naloxone and Ischemic-Attack--Transient

It has been proposed that endogenous opioids play a pathophysiologic role in the secondary injury that follows spinal trauma, brain trauma, and cerebral ischemia. Opiate antagonists, at high doses, have been found to improve outcome in various experimental models of central nervous system injury. Thyrotropin-releasing hormone, which appears to act in part as a functional antagonist of opioid systems, has proved effective in the treatment of experimental spinal cord and brain trauma. The literature relating to these developments is reviewed, with emphasis on the potential clinical application of these classes of substances.

Topics: Animals; Cats; Central Nervous System Diseases; Dynorphins; Humans; Ischemic Attack, Transient; Naloxone; Narcotic Antagonists; Narcotics; Rabbits; Spinal Cord Injuries; Thyrotropin-Releasing Hormone

The present study was designed to investigate the possible role of opioids and K(ATP) channels in ischemic postconditioning-induced reversal of global cerebral ischemia and reperfusion (I/R) induced neuronal injury. Mice were subjected to global ischemia by bilateral carotid artery occlusion for 10 min followed by reperfusion for 24 h, to produce neuronal injury. Ischemic postconditioning was induced by three episodes of carotid artery occlusion and reperfusion of 10 s each, immediately after global ischemia. Morphine postconditioning was induced by administration of morphine (5 mg/kg i.v.), 5 min prior to reperfusion. Naloxone (5 mg/kg i.v.), opioid receptor antagonist, and glibenclamide (5 mg/kg i.v.), K(ATP) channel blocker were administered 10 min before global ischemia. Extent of cerebral injury was assessed by measuring cerebral infarct size using triphenyl tetrazolium chloride (TTC) staining. Short-term memory was evaluated using the elevated plus maze test, while degree of motor incoordination was evaluated using inclined beam-walking, rota-rod and lateral push tests. Bilateral carotid artery occlusion followed by reperfusion resulted in significant increase in infarct size, impairment in short-term memory and motor co-ordination. Ischemic/morphine postconditioning significantly attenuated I/R induced neuronal injury and behavioural alterations. Pretreatments with naloxone and glibenclamide attenuated the neuroprotective effects of ischemic/morphine postconditioning. It may be concluded that ischemic/morphine postconditioning protects I/R induced cerebral injury via activating opioid receptor and K(ATP) channel opening.

Topics: Analgesics, Opioid; Animals; Cerebral Infarction; Ischemic Attack, Transient; Ischemic Preconditioning; KATP Channels; Male; Memory, Short-Term; Mice; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Postural Balance; Psychomotor Performance; Reperfusion Injury

Whether naloxone may modulate energy metabolism and endogenous antioxidant enzyme activities in ischemic cortex was studied. Cerebral ischemia/reperfusion (I/R) was produced by occluding two common carotid arteries and the right middle cerebral artery for 90 min followed by reperfusion in anesthetized Sprague-Dawley rats. Both pre-treatment (0.03 or 0.3 mg) and post-treatment (0.3 mg) of naloxone by intracerebroventricular infusion significantly reduced cortical infarct volumes. Pre-treatment with 0.03 mg reduced ischemia-induced suppression of extracellular pyruvate level and enhancement of lactate/pyruvate ratio as well as cerebral I/R-induced increases of endogenous catalase, glutathione peroxidase, and manganese superoxide dismutase activities. In conclusion, neuroprotective effects of naloxone in terms of reducing brain infarction involve attenuation of the disturbance of cellular functions following cerebral I/R via restoration of mitochondrial activities or energy metabolism.

Topics: Animals; Antioxidants; Brain; Catalase; Energy Metabolism; Free Radicals; Glutathione Peroxidase; Ischemic Attack, Transient; Lactic Acid; Male; Microdialysis; Naloxone; Narcotic Antagonists; Opioid Peptides; Pyruvic Acid; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Stroke; Superoxide Dismutase

