naloxone and Brain-Ischemia

Although approximately 500,000 patients suffer from a stroke each year in the United States, treatment of these patients to date has consisted primarily of prevention, supportive measures, and rehabilitation. The modification of experimental cerebral infarction by new pharmacologic agents, along with encouraging results from the restoration of blood flow to areas of focal ischemia in both laboratory and clinical trials, suggests that a more aggressive approach might be considered in selected patients with acute stroke.

Topics: Anticoagulants; Barbiturates; Brain Edema; Brain Ischemia; Calcium Channel Blockers; Cerebral Revascularization; Cerebrovascular Circulation; Fluorocarbons; Hemodilution; Humans; Mannitol; Microcirculation; Naloxone

Topics: Adrenal Cortex Hormones; Anesthetics; Animals; Anticonvulsants; Brain Ischemia; Calcium Channel Blockers; Dimethyl Sulfoxide; Drug Combinations; Epoprostenol; Fluorocarbons; Free Radicals; Heparin; Humans; Hydroxyethyl Starch Derivatives; Indomethacin; Naloxone; Prostaglandins; Streptokinase; Vasoconstrictor Agents

Topics: Adenosine Triphosphate; Anesthesia; Anesthetics; Aneurysm; Animals; Barbiturates; Brain; Brain Diseases; Brain Ischemia; Cerebrovascular Circulation; Electroencephalography; Energy Metabolism; Humans; Hypothermia, Induced; Intraoperative Complications; Isoflurane; Naloxone; Phenytoin; Thiopental

Naloxone and related opioid antagonists have been shown to have therapeutic utility in a variety of conditions. The effects of opioid antagonists in either physiological or pathological processes are most clearly seen when there is excessive occupancy of opioid receptors, as in opiate overdose. Opioid antagonists are also able to reverse several types of cardiovascular shock, conditions in which endogenous opioids appear to be mobilised, resulting in increased opioid receptor occupation. There are also more controversial circumstances in which excessive occupation of opioid receptors may assume pathological significance, such as hypercapnia. Opioid antagonists could be useful in such a situation by re-sensitising the respiratory centres to carbon dioxide. There is some evidence that opioid antagonists may benefit some schizophrenic and manic-depressive patients, suggesting that an endogenous opioid ligand might cause disturbances in mental functioning. The diversity and complexity of opioid mechanisms in the central nervous system suggest that more specific opioid antagonists could be more selective in altering physiological or pathological functioning.

Topics: Alcohol Deterrents; Animals; Bipolar Disorder; Blood Pressure; Brain Ischemia; Clinical Trials as Topic; Humans; Lung Diseases, Obstructive; Naloxone; Naltrexone; Narcotic Antagonists; Receptors, Opioid; Respiration; Schizophrenia; Shock; Spinal Injuries

Topics: Animals; Brain; Brain Ischemia; Cardiovascular Physiological Phenomena; Cardiovascular System; Endorphins; Enkephalins; Humans; Hypertension; Hypotension; Morphine; Naloxone; Pressoreceptors; Receptors, Opioid; Reflex; Shock; Shock, Hemorrhagic; Shock, Septic; Spinal Cord Injuries; Thyrotropin-Releasing Hormone

Attention has focused on naloxone, an opiate receptor antagonist, because of its potential benefit in reversing neurological damage after acute cerebral ischemia. To evaluate the safety and possible efficacy of high-dose naloxone in ischemic stroke patients we planned a double blind pilot study. Between January 1989 and May 1990 24 patients were randomly assigned to the naloxone or placebo group according to age and neurological deficit. Naloxone was given in a loading dose of 5 mg/kg over 10 minutes followed by a 24-hour infusion at the rate of 3.5 mg/kg/h. 10 patients experienced minor side effects but none of them had to discontinue the treatment. 9 patients improved: 6 in the naloxone group and 3 in the placebo group, but no significant difference was found using the non parametric Mann-Whitney test. Our study suggests that naloxone is safe at the dose used, but the results do not support the planning of similar trials on a larger scale.

Topics: Acute Disease; Aged; Brain Ischemia; Cerebrovascular Disorders; Double-Blind Method; Female; Humans; Male; Middle Aged; Naloxone

The opiate antagonist naloxone was suggested for the amelioration of cerebral ischemia after subarachnoid hemorrhage (SAH) following the 1981 report of clinical improvement of ischemic deficits in 2 patients. The deficit in 1 patient was exacerbated by morphine, suggesting that analgesics acting on opiate receptors should be avoided after SAH, and this would include codeine phosphate and dihydrocodeine, both widely used for post-SAH headache. We studied 21 consecutive patients with aneurysmal SAH whose condition was worse than Grade 1 on the Hunt and Hess scale. A single observer graded them to avoid interobserver error, and they were also given a score on the Glasgow coma scale. Each patient was then given an intravenous injection of 0.9% saline as placebo or 0.4 mg (7 patients) or 2.0 mg (14 patients) of naloxone. Five minutes later, the same observer regraded the patient. After 30 minutes, a second injection of placebo or naloxone was given, and the patient was regraded a third time. Each patient received placebo in one injection and naloxone in the other, but the order was randomized and unknown to the observer. There was no beneficial effect of 0.4 mg of naloxone after aneurysmal SAH, and we did not find an elevated level of the endogenous opiate beta-endorphin in the cerebrospinal fluid in the majority (6 of 8 of the patients in whom it was assayed). Five of the patients given 2.0 mg of naloxone did improve transiently, and none deteriorated after the drug, suggesting that naloxone in a high dose may have a place in the management of some post-SAH deficits.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; beta-Endorphin; Brain Ischemia; Cerebrospinal Fluid; Endorphins; Female; Humans; Intracranial Aneurysm; Male; Middle Aged; Naloxone; Rupture, Spontaneous; Subarachnoid Hemorrhage

Naloxone and related opioid antagonists have been shown to have therapeutic utility in a variety of conditions. The effects of opioid antagonists in either physiological or pathological processes are most clearly seen when there is excessive occupancy of opioid receptors, as in opiate overdose. Opioid antagonists are also able to reverse several types of cardiovascular shock, conditions in which endogenous opioids appear to be mobilised, resulting in increased opioid receptor occupation. There are also more controversial circumstances in which excessive occupation of opioid receptors may assume pathological significance, such as hypercapnia. Opioid antagonists could be useful in such a situation by re-sensitising the respiratory centres to carbon dioxide. There is some evidence that opioid antagonists may benefit some schizophrenic and manic-depressive patients, suggesting that an endogenous opioid ligand might cause disturbances in mental functioning. The diversity and complexity of opioid mechanisms in the central nervous system suggest that more specific opioid antagonists could be more selective in altering physiological or pathological functioning.

