofacial muscle nociception and inflammation.

Topics: Animals; Dizocilpine Maleate; Edema; Excitatory Amino Acid Antagonists; Male; Masseter Muscle; Mustard Plant; Nociceptors; Pain; Plant Extracts; Plant Oils; Rats; Receptors, N-Methyl-D-Aspartate

This study characterizes the receptor subtypes and investigates some of the mechanisms by which glutamate, injected intraplantarly (i.pl.) into the mouse paw, produces nociception and paw oedema. I.pl. injection of glutamate induced a rapid-onset, dose-related pain response associated with oedema formation, with mean ED(50) values of 2.6 (1.6-4.3) and 0.5 (0.4-0.7) micromol/kg, respectively. Pretreatment with Chicago sky blue 6B (100 microg/kg), an inhibitor of glutamate uptake, caused a significant (about sixfold) reduction of the mean ED(50) value for glutamate-induced nociception, but not paw oedema. NMDA receptor antagonist MK 801, given by systemic (i.p.), intracerebroventricular (i.c.v.), i.pl. or intrathecal (i.t.) routes, produced graded inhibition of glutamate-induced nociception. Non-NMDA receptor antagonists NBQX or GAMS, metabotropic antagonist E4CPG, and also the antagonist that acts at the NMDA receptor-associated glycine binding site felbamate, significantly inhibited the nociception induced by glutamate. L(omega)-N-nitro-arginine (given i.p., i.t., i.pl. or i.c.v.) prevented the nociception and paw oedema caused by glutamate, an effect that was reversed by L-arginine but not by D-arginine. S-nitroso-N-acetyl-D,L-penicillamine (SNAP), given i.pl., greatly potentiated glutamate-induced nociception and oedema formation. Finally, the i.pl. injection of glutamate was accompanied by a graded increase in the nitrite levels of the hindpaw exudate. It is concluded that the nociception caused by i.pl. injection of glutamate probably involves the activation of NMDA and non-NMDA receptors by a mechanism which largely depends on the activation of L-arginine-nitric oxide pathway. Glutamate-induced paw oedema seems to be primarily mediated by non-NMDA ionotropic glutamate receptors and release of nitric oxide.

Topics: Animals; Azo Compounds; Coloring Agents; Dizocilpine Maleate; Dose-Response Relationship, Drug; Edema; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Extremities; Glutamic Acid; Glutamine; Male; Mice; Nitric Oxide; Nitric Oxide Donors; Nitrites; Nitroarginine; Nociceptors; Penicillamine; Quinoxalines; Trypan Blue

Glutamate release, particularly in pathologic conditions, may result in cellular swelling. The authors studied the effects of glutamate, N-methyl-D-aspartate (NMDA), and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) on extracellular pH (pH(e)), extracellular potassium concentration ([K(+)](e)), and changes in extracellular space (ECS) diffusion parameters (volume fraction alpha, tortuosity lambda) resulting from cellular swelling. In the isolated spinal cord of 4-to 12-day-old rats, the application of glutamate receptor agonists induced an increase in [K(+)](e), alkaline-acid shifts, a substantial decrease in alpha, and an increase in lambda. After washout of the glutamate receptor agonists, alpha either returned to or overshot normal values, whereas lambda remained elevated. Pretreatment with 20 mmol/L Mg(++), MK801, or CNQX blocked the changes in diffusion parameters, [K(+)](e) and pH(e) evoked by NMDA or AMPA. However, the changes in diffusion parameters also were blocked in Ca(2+)-free solution, which had no effect on the [K(+)](e) increase or acid shift. The authors conclude that increased glutamate release may produce a large, sustained and [Ca(2+)](e)-dependent decrease in alpha and increase in lambda. Repetitive stimulation and pathologic states resulting in glutamate release therefore may lead to changes in ECS volume and tortuosity, affecting volume transmission and enhancing glutamate neurotoxicity and neuronal damage.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Calcium; Cell Death; Chelating Agents; Diffusion; Dizocilpine Maleate; Edema; Egtazic Acid; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Extracellular Space; Gliosis; Glutamic Acid; Hydrogen-Ion Concentration; In Vitro Techniques; Magnesium; N-Methylaspartate; Potassium; Rats; Rats, Wistar; Spinal Cord

To determine whether MK801, an NMDA receptor antagonist, blocks glutamate excitotoxicity directly or via other mechanisms such as improving blood supply at the injury site in a rat model of spinal cord injury (SCI). In the present study, the effects of pre- and posttreatment with MK801 on axonal function, spinal cord blood flow (SCBF) and cord water content were studied after acute SCI in rats.. Somatosensory evoked potentials (SSEPs) and cerebellar evoked potentials (CEPs) were used to quantify electrophysiological function, and the hydrogen clearance technique and wet-dry weight measurements were used to measure SCBF and cord water content, respectively. Twenty rats received a 21 g clip compression injury of the cord at T1, and were then randomly and blindly allocated to either MK801 or saline groups. Each rat received an intravenous infusion of drug or saline four times during the experiment (16 min/infusion) with the first infusion (MK801 3 mg/kg) beginning 8 min pre-injury, and the other infusions (MK801 1. 5 mg/kg) at 1 h intervals after injury. Control experiments on uninjured rats were performed in 10 rats using the same procedure as above except the clip compression injury of the cord was omitted.. In the MK801 groups with or without SCI, the amplitude of the evoked potential peaks, especially the SSEPs, was significantly lower than in the saline group. There were no differences in SCBF or cord water content between the MK801 and saline groups.. Pre- and posttreatment with MK801 inhibits evoked potentials, but does not improve SCBF or cord edema after acute compression SCI in rats. For the first time it has been shown that MK801 produced a blockade of glutamate excitatory transmission in afferent pathways after SCI. Further work is required to determine whether this inhibition is reversible and related to neuroprotection and functional recovery after SCI.