We investigated the postischemic alterations in [3H]MK-801, [3H]muscimol, and [3H]naloxone binding in the gerbil brain, and examined the effect of pentobarbital against these alterations. [3H]MK-801, [3H]muscimol, and [3H]naloxone were used to label N-methyl-D-aspartate (NMDA), gamma-aminobutyric acidA (GABAA), and opiate receptors, respectively. Transient cerebral ischemia was induced for 10 min, and pentobarbital (40 mg/kg) was administered intraperitoneally 30 min before ischemia. Five hours after ischemia, no conspicuous alteration in [3H]MK-801, [3H]muscimol, and [3H]naloxone binding was found in the striatum and hippocampus. Seven days after ischemia, [3H]MK-801 and [3H]naloxone binding was significantly decreased in the striatum and hippocampal area where histological neuronal damage was noted. By contrast, no significant change in [3H]muscimol binding was seen in the above regions except for the hippocampal CA3 sector. The treatment of pentobarbital caused a significant alteration in the binding of [3H]naloxone and [3H]muscimol in various brain areas 5 h after ischemia. However, this drug showed no significant change in [3H]MK-801 binding in the brain. Seven days after ischemia, pentobarbital partly ameliorated a significant reduction in [3H]MK-801 and [3H]naloxone binding in the striatum and hippocampus. A histological study also showed that pentobarbital afforded neuronal protection against the damage to the brain except for the hippocampal CA1 sector 7 days after ischemia. These results suggest that NMDA and opiate receptors are damaged after ischemia, whereas GABAA receptors are unaffected. They also demonstrate that opiate receptors are severe affected by the treatment of pentobarbital, compared with NMDA and GABAA receptors. These findings are of interest in relation to the mechanism of ischemic neuronal damage.

Topics: Animals; Brain; Dizocilpine Maleate; Gerbillinae; Ischemic Attack, Transient; Male; Muscimol; Naloxone; Pentobarbital; Radioligand Assay

Hemorrhagic hypotension in spontaneously hypertensive rats induces attenuation of somatosensory evoked potentials. In this model of relatively mild cerebral ischemia, our previous studies have shown that naloxone stereospecifically enhances the evoked potentials, without changes in cortical blood flow. The high dose of naloxone needed to enhance the evoked potentials suggests that the attenuation is mediated by low affinity opioid receptors (delta or kappa). In the present study, we used this model to study the effects of naloxone-methobromide (5 mg kg-1, a quaternary derivative of naloxone with selective peripheral action when injected intravenously), MR 2266 (1 mg kg-1, a kappa receptor antagonist), and naloxone (5 mg kg-1) as well as saline injection (as control) in four different groups of rats. Following injection, we examined the changes in somatosensory evoked potentials, cortical blood flow and heart rate for 15 min while mean arterial pressure was held constant by a pressure-regulating reservoir. Only naloxone changed the somatosensory evoked potential amplitude significantly compared with the saline group in which no effect was seen. However, there was a tendency for a delayed effect of naloxone-methobromide on the evoked potentials, possibly indicating that the substance slowly passes the blood-brain barrier. Naloxone and MR 2266 caused a transient decrease in heart rate, while following naloxone-methobromide injection there was a slight increase in heart rate. Our results thus indicate that the beneficial effects of naloxone on somatosensory evoked potentials during relative cerebral ischemia may be centrally mediated by a non-kappa mechanism.

Topics: Animals; Benzomorphans; Blood Flow Velocity; Cerebral Cortex; Evoked Potentials, Somatosensory; Heart Rate; Ischemic Attack, Transient; Male; Naloxone; Oxymorphone; Rats; Rats, Inbred SHR

Transient forebrain ischemia induced in rats by the four-vessel occlusion method produced analgesic effects in the hotplate test that persisted for 2 weeks. Ischemia-induced analgesia was attenuated by low doses of alpha 2-agonist clonidine (0.01-0.10 mg/kg, IP) and enhanced by low doses of alpha 2-antagonists yohimbine (1-2 mg/kg, IP) and idazoxan (0.25-1.00 mg/kg, IP) administration 7 days after ischemia. Ischemia-induced analgesia was not affected by methysergide, naloxone, propranolol, or phenoxybenzamine administered 7 days after ischemia, when motor control and arousal level of rats recovered to normal conditions. The enhanced response to yohimbine was antagonized by pretreatment with clonidine (0.75 mg/kg, IP) and naloxone (10 mg/kg, IP), suggesting the involvement of endogenous opioid peptides. The enhanced response to yohimbine was still present 2 months after ischemia, when preischemic hotplate threshold was restored. As alpha 2-agonists reduce and alpha 2-antagonists increase the outflow of central noradrenaline, it is suggested that activation of central noradrenergic systems is involved in the mediation of ischemia-induced analgesia.