Topics: Alcohol Deterrents; Animals; Bipolar Disorder; Blood Pressure; Brain Ischemia; Clinical Trials as Topic; Humans; Lung Diseases, Obstructive; Naloxone; Naltrexone; Narcotic Antagonists; Receptors, Opioid; Respiration; Schizophrenia; Shock; Spinal Injuries

Topics: Acute Disease; Adult; Aged; Brain Ischemia; Cerebral Infarction; Double-Blind Method; Female; Hemiplegia; Humans; Morphine; Naloxone; Pain

Recent studies show that morphine possesses protective preconditioning effects in different ischemia/reperfusion models. However, there is very little information about the antineuroinflammatory role of morphine and its protective effect against memory deficit. In the present study, we evaluated the role of morphine preconditioning in a model of mild neuroinflammation induced by intraperitoneal lipopolysaccharide (LPS) injection (1 mg/kg). Rats were trained on passive avoidance apparatus and challenged with LPS 20 h later. Four hours after LPS, rats were subjected to passive avoidance testing and then for the assessments of inflammatory and apoptotic cell death mediators in the hippocampus. LPS significantly increased the nuclear NF-κB and expression of COX-2, IL-1β, and TNF-α, augmented the activity of caspase-3 and PARP cleavage, and in parallel shortened the latencies to enter the dark compartment. Although morphine injection in a noninflammatory context was able to induce a neuroinflammatory response and memory loss, morphine preconditioning at the dose of 4 mg/kg significantly prevented the LPS-induced neuroinflammation and memory deficit. Morphine preconditioning was abolished by naloxone and, therefore, is dependent on opioid receptors. These results suggest that acute morphine injection, in spite of the induction of a neuroinflammatory response and amnesia per se, exerts an antineuroinflammatory role and protects from cell death and memory deficit in an inflammatory context.

Topics: Analgesics, Opioid; Animals; Avoidance Learning; Brain Ischemia; Caspase 3; Encephalitis; Ischemic Preconditioning; Lipopolysaccharides; Male; Memory Disorders; Morphine; Naloxone; Narcotic Antagonists; Neuroprotective Agents; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Random Allocation; Rats; Rats, Wistar; Receptors, Opioid

To assess the effects of ischemic postconditioning, remote ischemic postconditioning and naloxone postconditioning on focal cerebral ischemia-reperfusion injury in rats.. A total of 110 adult SD rats were randomly divided into 5 groups (n = 22 each). The focal cerebral ischemia-reperfusion injury was induced by a 90-minute occlusion of right middle cerebral artery (MCA) and a 24-hour reperfusion sequentially. Group 1 was of ischemia-reperfusion control; Group 2 ischemic postconditioning induced by three 30-second cycles of MCA occlusion followed by a 30-second reperfusion; Group 3 remote ischemic postconditioning performed via a transient occlusion of right femoral artery at 5 min before the initiation of reperfusion; Group 4 naloxone postconditioning with naloxone 10 mg/kg intraperitoneally injected at the initiation of reperfusion; Group 5 combined ischemic, remote ischemic & naloxone postconditioning performed simultaneously in accordance with the methods used in Groups 2, 3 & 4. The neurologic deficit scores (NDS) were obtained at 2 h & 24 h post-reperfusion. At 24 h post-reperfusion, the anesthetized rat was sacrificed by decapitation and the brain rapidly extracted to assess the size of cerebral infarct (n = 10), detect the cerebral expression of microtubule-associated protein-2 (MAP2) (n = 6), measure the plasma volume of cerebral tissues and quantify the diameter and segment length of cerebral microvessel (n = 6).. There were no significant differences in the heart rate (HR) and mean arterial pressure (MAP) among the above five groups at all observed time points (P > 0.05). At 24 h post-reperfusion, the percentage of ischemic cerebral infarct size was 43% ± 6%, 31% ± 4%, 32% ± 5%, 28% ± 6% & 21% ± 7% in ipsilateral hemisphere area (i.e., cerebral infarct severity) in Groups 1-5 respectively. Compared with Group 1, the levels of NDS and cerebral infarct severity significantly decreased at ischemic side in Groups 2-5 (P < 0.05). And the cerebral expression of MAP2, plasma volume of cerebral tissues, diameter and segment length of cerebral microvessel significantly increased at the ischemic side (all P < 0.05). However, there were no significant differences in the above-mentioned parameters at ischemic side among Groups 2, 3 and 4 (all P > 0.05). The parameters of NDS, cerebral infarct severity, cerebral expression of MAP2 and plasma volume of cerebral tissues in the ischemic side significantly increased in Group 5 compared with Groups 1, 2, 3 and 4 (all P < 0.05). The diameter and segment length of cerebral microvessel at ischemic side were not different among Groups 2, 3, 4 and 5 (all P > 0.05).. In focal cerebral ischemia-reperfusion rats, ischemic, remote ischemic and naloxone postconditioning may produce significant neuroprotective effects of reduced cerebral infarct severity and improved neurologic dysfunctions. A combination of three postconditioning approaches enhances the above neuroprotective effects.

Topics: Animals; Brain Ischemia; Ischemic Postconditioning; Male; Naloxone; Rats; Rats, Sprague-Dawley; Reperfusion Injury

To investigate the effects of ephedrine combined with various doses of naloxone on neural plasticity in rats after cerebral ischemia/reperfusion injury to explore the possibility of synergistic effect about ephedrine combined with naloxone, promoting the optimum ratio of neural remodeling and its molecular mechanism.. A total of 192 healthy adult Sprague-Dawley rats, 220-250 g, were used to establish models of left middle cerebral artery occlusion using the suture occlusion method. Were randomly divided into 8 groups: the rats were intraperitoneally injected with 1.5 mg x kg(-1) x d(-1) ephedrine (ephedrine group), with 0.1, 0.2, 0.3 mg x kg(-1) x d(-1) naloxone (low, moderate and high doses of naloxone groups) , with 1.5 mg x kg(-1) x d(-1) ephedrine + 0.1, 0.2, 0.3 mg x kg(-1) x d(-1) naloxone (ephedrine + low, moderate and high doses of naloxone groups), and with 0.5 mL saline (model group), respectively. At 1-4 weeks following cerebral ischemia, sensorimotor integration in rats was assessed using the beam walking test, brain-derived neurotrophic factor (BDNF) expression was detected in the hippocampal CA3 area using immunohistochemistry 1-4 weeks after surgery, immunofluorescence method of detecting ischemic hemisphere hippocampal expression, The number of nerve cells apoptosis was detected using TUNEL assay.. BWT, BDNF, TUNEL assay results showed three doses of naloxone group had no significant effect, the effects increased together with the quantitative ephedrine, and had the amount-effect relationship, in which ephedrine + high dose of naloxone group the recovery of movement was fastest, BDNF expression in the best and ischemic apoptosis in the hippocampus at least, ischemic injury to the minimum, speed up the process of neural remodeling.. The ephedrine and ephedrine + naloxone groups were accelerated motor function recovery rate in rat after cerebral ischemia, and the promotion of neural remodeling is closely related to the expression of BDNF, inhibit apoptosis in ischemic area, and with the increase of naloxone amount of additives, its role more clearly, the mechanism may be related to the dose of naloxone can significantly inhibit the ischemic area of apoptosis in early cerebral ischemia, so had the positive synergy effect with ephedrine to speed up the formation of neural remodeling.