Topics: Acute Disease; Animals; Body Water; Cerebellum; Dizocilpine Maleate; Edema; Evoked Potentials; Evoked Potentials, Somatosensory; Excitatory Amino Acid Antagonists; Male; Neuroprotective Agents; Random Allocation; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Spinal Cord Diseases; Synaptic Transmission

The role of norepinephrine and excitatory amino acids in edema of the spinal cord after an acute experimental compression injury was studied in rats. Control rats received the compression injury only. Intraspinal norepinephrine was depleted in one rat group by injection of 6-hydroxydopamine (6-OHDA) into the subarachnoid space to selectively destroy catecholamine neurons and in a third group MK-801 was administered intravenously to block receptors for N-methyl-d-aspartate (NMDA), an excitatory amino acid. Recovery from motor paralysis and suppression of edema of the spinal cord were then compared in the three groups. Significant recovery from motor paralysis was found 12 h after injury in the 6-OHDA-treated rats, compared with the controls, and 24 h after injury in the MK-801-treated rats. Edema of the spinal cord was significantly suppressed for up to 24 h after injury in the 6-OHDA-treated rats. The MK-801-treated rats showed no significant suppression of the edema until 24 h after the spinal cord injury. It was concluded that norepinephrine is primarily involved in the formation of vasogenic edemas, which develop in the early stages after an injury, whereas excitatory amino acids affect the formation of cytotoxic edemas, which develop at a relatively later stage.

Topics: Analysis of Variance; Animals; Body Water; Disease Models, Animal; Dizocilpine Maleate; Edema; Excitatory Amino Acid Antagonists; Excitatory Amino Acids; Injections, Spinal; Male; Motor Activity; Norepinephrine; Oxidopamine; Rats; Rats, Wistar; Reference Values; Spinal Cord; Spinal Cord Compression; Statistics, Nonparametric

To clarify the role of N-methyl-D-aspartate (NMDA) receptors in acute spinal cord injury, changes in the intraspinal microcirculation after acute spinal cord injury in rabbits were examined. Systemic administration of MK-801, an NMDA receptor antagonist, at a dose of 5 mg/kg, significantly improved motor recovery after injury and significantly reduced edema formation at the injured site without altering spinal cord blood flow or vascular permeability at the injured site. These findings indicate that excitatory amino acids contribute to secondary spinal cord damage, especially edema formation, mediated by NMDA receptors in the early stage after injury.

Topics: Acute Disease; Animals; Blood Pressure; Capillary Permeability; Dizocilpine Maleate; Edema; Excitatory Amino Acid Antagonists; Microcirculation; Rabbits; Receptors, N-Methyl-D-Aspartate; Regional Blood Flow; Spinal Cord; Spinal Cord Diseases; Spinal Cord Injuries

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

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Chickens; Dizocilpine Maleate; Edema; Electron Transport; Glycolysis; Hypoglycemia; Hypoxia; Iodoacetates; Iodoacetic Acid; Ischemia; N-Methylaspartate; Potassium Cyanide; Quinoxalines; Receptors, N-Methyl-D-Aspartate; Retina; Tetrodotoxin

Excitotoxin-induced neural tissue damage is mediated through specific receptors. We studied the in vivo effect of two selective N-methyl-D-aspartate receptor antagonists on the compressed spinal cord segments of rats harboring a thoracolumbar epidural tumor. The effect of a single intramuscular treatment with either MK-801 (3 mg/kg) or ketamine (110 mg/kg) given at the onset of paraplegia was evaluated 30 hours later. In saline-treated control animals, significant increases in water content, prostaglandin E2, and 6-keto-prostaglandin F1 alpha were evident. Treatment with either agent resulted in a normal water content in the compressed segments but had no effect on prostaglandin synthesis. Evaluation of the effect of treatment on the course of the disease required dose reduction by 45% for ketamine and by 30% for MK-801, to avoid the excessive sedative effect. Treatment was started at the first appearance of neurological dysfunction (Grade 1) and continued to paraplegia (Grade 5). The mean time interval between Grades 1 and 5 was 2.1 +/- 0.3 days in saline-treated control animals, and it was not significantly altered by either ketamine or MK-801. Our study indicates that in the end stage of epidural compression, when ischemia is present, excitotoxins probably participate in the evolution of a cytotoxic edema. It is suggested that treatment initiated at the onset of paraplegia may still reduce the cytotoxic edema, but its potential clinical value requires further investigations.

Topics: Analysis of Variance; Animals; Brain Edema; Dibenzocycloheptenes; Dizocilpine Maleate; Edema; Histiocytoma, Benign Fibrous; Ketamine; Neurons; Prostaglandins; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Spinal Cord Compression; Spinal Cord Neoplasms