Topics: Adrenergic alpha-Antagonists; Analgesia; Animals; Brain; Carotid Artery, Common; Clonidine; Dioxanes; Endorphins; Idazoxan; Ischemic Attack, Transient; Male; Methysergide; Naloxone; Norepinephrine; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha; Serotonin; Synaptic Transmission; Yohimbine

Receptor autoradiographic and histological techniques were used to investigate sequential alteration of naloxone receptors in the gerbil brain 1 h-7 days after transient cerebral ischemia. Transient ischemia was induced for 10 min. [3H]Naloxone binding showed a transient elevation in the striatum 1 h after ischemia, whereas the hippocampus revealed no significant alteration in the binding. Thereafter, no conspicuous alteration in [3H]naloxone binding was seen in the striatum and hippocampus up to 24 h after ischemia. However, a significant elevation in [3H]naloxone binding was found in the hippocampal region 48 h after ischemia. In contrast, the striatum showed no significant alteration in [3H]naloxone binding. Seven days after ischemia, a severe reduction in [3H]naloxone binding was seen not only in the dorsolateral striatum and hippocampal CA3 pyramidal cell layer, where irreversible neuronal damage was found, but also in the histopathological intact dentate gyrus. However, the hippocampal CA1 sector which was most vulnerable to ischemia, revealed no conspicuous alteration in [3H]naloxone binding. These results demonstrate that alteration of naloxone receptors precedes ischemic neuronal damage to the striatum and hippocampus. They also suggest that the damage between striatum and hippocampus may be produced with different processes.

Topics: Animals; Autoradiography; Corpus Striatum; Gerbillinae; Hippocampus; Ischemic Attack, Transient; Male; Naloxone; Neurons; Pyramidal Tracts; Receptors, Opioid; Tritium

We investigated the long-term changes that occur in the gerbil brain following transient cerebral ischemia using histology and receptor autoradiography. Transient ischemia was induced for 3 and 10 min, and animals were allowed to survive for 8 months. A histological study showed that 3-min ischemia caused neuronal damage and mild atrophy only in the hippocampal CA1 sector, and that 10-min ischemia produced severe neuronal damage and marked shrinkage in the hippocampal CA1 and CA3 sectors. Furthermore, severe neuronal damage was seen in the striatum after 10-min ischemia. Autoradiography study revealed that 3-min ischemia caused a significant reduction in [3H] naloxone binding in the frontal cortex, striatum, dentate gyrus, and thalamus, whereas [3H]SCH 23390 and [3H] forskolin binding was not significantly altered in all regions. In contrast, 10-min ischemia produced marked alteration in these binding sites in the striatum, hippocampus, thalamus, and substantia nigra. The alteration was especially notable in the hippocampal region and substantia nigra. These results indicate that hippocampal damage after transient ischemia, compared with that in other regions, is not static, but particularly progressive. Furthermore, they demonstrate a reduction in adenylate cyclase system in the striatum and substantia nigra after transient ischemia. Moreover, our results suggest that long-term survival after ischemia may induce synaptic modification of neurotransmitter and adenylate cyclase system in the hippocampus.

Topics: Animals; Autoradiography; Benzazepines; Brain; Colforsin; Gerbillinae; Ischemic Attack, Transient; Male; Naloxone; Radioligand Assay; Time Factors

Transient forebrain ischemia was produced in gerbils by short-term occlusion of the common carotid arteries under halothane anesthesia. Histological analysis of brains 7 days post-ischemia demonstrated characteristic destruction of CA1 pyramidal cells. lambda Opiate binding (measured with [3H]naloxone in the presence of 300 nM diprenorphine) at 7 days post-ischemia was significantly increased in the stratum lucidum of the hippocampus (the mossy fiber layer), but not in any other region measured, including other hippocampal regions, cortex, amygdala, caudate putamen, thalamus, and hypothalamus. The increase in mossy fiber lambda binding was slow to develop (no increase detected up to 48 h post-ischemia), and long-lasting (binding remained elevated at 32 days post-ischemia). While MK-801 significantly inhibited CA1 pyramidal cell destruction when administered 20 min prior to ischemia, the increase in mossy fiber lambda binding was still evident. None of seven different opioid agonists and antagonists examined had an effect on either the pyramidal cell damage or increased mossy fiber lambda binding seen 7 days after ischemia.

Topics: Afferent Pathways; Animals; Dizocilpine Maleate; Female; Gerbillinae; Hippocampus; Ischemic Attack, Transient; Naloxone; Nerve Fibers; Neurons; Prosencephalon

Topics: Humans; Ischemic Attack, Transient; Male; Middle Aged; Naloxone; Subarachnoid Hemorrhage