Topics: Animals; Apoptosis; Brain Ischemia; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Ephedrine; Female; Hippocampus; Humans; Male; Naloxone; Neuronal Plasticity; Random Allocation; Rats; Rats, Sprague-Dawley

This article describes two patients with major ischemic stroke symptoms who had extremely small areas of acute brain infarction, suggestive of acute intrahemispheric diaschisis. Both patients were using narcotic analgesics during their stroke, and in both cases the clinical deficits improved dramatically with naloxone.. We postulate that the narcotics amplified the ischemic stroke symptoms and that this effect was antagonized by naloxone.. This suggests that the opiate system may be involved in the process of intrahemispheric diaschisis.

Topics: Acute Disease; Aged; Brain Ischemia; Female; Humans; Hydrocodone; Hydromorphone; Male; Naloxone; Narcotic Antagonists; Narcotics; Pain, Postoperative

The interrelationship between the hypothalamic-pituitary-adrenal (HPA) activity and expression of central opioids is determined in ischemic Sprague-Dawley rats to support the therapeutic role of naloxone against cerebral ischemia. Two-month old rats received bilateral common carotid artery occlusion plus unilateral (right side) middle cerebral artery occlusion for 90 min under the anesthesia, and followed by reperfusion for various times. The plasma contents of adrenocorticotropin (ACTH) and RNA expression levels of proopiomelanocortin (POMC) were then determined in ischemic rats with or without naloxone treatment. Results showed that ischemia stimulates but reperfusion suppresses the activity of HPA axis. The induced expression of POMC at striatum and cortex areas appears to suppress the release of ACTH from the HPA axis. The suppression on the other hand is prevented by naloxone.

Topics: Adrenocorticotropic Hormone; Animals; Brain Ischemia; Cerebral Cortex; Cerebrovascular Circulation; Corpus Striatum; Down-Regulation; Homeostasis; Hypothalamo-Hypophyseal System; Naloxone; Narcotic Antagonists; Opioid Peptides; Pituitary-Adrenal System; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; Reperfusion Injury; RNA, Messenger

The pathogenesis of cerebral ischemia/reperfusion (I/R) involves cytokine/chemokine production, inflammatory cell influx, astrogliosis, cytoskeletal protein degradation and breakdown of the blood-brain barrier. (-)-Naloxone is able to reduce infarct volume and has been used as a therapeutic agent for cerebral I/R injuries. However, its effects on the mentioned pathophysiologic changes have scarcely been addressed. Cerebral I/R was produced by occluding and opening bilateral common carotid artery and unilateral middle cerebral artery in Sprague-Dawley rats. After cerebral I/R, the degradation of neuronal microtubule-associated protein-2 (MAP-2) was strongly associated with astrogliosis, inflammatory cell infiltration, cytokine/chemokine overproduction, and matrix metalloproteinase-9 activation. (-)-Naloxone pretreatment suppresses post-ischemic activation and preserves more MAP-2 protein. Therefore, (-)-naloxone administration might be an effective therapeutic intervention for reducing ischemic injuries.

Topics: Animals; Brain Ischemia; Cerebral Cortex; Glial Fibrillary Acidic Protein; Male; Matrix Metalloproteinase 9; Microtubule-Associated Proteins; Naloxone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Reperfusion Injury

Topics: Adult; Brain Ischemia; Cerebral Infarction; Coma; Drug Therapy, Combination; Emergency Medical Services; Female; Flumazenil; GABA Modulators; Glucose; Humans; Hypertonic Solutions; Naloxone; Narcotic Antagonists; Thiamine; Vasodilator Agents

Stroke is an infrequent but recognized complication of heroin addiction. Two heroin addicts, aged 34 and 19 years, developed ballistic movements after intravenous heroin overdose. Patient 1 presented bilateral ballism 1 week after intravenous heroin injection. Magnetic resonance imaging (MRI) showed bilateral ischemic lesions of the globus pallidus, suggesting a generalized cerebral hypoxia during the comatose state as pathogenic mechanism. Patient 2 presented an acute left hemiballismus when consciousness was restored with naloxone. MRI demonstrated an ischemic infarct in the right striatum. An embolic mechanism of stroke was suspected in this patient, considering the normal results of blood analysis, echocardiogram and cerebral arteriograms. Ballistic movements ceased after administration of haloperidol; both patients remained without abnormal movements thereafter.

Topics: Adult; Anti-Dyskinesia Agents; Basal Ganglia; Brain Ischemia; Coma; Corpus Striatum; Drug Overdose; Globus Pallidus; Haloperidol; Heroin; Humans; Magnetic Resonance Imaging; Male; Movement Disorders; Naloxone; Narcotic Antagonists; Substance Abuse, Intravenous; Tomography, X-Ray Computed

We examined the effects of mu-opioid receptor agonist and antagonists, and kappa-opioid receptor agonist on the hypoxia/hypoglycemia-induced reduction in 2-deoxyglucose uptake of rat hippocampal slices. Naloxone, a mu-opioid receptor antagonist and (5,7,8)-(+)-3,4-dichloro-N-methyl-N-(7,8,1-pyrrolidinyl)-1-oxaspirol+ ++ (4,5)dec-8-yl)-benzeneacetamide methanesulfonate, U-62,066E, a kappa-opioid receptor receptor agonist, showed neuroprotective actions against the hypoxia/hypoglycemia-induced deficit in glucose uptake. In contrast, morphine exhibited an exacerbating action. These results suggest that blockade of mu-opioid receptor- and stimulation of kappa-opioid receptor-mediated functions has a protective role against the hypoxia/hypoglycemia-induced decreases in glucose metabolism in hippocampal slices. Chronic administration of morphine (10 mg/kg) for 9 days affected neither the basal nor the hypoxia/hypoglycemia-induced reduction in 2-deoxyglucose uptake. Rats treated with morphine chronically exhibited not only tolerance to the analgesic effect but also tolerance to the exacerbating action. However, chronic morphine did not modify U-62,066E-induced neuroprotection. These findings indicate that the receptor mechanisms of neuroprotection produced by the activation of kappa-opioid receptors may not be involved in mu-opioid receptor function.

Topics: Analgesics; Analgesics, Opioid; Animals; Benzomorphans; Brain Ischemia; Deoxyglucose; Drug Tolerance; Hippocampus; Hypoglycemia; Hypoxia, Brain; In Vitro Techniques; Male; Morphine; Naloxone; Narcotic Antagonists; Pyrrolidines; Rats; Rats, Wistar; Receptors, Opioid, kappa

In this study, the effect of naloxone and mannitol was investigated on focal cerebral ischemia induced by middle cerebral artery occlusion with the transorbital approach in the rabbit model. Rabbits were randomly and blindly assigned to one of three groups (six animals in each): (1) a control group that received equal volumes of physiological saline solution; (2) a naloxone group that received a 5 mg/kg bolus of naloxone i.v. 1 h after occlusion, followed by 2 mg/kg per hour i.v. infusion for 5 h; (3) a mannitol group that received 0.2 g/kg twice with an interval of 10 min at 5 h. The neurological outcome was better in rabbits treated with naloxone than in the others. The ratio of ischemic to total neurons in the cortex was smaller in the naloxone group than in the control and mannitol groups (P < 0.05). In addition, there was a statistically significance reduction in infarct size in the naloxone group compared with the other groups (P < 0.05). Edema was severe in the control and mannitol groups, but moderate in the naloxone group. There was no statistically significant difference in Na+, K+, and water content between groups. Our data provide evidence for the beneficial effects of naloxone on promoting neurological recovery and preserving the ischemic area.

Topics: Animals; Body Water; Brain Ischemia; Cerebral Cortex; Disease Models, Animal; Infusions, Intravenous; Mannitol; Motor Activity; Naloxone; Potassium; Rabbits; Random Allocation; Sodium; Water-Electrolyte Balance

Fetal hippocampal neurons were stereotaxically transplanted to five-day-old ischemic CA1 lesions in adult rat hippocampi. The recipient brains were examined 14 or 100 days later. The grafts survived well, and transplanted cells usually formed clusters in the host CA1 subfield. In vitro receptor autoradiography was employed to map the following receptors, the ligands indicated in parentheses being used for labeling: muscarinic cholinergic ([3H]quinuclidinyl benzilate), adenosine A1 ([3H]cyclohexyladenosine), kainate ([3H]kainic acid), spirodecanone ([3H]spiperone), opioid ([3H]naloxone), and GABAA ([3H]muscimol). The receptor autoradiographic technique showed significant binding of the six ligands in all hippocampal grafts two weeks after transplantation. One hundred days following transplantation, almost all receptors, especially muscarinic cholinergic, adenosine A1 and opioid receptor bindings in grafts, had significantly increased compared to bindings two weeks after transplantation. At this time, kainate and muscarinic cholinergic receptors in grafts had increased up to the near normal level of the CA1 in the hippocampus. Interestingly, adenosine A1 receptors in the grafted side had significantly increased not only in the CA1 but also in the stratum oriens of the CA3 compared with that in the non-grafted side. The increase of [3H]quinuclidinyl benzilate binding corresponded well with the innervation of acetylcholinesterase-positive fibers at 100 days after grafting. These results demonstrate that the transplanted neurons, which showed both pre- and post-synaptic autoradiographic markers in the ischemic CA1 lesions, are able to develop their properties and express the nature of normal hippocampal neurons.

Topics: Acetylcholinesterase; Animals; Autoradiography; Brain Ischemia; Brain Tissue Transplantation; Fetal Tissue Transplantation; Hippocampus; Kainic Acid; Ligands; Male; Muscimol; Naloxone; Nerve Tissue Proteins; Neuronal Plasticity; Neurons; Puromycin; Quinuclidinyl Benzilate; Rats; Rats, Wistar; Receptors, Neurotransmitter; Spiperone; Stereotaxic Techniques; Up-Regulation

The effect of opioids on delayed neuronal death was evaluated in the gerbil hippocampus. Male Mongolian gerbils were subjected to transient forebrain ischemia and neuronal density was evaluated in the hippocampus 7 days following ischemia. When hypothermia during and after ischemia was prevented, treatment with morphine, U-50488H, or naloxone provided no significant protection. In contrast, a spontaneous drop in rectal temperature to 32 degrees C at the end of ischemia produced near-complete protection of CA1 pyramidal neurons. No opioids modulate the protective effect of hypothermia.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Body Temperature; Brain Ischemia; Cell Count; Cell Death; Gerbillinae; Hippocampus; Male; Morphine; Naloxone; Neurons; Pyrrolidines; Receptors, Opioid

We have examined the effects of a single injection of naloxone (5 mg/kg, i.v.) in cats with cerebral ischemia produced by transorbital occlusion of the middle cerebral artery (MCA). Cerebral blood flow (CBF) was measured and the cerebral metabolic rate of oxygen consumption (CMRO2) was estimated based on measurements of arteriovenous (A-V) oxygen difference. Six cats were treated with naloxone 30 minutes after occlusion and 8 were treated 2 hours after occlusion. In 6 control animals, naloxone produced a 10-15% increase in mean arterial blood pressure (MABP), CBF and CMRO2 lasting 30 minutes. MCA occlusion reduced CBF by 70-75% in the ipsilateral MCA territory and by 15% in the contralateral hemisphere. Naloxone increased CBF by 3.5-6% in the ischemic region and 10-22% in the contralateral hemisphere in both treatment groups to the same extent as seen in control animals. There was no significant change in A-V oxygen difference and the estimated increase in CMRO2 of non-ischemic regions of both treatment groups was similar to that of control animals. These effects were transient and lasted 15-60 minutes. We have concluded that naloxone caused a transient increase in cerebral metabolism which equals or exceeds the corresponding increase in CBF. Therefore, naloxone would not be beneficial, and may be detrimental in the treatment of cerebral ischemia.

Topics: Animals; Blood Flow Velocity; Blood Pressure; Brain Ischemia; Carbon Dioxide; Cats; Cerebral Cortex; Cerebral Infarction; Cerebrovascular Circulation; Endorphins; Energy Metabolism; Female; Hydrogen-Ion Concentration; Male; Naloxone; Oxygen

We examined whether drugs that block calcium, prostaglandins, free radicals, and endorphin release could modify cerebral blood flow or nerve tissue pathology following a focal cerebrovascular lesion. Cats were randomly divided into six groups and were subjected to standard middle cerebral artery occlusion (MCAO) performed using a transorbital approach. One hour after MCAO, cats received the following compounds intravenously: (i) saline (CS), 1.5 mL/kg or polyethylene glycol, 300 micrograms (CP); (ii) naloxone (NX), 2 mg/kg; (iii) nimodipine (NM), 1 microgram.kg-1.min-1 x 60 min; (iv) dimethyl sulfoxide (DS), 0.9 g/kg in a 40% solution; (v) prostacyclin (PGI2), 200 ng.kg-1.min-1 for 60 min; or (vi) DS-PGI2 combined. At 1-h intervals, local CBF was recorded from the cortical tissue proximal and distal to the MCAO site using the hydrogen clearance method. Five hours after MCAO, cortical tissue was removed for catecholamine histofluorescence or perfused for tyrosine hydroxylase immunoreactive axon examination. Treatment with NX, NM, CP, or CS had no effect on either CBF or cortical tissue neurotransmitter morphology. PGI2 showed a transiently modest but significant increase of CBF, while DS provided moderate protection of catecholaminergic fibers and increased CBF by 27% after MCAO. The combination of DS-PGI2 resulted in significant cytoprotection of cortical catecholaminergic fibers and generated a sustained CBF increase of 68% of control values. These findings suggest that combining DS with PGI2 can yield a synergic effect with respect to cortical neurotransmitter and CBF protection after MCAO.