In the first part of this experiment, the effects of pharmacotherapy on the neurologic consequences of transient global ischemia were examined in Wistar rats. The control and four experimental groups each contained six rats. In comparison to the control group receiving normal saline (NS) solution, in which no rats survived, all rats given naloxone (Nx) (23 mg/kg), superoxide dismutase (SOD) (10,000 U/kg), or allopurinol (APL) (35 mg/kg), 15 minutes before interruption of cerebral blood flow, survived the 20-minute period of global ischemia (p less than 0.01, p less than 0.01, p less than 0.01, respectively). No rat receiving deferoxamine (DEF) (20 mg/kg) survived the same ischemic period. In the second part of the experiment, the arachidonic acid (AA) content of brain samples was determined by gas chromatography and was used as an indicator of cerebral ischemia. Two control and four experimental groups consisted of six rats each. An ischemia control group received NS, whereas experimental groups were given Nx, SOD, APL, or DEF with the same previous dosage schedule. The animals were decapitated 15 minutes after drug infusion and cerebral ischemia was simulated by incubation of the heads in a 37 degrees C water bath for 60 minutes. AA content of ischemic brain treated with NS was markedly elevated (60.0 +/- 24.1 micrograms/gm of brain tissue), whereas in comparison the AA content of brain treated with Nx (5.1 +/- 3.0 micrograms/gm of brain tissue, p less than 0.05), SOD (3.5 +/- 2.7 micrograms/gm of brain tissue, p less than 0.05), or APL (2.9 +/- 1.5 micrograms/gm of brain tissue, p less than 0.05) all demonstrated much lower levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Allopurinol; Animals; Arachidonic Acid; Arachidonic Acids; Brain; Deferoxamine; Ischemic Attack, Transient; Male; Naloxone; Rats; Rats, Inbred Strains; Superoxide Dismutase

The effect of the opiate antagonist naloxone on both the neurological deficit and regional cortical blood flow after middle cerebral artery occlusion in the cat was investigated. In animals with mild symptoms, naloxone did not consistently produce a significant behavioral effect. In all cats with neurological deficits, including hemiplegia or severe hemiparesis, 2 mg/kg naloxone administered intravenously 4 h after the ischemic lesion produced a reversal of neurological symptoms. This effect began within 2 min following naloxone injection and lasted for approximately 20 min. Animals were then anesthetized and cortical blood flow was measured by the hydrogen clearance method. Average cortical blood flow on the side of the occlusion was 50% that of the control side. Naloxone produced a significant additional decrease of 19.5% in cortical blood flow in the ischemic hemisphere, whereas no effect on blood flow on the control side was noted. Thus, although naloxone appears to temporarily reverse the severe neurological deficits resulting from middle cerebral artery occlusion in the cat, this effect appears to be accompanied by a decrease in local blood flow to the ischemic cortex.

Topics: Animals; Cats; Cerebral Arteries; Cerebral Cortex; Cerebrovascular Circulation; Cerebrovascular Disorders; Female; Ischemic Attack, Transient; Male; Naloxone

The effect of naloxone upon neurologic deficit was evaluated in a model of transient forebrain ischemia in rats. Awake male Wistar rats were subjected to a 30 minute ischemia by occluding both common carotid arteries 8 days after cauterizing vertebral arteries. Administration of naloxone 1 or 5 mg/kg iv 10 minutes after carotid occlusion or 1 mg/kg iv one hour after clamp removal failed to reduce immediate and tardive neurologic postischemic deficits. On the other hand, in rats treated by a dose of 1 mg/kg naloxone 10 minutes after carotid occlusion and perfused with an additional dose of 2 mg/kg/h for 80 minutes, neurologic score was improved one hour after ischemia. However mortality was not decreased whatever was the modality of naloxone administration. This result confirms previous data showing that naloxone exerts a protective effect when given at sufficiently high dosage.

Topics: Animals; Ischemic Attack, Transient; Male; Naloxone; Rats; Rats, Inbred Strains; Time Factors

The effects on regional cerebral blood flow (rCBF) of raised intracranial pressure (ICP) and of naloxone and thyrotropin releasing hormone (TRH) during this condition were studied in anaesthetized rabbits. The ICP was elevated until a central ischaemic response was observed. The regional blood flow was determined with the microsphere technique before and during elevation of the ICP (ICPe) and after drug treatment. Total CBF was reduced by about 70% during ICPe while the uveal blood flow increased slightly and some other peripheral tissue blood flows remained unaffected. The administration of TRH caused an increase in mean arterial blood pressure (MAP) from 11.9 +/- 0.6 to 14.6 +/- 0.7 kPa and a normalization of the rCBF. In some peripheral tissues, e.g. gastric mucosa and spleen, TRH reduced the blood flow by 53% and 76%, respectively. In blood pressure stabilized animals no effect on rCBF was seen after TRH. Naloxone had no consistent effect on MAP or local blood flow. It was concluded that in the range of cerebral perfusion pressure studied there was a passive relationship between cerebral blood flow and perfusion pressure. The lack of effect of naloxone and the marked effect of TRH during cerebral ischaemia are consistent with a mechanism of action of TRH not related to a 'physiological' antagonism of opioids.