Topics: Animals; Body Temperature; Brain Ischemia; Carbon Dioxide; Cats; Cerebrovascular Circulation; Dimethyl Sulfoxide; Drug Synergism; Epoprostenol; Female; Male; Naloxone; Nimodipine; Oxygen Consumption; Perfusion; Synaptic Transmission; Tyrosine 3-Monooxygenase

The effects of naloxone on local tissue oxygen partial pressure (pO2) and on the somatosensory evoked potentials (SEP) were studied in the brain of cat during focal cerebral ischemia. Ischemia, produced by clamping of the middle cerebral artery (MCA) by a transorbital approach, was performed in two series of cats for 3 h. In one group of cats (n = 5), naloxone 5 mg.kg-1 was injected i.v. 0.5 h after clamping. The pO2 was continuously recorded on different depths (0-5000 microns) of the median gyrus by a polarographic oxygen microelectrode. After MCA clamping, pO2 (depth of 0-1000 microns) decreased markedly and hypoxia occurred in the ischemic area. But in the deeper brain (1001-5000 microns) pO2 did not change significantly. The amplitude of SEP decreased after MCA clamping, while the conduction time of SEP did not significantly decrease. The mean pO2 values in the ischemic area were increased as compared to the control group after naloxone, especially at the depths of 0-1000 microns, and the hypoxia was improved. The amplitude of SEP was increased after naloxone in comparison to the situation of ischemia without naloxone. The conduction time of SEP was not improved significantly. We conclude that naloxone can improve the oxygen supply and the electrical activity of neurons in the ischemic region of the brain.

Topics: Animals; Brain; Brain Ischemia; Cats; Evoked Potentials, Somatosensory; Female; Male; Naloxone; Oxygen; Oxygen Consumption; Partial Pressure

The cerebral protective actions of a new thyrotropin releasing hormone (TRH) analogue, YM-14673, [Na-[[(S)-4-oxo-2-azetidinyl-carbonyl]-L-histidyl-L-prolinamide] dihydrate), were compared with those of CDP-choline (cerebral metabolic enhancer) and naloxone in rats rats subjected to unilateral carotid artery ligation and anoxic exposure (Levine rats). Drugs were administered intraperitoneally or orally 20, 80, and 140 min after anoxia. YM-14673 (0.03 to 1 mg/kg i.p. and 0.3 to 10 mg/kg p.o.) decreased the incidence of neurological deficits, such as hemiplegia and convulsion followed by coma and death, for 48 h after ischemia and anoxia. Both the increase in the brain water content and the degeneration of neurons in the cerebral cortex and thalamus were prevented by YM-14673 at a dose of 0.1 mg/kg (i.p.). CDP-choline (400 mg/kg i.p.), which is currently used in the therapy of cerebral vascular diseases, and naloxone (3 mg/kg i.p.) also decreased the incidence of the neurological deficits. These results suggest that YM-14673 protects Levine rats against neurological deficits, presumably by attenuating the development of brain edema and preventing neuronal damage. This compound may be useful in the therapeutic treatment of cerebral vascular diseases.

Topics: Animals; Azetidines; Azetines; Body Water; Brain; Brain Chemistry; Brain Ischemia; Carbon Dioxide; Cytidine Diphosphate Choline; Dipeptides; Hypoxia, Brain; Injections, Intraperitoneal; Male; Naloxone; Nervous System; Oxygen Consumption; Rats; Rats, Inbred Strains

The Na(+)-K(+)-adenosine triphosphatase (Na(+)-K(+)-ATPase) activity and beta-endorphin immunoreactivity were determined in rat brain at the acute stage of ischemia produced by unilateral occlusion of the middle cerebral artery (MCA). The effect of pretreatment with naloxone on these activities was also evaluated in the same model. After MCA occlusion, Na(+)-K(+)-ATPase activity was promptly reduced in the ischemic hemisphere and remained at a lower level than in the contralateral hemisphere during 90 minutes of ischemia. A single intraperitoneal 0.5-mg injection of naloxone prior to MCA occlusion attenuated the inactivation. On the other hand, beta-endorphin immunoreactivity was significantly increased following ischemia. The increase was marked in the ischemic hemisphere and was also observed in the contralateral hemisphere; this increase was not affected by the administration of naloxone. These results indicate the possibility that naloxone contributes to protecting the brain from ischemia through stabilizing the cellular membrane. The possible mechanism by which naloxone attenuates the inactivation of Na(+)-K(+)-ATPase in the ischemic brain is discussed in view of alterations of the central beta-endorphin system during ischemia.

Topics: Acute Disease; Animals; beta-Endorphin; Brain; Brain Ischemia; Male; Naloxone; Radioimmunoassay; Rats; Rats, Inbred Strains; Sodium-Potassium-Exchanging ATPase

Endogenous opioids have been shown to produce beneficial effects in experimental stroke. To evaluate both neurophysiological and biochemical parameters, we induced massive cerebral ischemia in 11 rabbits according to the method standardized in our laboratory, using microspheres injected through the internal carotid artery. Binding studies were performed in the 11 embolized, in nine control, and in five sham-operated rabbits using the appropriate concentration of [3H]dynorphin A (1-8). Neurophysiological parameters were evaluated under baseline conditions and 1 hour after embolization, surgical preparation, or sham operation in 17 rabbits. Comparison of visual readings of the electroencephalograms and analyses of the quantified electroencephalograms under baseline conditions and after embolization indicated a marked and statistically significant (p less than 0.01) increase in bilateral delta activity; histologic examination confirmed bilateral brain edema. Binding studies on kappa-opioid receptors indicate that 1 hour after embolization there were significantly more (28%) kappa-opioid receptors (Bmax) in six embolized rabbits than in five sham-operated animals. No significant changes were observed in the affinity parameters, particularly in the dissociation constant (Kd). Our results indicate a role for endogenous dynorphin peptides in the pathogenesis of stroke.

Topics: Animals; Brain Edema; Brain Ischemia; Electroencephalography; Naloxone; Rabbits; Receptors, Opioid; Receptors, Opioid, kappa

To evaluate the safety and possible efficacy of high-dose naloxone for the treatment of acute cerebral ischemia, 38 patients received a loading dose of 160 mg/m2 over 15 minutes followed by a 24-hour infusion at the rate of 80 mg/m2/hr. Nausea and/or vomiting were common side effects. Naloxone was discontinued in seven patients (because of hypotension in one, bradycardia and hypotension in two, myoclonus in one, focal seizures in two, and hypertension in one); all seven patients responded to treatment and no permanent sequelae to naloxone were noted. Twelve of the 38 patients showed early neurologic improvement (by completion of the naloxone loading dose). However, there was no correlation between such a loading dose response and clinical outcome at 3 months. Our experience suggests that naloxone is safe at the dose used, but data for efficacy are inconclusive.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Blood Pressure; Brain Ischemia; Cerebrovascular Disorders; Drug Evaluation; Female; Gastrointestinal Diseases; Humans; Infusions, Intravenous; Male; Middle Aged; Naloxone; Seizures

Forty rats under urethane anesthesia were subjected to cerebral ischemia by ligation of the right carotid, the right plus the left carotid, or the right carotid plus two vertebral arteries. Ischemia caused three types of changes in the field potential of the right hippocampal CA1 region evoked by fimbrial stimulation: 1) completely reversible deterioration (57% and 16% of the rats with unilateral and bilateral carotid artery ligation, respectively), 2) moderate deterioration (37% and 24% of the rats with unilateral and bilateral carotid artery ligation) and 3) irreversible loss of the evoked activity (6% and 60% of the rats with unilateral and bilateral carotid artery ligation and all the rats subjected to three-vessel occlusion). Naloxone improved the moderate deterioration in 10 of 11 rats (1-3 mg/kg i.v.) and in 15 of 16 (50-150 nA) iontophoretic applications, but naloxone did not restore the lost evoked activity. Intravenous morphine (10 mg/kg) aggravated the ischemic changes, and this effect was reversed by naloxone, while iontophoretic administration of morphine caused only excitation. These findings suggest that naloxone has a favorable effect on cerebral ischemia not severe enough to cause transmission failure. The reversal of ischemic changes by iontophoretic naloxone indicates that its site of action is at the neuronal or microcirculatory level.

Topics: Animals; Brain Ischemia; Electric Stimulation; Evoked Potentials; Hippocampus; Iontophoresis; Male; Morphine; Naloxone; Rats; Synaptic Transmission

CBF and somatosensory evoked potentials (SEPs) were measured in a model of moderate cerebral ischemia in anesthetized spontaneously hypertensive rats. The rats were bled to reduce SEP amplitudes to about 50% of prebleeding control. The consequent blood pressure fall reduced CBF to 77% of control as measured by the laser-Doppler technique. Naloxone (5 mg kg-1 i.v. plus 25 mg kg-1 h-1 i.v. for 30 min) caused a significant increase in SEP amplitudes, while CBF did not change significantly. In addition, the latency of the first SEP component decreased toward prebleeding values. Heart rate (HR) decreased, but MABP was held constant by a pressure-regulating reservoir. In unbled rats, naloxone (5 mg kg-1 i.v.) caused a transient small increase in MABP and SEP amplitudes and decrease in HR. These results indicate that sensory input is regulated by opioid systems. Increased opioid activity may inhibit ascending sensory pathways during relative cerebral ischemia and thereby depress SEP responses. Thus, naloxone can release this inhibition and enhances SEP independently of CBF during relative cerebral ischemia. Similar mechanisms might explain the apparently beneficial effects of naloxone in some stroke models.

Topics: Animals; Blood Flow Velocity; Brain Ischemia; Cerebral Hemorrhage; Cerebrovascular Circulation; Evoked Potentials, Somatosensory; Heart Rate; Infusions, Intravenous; Male; Naloxone; Rats; Rats, Inbred SHR

The effect of naloxone (NAL) treatment on cerebral blood flow in the partially ischemic gerbil brain was investigated. Under pentobarbital anesthesia, the right carotid artery in female gerbils was cannulated. A permanent ischemia was produced in the right anterior brain portion by carotid ligation. One hour after the surgical procedure, radioactive 51Cr, microspheres were injected via the carotid catheter before intraperitoneal administration of NAL (50 mg/kg) in saline solution. Five minutes later, radioactive 46Sc microspheres were injected via the carotid catheter. Controls were injected in the same manner with vehicle and microspheres. Brain quarters were assessed for 51Cr and 46Sc radioactivity with a gamma counter. A significant decrease in microsphere deposition was observed with NAL treatment in the right rear, nonischemic part of the brain. No changes in radioactivity were detected in the ischemic portion. These findings suggest that NAL may alter brain blood flow independently of ischemia.

Topics: Animals; Brain Ischemia; Cerebrovascular Circulation; Female; Gerbillinae; Naloxone

The present study was conducted to examine the mechanisms behind the previously reported beneficial effects of high doses of naloxone on impaired cerebral function due to hypotensive haemorrhage in spontaneously hypertensive rats (SHR). The stereospecificity of the effects of two opioid receptor antagonists, naloxone (Nal) and Win 44.441-3 (Win), was tested. The effects of thyrotropin releasing hormone (TRH) were also examined, because this peptide has been shown to have beneficial effects in neuronal ischaemia due to spinal injury. In addition, we were interested in seeing what effect the GABA antagonist, bicucculine (Bic), had on cerebral function during relative ischaemia, because Nal in high doses is suspected to antagonize GABA transmission. Mean arterial pressure (MAP), heart rate (HR) and somatosensory evoked potentials (SEP) were recorded in chloralose-anaesthetized SHR. The rats were bled and MAP was rapidly lowered to 50 mmHg. This resulted in transient bradycardia and attenuated SEP. When the first SEP component had decreased to 40-50% of control, the animals were retransfused to a MAP of 60-80 mmHg, to prevent further deterioration of SEP, and maintained at the new pressure level for the rest of the experiment. Fifteen to twenty minutes later, Nal, Win, TRH or Bic was injected i.v. Both (-)Nal (5 mg kg-1) and (-)Win (1 mg kg-1) improved SEP in a stereospecific manner. (+)Naloxone or (+)Win did not affect SEP significantly. Thyrotrophin releasing hormone (2 mg kg-1) caused further attenuation of a late SEP component.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Azocines; Bicuculline; Brain; Brain Ischemia; Evoked Potentials, Somatosensory; Hemodynamics; Male; Naloxone; Rats; Rats, Inbred SHR; Receptors, Opioid; Thyrotropin-Releasing Hormone

The purpose of the study was to examine the effects of naloxone on signs of cerebral ischaemia during hypotensive haemorrhage in unanaesthetized spontaneously hypertensive rats. Mean arterial blood pressure (MAP), heart rate (HR) and somatosensory evoked potentials (SEP) were recorded. Arousal tests were also performed and the behavioural responses quantified. The SEP alone were a poor indicator of cerebral function in these unanaesthetized rats, because they were markedly influenced by changes in activity and arousal of the animals. Hypotensive haemorrhage resulted in a biphasic tachycardia response, an attenuation of the first SEP component and a reduction of the behavioural response score. Naloxone, 5 mg kg-1 i.v., induced transient bradycardia and a dramatic improvement in arousal test responses, while SEP were not clearly altered. The MAP was kept constant after naloxone injection by adjustments of bleeding and transfusion. Injection of naloxone in unbled control SHR also induced bradycardia but without any changes in SEP and the behavioural responses. The results indicate that naloxone can have beneficial effects in cerebral ischaemia. Possible mechanisms are discussed.

Topics: Animals; Arousal; Behavior, Animal; Brain Ischemia; Depression; Evoked Potentials, Somatosensory; Hemodynamics; Hemorrhage; Hypotension; Male; Naloxone; Rats; Rats, Inbred SHR

A therapeutic role for naloxone during stroke has been suggested, but a neurochemical site of action remains to be determined. Previous work with the gerbil cerebral cortex has shown that either bilateral secondary ischemia (60-min occlusion of the carotid arteries followed by 40-min reflow) or unilateral primary ischemia (permanent ligation of one carotid artery for 6 hr in symptomatic animals) produced deficits in both Na+, K+-ATPase (EC 3.6.1.3) activity and various parameters of activation of adenylate cyclase (EC 4.6.1.1). Pretreatment of gerbils with either naloxone or morphine failed to ameliorate or exacerbate, respectively, the neurological signs of ischemia; however, morphine did reduce mortality. Infusion of naloxone prior to ischemia afforded varying degrees of protection to forskolin, GTP analogs, and NE (norepinephrine) activation of adenylate cyclase, as well as to Na+, K+-ATPase (bilateral ischemia only). Similarly, morphine inhibited damage to basal activity of adenylate cyclase and to stimulation by NE, forskolin, and Gpp (NH)p (5'-guanylyl imidodiphosphate). Under in vitro conditions morphine increased the basal activity of adenylate cyclase but reduced responses to NE and forskolin. Furthermore, morphine injected into control gerbils elevated basal- and forskolin-elicited activities but reduced the activation of adenylate cyclase by NE.