Topics: Animals; Blood Pressure; Cerebrovascular Circulation; Female; Intracranial Pressure; Ischemic Attack, Transient; Male; Microcirculation; Naloxone; Rabbits; Thyrotropin-Releasing Hormone

Topics: Anticoagulants; Bloodletting; Cerebral Infarction; Cerebrovascular Disorders; Fibrinolytic Agents; Heparin; Humans; Intracranial Embolism and Thrombosis; Ischemic Attack, Transient; Naloxone; Recurrence; Vasodilator Agents; Warfarin

The effect of the opiate antagonist naloxone was evaluated in 11 unselected patients with cerebral ischemia. Naloxone reversed neurological deficits in the 4 patients with less evident signs of vascular damage.

Topics: Adult; Aged; Humans; Ischemic Attack, Transient; Middle Aged; Naloxone

Topics: Humans; Hypotension; Ischemic Attack, Transient; Naloxone; Steroids; Thromboxanes

Experimental vasospasm was studied in a canine model utilizing subarachnoid injection of autologous blood. Alterations in the size of the basilar artery were noted angiographically. Naloxone, an opioid receptor antagonist, has been reported to have a beneficial effect on neurological dysfunction secondary to cerebral ischemia. No significant change in the diameter of the basilar artery was noted in dogs either with or without spasm when treated with naloxone. We have concluded that naloxone has no detectable vasodilatory effect on the cerebral arteries of dogs.

Topics: Animals; Dogs; Female; Ischemic Attack, Transient; Male; Models, Biological; Naloxone; Vasodilation

The effects of an opiate agonist (morphine) and antagonist (naloxone) on neurologic function in conditions of acute and subacute focal cerebral ischemia were tested in a baboon model. Fourteen baboons (Papio papio) underwent unilateral transorbital microsurgical occlusion of the middle cerebral artery (MCA). Blood pressure, heart rate and core temperature were monitored continuously; frequent arterial blood gas measurements were made. Cardiac output, cardiac filling pressures, and regional cerebral blood cross-flow were measured in selected baboons. Naloxone administered intravenously consistently reversed hemiparesis and hemiplegia in all baboons for as long as they lived (4 h to 8 days postocclusion). Morphine administered intravenously converted hemiparesis to hemiplegia; this effect was naloxone-reversible. There were no significant changes in any parameter measured after the administration of either drug. Phenylephrine (used to elevate mean arterial pressure to 20 mm higher than the highest pressure measured after naloxone administration) and isoproterenol (used to elevate cardiac output to 1 l/min higher than the highest value measured after naloxone administration) produced no change in neurologic function. It appears that naloxone can reverse, and morphine exacerbate, focal ischemic neurologic deficits produced in baboons by MCA occlusion. The observed changes in neurologic function are not associated with or mediated by alterations in core temperature or cardiopulmonary functions.

Topics: Animals; Blood Pressure; Body Temperature; Cardiac Output; Cerebrovascular Circulation; Female; Heart; Heart Rate; Hemiplegia; Ischemic Attack, Transient; Male; Morphine; Naloxone; Papio

Focal incomplete cerebral ischemia was created in 20 adult cats by retro-orbital middle cerebral artery (MCA) occlusion under halothane anesthesia. Arterial blood flow (CBF), bilateral electroencephalographic (EEG) recordings, and systemic arterial blood pressure (SABP) were monitored for the 1st hour of occlusion. Ten animals were treated with 10 mg/kg of naloxone within 10 minutes of MCA clipping, followed by a continuous infusion of naloxone at 2 mg/kg/hr for the duration of the occlusion (8 hours). Ten animals were treated in a similar fashion with physiological saline (control). Blood flow was restored after 8 hours. The brains were examined at the time of death or 7 days after the occlusion period. There was no difference between the two groups regarding cerebral infarction size or distribution, neurological outcome, SABP, PaCO2, or CBF. Minor changes in EEG amplitude observed in the naloxone-treated group appear to represent interaction of the drug with halothane after prolonged administration. The authors conclude that naloxone did not modify the outcome of focal cerebral ischemia in the cat.

Topics: Animals; Brain; Cats; Cerebral Infarction; Cerebrovascular Circulation; Collateral Circulation; Electroencephalography; Female; Ischemic Attack, Transient; Male; Naloxone