Topics: Adenosine Triphosphatases; Adenylyl Cyclases; Animals; Brain Ischemia; Cerebrovascular Circulation; Colforsin; Female; Frontal Lobe; Gerbillinae; Guanine Nucleotides; In Vitro Techniques; Morphine; Motor Activity; Naloxone; Norepinephrine

The effects of intracarotid injection of the stable enkephalin analogue (D-Met2,Pro5)-enkephalinamide (ENK) and intravenous administration of naloxone on the cerebrocortical blood flow (dye dilution method) and cerebral blood volume (CBV) (photoelectric method) were investigated during unilateral brain ischemia in anesthetized cats. Both parameters were measured simultaneously in the intact and ischemic (middle cerebral artery occluded) hemispheres. An intracarotid injection of ENK 0.5 mg/kg induced a significant increase in cortical vascular resistance and a -87% decrease in cerebrocortical blood flow from 25 +/- 3 to 4 +/- 3 ml/100 g/min, without CBV alteration in the ischemic hemisphere. Naloxone (1 mg/kg i.v.), on the other hand, induced a marked two-fold increase in cerebrocortical blood flow and a significant elevation of CBV from 5.9 +/- 0.5 to 7.4 +/- 0.7 vol% in the ischemic hemisphere. No change in cerebrocortical blood flow or CBV was observed in the intact hemisphere either after ENK or after naloxone administration. Arterial blood gases and hematocrit remained unchanged. On the basis of the present findings, we conclude that besides other factors, endogenous opioid mechanisms may also participate in ischemic cerebrovascular reactions and the cerebral circulatory effects of naloxone probably reflect its opiate receptor blocking property and not simply its other non-opiate-related actions.

Topics: Animals; Blood Volume; Brain; Brain Ischemia; Cats; Cerebral Cortex; Cerebrovascular Circulation; Enkephalin, Methionine; Female; Male; Naloxone; Receptors, Opioid; Vascular Resistance

Transient global cerebral ischemia (TGI) was induced in awake rats using the "four-vessel" occlusion model of Pulsinelli and Brierley. Blood pressure, arterial blood gases, cerebral blood flow, and cardiac output were measured during the acute (up to 2 hours) and chronic (2 to 72 hours) postischemic time periods. Coincident with the onset of TGI, cardiac output and caudate blood flow were depressed. The former returned to baseline within 30 minutes after the conclusion of TGI, and the latter progressed to hyperemia at 12 hours (81.8 +/- 4.9 vs 68.6 +/- 3.9 ml/min/100 gm tissue (mean +/- standard error of the mean] and oligemia at 72 hours (45.5 +/- 4.8 ml/min/100 gm tissue) post-TGI in the untreated control rats. Arterial blood gases and blood pressure were unchanged. Naloxone (1mg/kg) given at the time of TGI or as late as 60 minutes post-TGI and every 2 hours thereafter for 24 hours or bilateral cervical vagotomy prevented the depression in cardiac output and blocked the hyperemic-oligemic cerebral blood flow pattern that was predictive of stroke in this rat model. Changes in cardiac output after TGI in this model appear to be mediated by parasympathetic pathways to the heart from the brain stem. Opiate receptor blockade probably blocks endogenous opioid peptide stimulation of these brain-stem circulatory centers, which results in inhibition of parasympathetic activity and improvement in cardiac output. The usefulness of naloxone in the treatment of experimental stroke may be a function of its ability to improve cerebral perfusion in pressure-passive cerebrovascular territories. Variations in cardiac output during experimental stroke may explain the dissimilar responses to naloxone treatment reported by other investigators of experimental stroke.

Topics: Animals; Blood Pressure; Brain Ischemia; Cardiac Output; Cerebrovascular Circulation; Female; Naloxone; Rats; Rats, Inbred Strains

The proximal left M1 and the common trunk of A2 were clipped in 12 adult dogs. Naloxone was injected after placing the clips onto 6 dogs. Neither the systemic blood pressure nor the local cerebral blood flow were influenced by naloxone. In another group of 6 dogs with chronic right hemiplegia, naloxone proved passably effective in improving the hemiplegia. Eight patients with neurological deficits of various etiologies were administered levallorphan. The improvement in motor performance and/or elevation of mental activity was observed more or less in all but 2 of the patients. It was considered that the effect of opiate antagonists is based partially on the facilitation of synaptic transmission exaggerated by the arousal response.

Topics: Adult; Aged; Animals; Blood Flow Velocity; Brain Ischemia; Cats; Cerebrovascular Circulation; Chick Embryo; Disease Models, Animal; Dogs; Female; Humans; Injections, Intravenous; Levallorphan; Male; Middle Aged; Naloxone; Narcotic Antagonists; Nervous System Diseases; Tomography, X-Ray Computed

The effect of naloxone on blood platelet aggregation and cerebral blood flow in gerbils was studied. Administration of naloxone in dose 1 mg/kg to intact gerbils resulted in a marked increase in platelet aggregability accompanied by 27% reduction in cerebral blood flow. Focal cerebral ischemic injury significantly enhanced platelet aggregatory response and treatment with naloxone was without any additional effect on platelet aggregation. Cerebral blood flow in ischemic hemisphere, however, increased following naloxone injection by 46%. In vitro naloxone in millimolar concentrations inhibited platelet aggregation in a dose-dependent way. Apparent decrease in fluorescence of platelet membranes tagged with fluorescence probe due to naloxone suggests conformational changes in platelet membrane as a primary mechanism for the antiaggregatory effect of naloxone in vitro.

Topics: Animals; Blood Gas Analysis; Blood Platelets; Blood Pressure; Brain Ischemia; Cerebrovascular Circulation; Dose-Response Relationship, Drug; Gerbillinae; Injections, Intraperitoneal; Naloxone; Platelet Aggregation; Regional Blood Flow

The purpose of this study was to examine the effects of naloxone on signs of relative cerebral ischaemia induced by hypotensive haemorrhage. Mean arterial blood pressure (MAP), heart rate (HR), renal sympathetic nerve activity (rSNA) and somatosensory evoked potentials (SEP) were recorded in chloralose-anaesthetized spontaneously hypertensive rats exposed to graded bleeding. Hypotensive haemorrhage resulted, after a very brief sympathetic excitation, in marked sympathetic inhibition and bradycardia and a considerable reduction of SEP, indicating relative cerebral ischaemia. However, after 25-30 min this sympatho-inhibitory response was reversed to pronounced sympathetic excitation and tachycardia, which was accompanied by a further attenuation of SEP. A single bolus of naloxone (10 mg kg-1) caused transient sympathetic inhibition and bradycardia, which was accompanied by an improvement of SEP. A bolus injection (5-10 mg kg-1) followed by a 30 min infusion of naloxone (25-35 mg kg-1 h-1) caused a sustained SEP improvement despite the fact that MAP was kept constant during naloxone administration. We conclude that naloxone can have beneficial effects on brain function during cerebral ischaemia, effects that are probably due to blockade of opioid receptors. Our model of relative cerebral ischaemia might be useful for evaluating the mechanisms behind the naloxone effects during this condition.

Topics: Animals; Blood Pressure; Brain; Brain Ischemia; Evoked Potentials, Somatosensory; Heart Rate; Hemorrhage; Hypotension; Male; Naloxone; Rats; Rats, Inbred SHR; Sympathetic Nervous System

The effects are reported of acute and long-term continuous administration of three opiate antagonists--naloxone, naltrexone, and diprenorphine--on neurological function, survival, and infarct size in a feline model of acute focal cerebral ischemia. All three drugs produced statistically significant improvement in motor function following acute administration without concomitant changes in level of consciousness; saline had no effect. Naloxone and naltrexone significantly prolonged survival (p less than 0.01); diprenorphine did not. Infarct size was not altered by any treatment administered. These findings confirm previous work suggesting that, with the appropriate methodology, treatment with opiate antagonists partially reverses neurological deficits. They also show that opiate antagonists prolong survival in certain conditions of acute and subacute focal cerebral ischemia without altering the area of infarcted tissue.

Topics: Animals; Brain Ischemia; Cats; Cerebrovascular Disorders; Consciousness; Diprenorphine; Disease Models, Animal; Male; Morphinans; Movement; Naloxone; Naltrexone; Pupil; Sensation

We studied the effects of acute and long-term, continuous administration of six opioid compounds--naloxone, naltrexone, diprenorphine, leucine enkephalin, dynorphin 1-13, and dynorphin 3-13--on neurologic function, survival, and infarct size in a feline model of acute focal cerebral ischemia. Acutely, naloxone, naltrexone, and diprenorphine significantly improved motor function over baseline scores; the other drugs and saline (control) had no effect. In the long-term condition, no substance administered significantly affected level of consciousness, sensory function, or pupillary reactions. Naloxone, naltrexone, and dynorphin 1-13 significantly prolonged survival (p less than 0.1); the other substances had no effect. Evaluations of cat brains postmortem showed that the infarcts involved the sensory and motor cortex, internal capsule, and caudate nucleus. Infarct size was unaltered by any treatment administered; results among groups were remarkably similar. In evaluations of opiate receptor binding characteristics, high-affinity binding of ekylketocyclozocine was significantly reduced in the right (occluded) side of the cortex. Dynorphin 1-13 given 8 h postocclusion but before sacrifice increased this binding affinity to the previous level in non-occluded cortex. The observed protective effect of dynorphin 1-13 warrants further investigation. Our results support the involvement of endogenous opioid peptides in the pathophysiology of cerebral ischemia and suggest that, administered appropriately, opiate antagonists may be useful in the treatment of focal ischemic neurologic deficits.

Topics: Acute Disease; Animals; Brain Ischemia; Cats; Dynorphins; Enkephalin, Leucine; Male; Naloxone; Naltrexone; Narcotic Antagonists; Peptide Fragments

Endorphins have been implicated in the pathophysiology of both spinal cord injury and cerebral ischemia. This review examines the nature of the experimental evidence to support this hypothesis. Present studies suggest that naloxone administration improves neurological function and outcome in the setting of the spinal cord trauma by centrally inhibiting an opiate receptor-mediated diminution of spinal cord flow. In the setting of spinal shock, naloxone administration is associated with improvement in vital sign and cardiovascular parameters as measured by mean arterial pressure, cardiac output, body temperature, and ventilation. Experiments using a variety of animal stroke models similarly support the notion that naloxone improves neurological function in the setting of cerebral ischemia by a stereospecific opiate receptor-mediated effect, but this improvement does not seem to be accompanied by augmentation of blood flow to affected areas of the brain or by any improvement in vital signs or cardiovascular parameters as seen in spinal cord trauma. A variety of mechanisms are discussed to explain these observations. The therapeutic implications of administering opiate agonists and antagonists in the setting of neurological deficits are outlined for the neurosurgeon.

Topics: Animals; beta-Endorphin; Brain Ischemia; Cats; Cerebral Infarction; Cerebrovascular Circulation; Endorphins; Evoked Potentials, Somatosensory; Hemodynamics; Naloxone; Rats; Receptors, Opioid; Respiration; Spinal Cord; Spinal Cord Injuries

The effect of naloxone, opiate antagonist, was investigated on systemic arterial blood pressure(BP), cerebral blood flow (CBF), and cerebral oxygen consumption in the cat brain following occlusion of the middle cerebral artery(MCA). A total of 21 adult cats was studied under the anesthesia of alpha-chloralose (50 mg/kg). The left MCA was exposed and coagulated using transorbital approach under a operation microscope. Naloxone of 5 mg/kg was administrated intravenously within 30 minutes after MCA occlusion in early therapy group and 2.5 hours after the occlusion in delayed therapy group. Isotonic saline was administrated in the control group. The basal value of CBF in the intact animals was 54.0 +/- 5.9 (+/- SEM) ml/100g/min. Significant increases in mean BP of 13%, CBF of 12%, and CMRO2 of 16% were noted in the intact animals after naloxone administration. The CBF in MCA territory reduced to 24% after MCA occlusion and 85% in contralateral hemisphere. MCA occlusion had no significant effect on either mean BP or the difference in oxygen concentration between arterial and superior sagittal sinus blood. Naloxone increased these reduced CBF and mean BP significantly, but increase in oxygen consumption was not significant. There was no difference between early therapy group and delayed therapy group in pathological study. The effect of naloxone was temporary. Therapy of repeated or continuous naloxone administration appears to be effective during temporary focal cerebral ischemia.

Topics: Animals; Blood Pressure; Brain; Brain Ischemia; Cats; Cerebrovascular Circulation; Naloxone; Oxygen Consumption

Topics: Brain Ischemia; Echoencephalography; Humans; Movement Disorders; Naloxone; Neurosurgery; Retrospective Studies

A 65-year-old man showed naloxone-reversible unconsciousness followed by downward gaze paralysis. CT scan suggested an ischaemic lesion in the mesodiencephalic region. This observation represents the first case of naloxone-reversible coma related to brainstem ischaemia.

Topics: Aged; Brain Ischemia; Brain Stem; Coma; Humans; Male; Naloxone; Ophthalmic Nerve; Ophthalmoplegia; Tomography, X-Ray Computed

Topics: Animals; Barbiturates; Brain Ischemia; Calcium Channel Blockers; Humans; Naloxone; Resuscitation

Topics: Animals; Brain Ischemia; Drug Therapy, Combination; gamma-Aminobutyric Acid; Hypoxia, Brain; Male; Naloxone; Rats; Rats, Inbred Strains; Respiration, Artificial

Naloxone has recently been reported to be of benefit in the treatment of central nervous system ischemia. To study the effect of naloxone in an experimental stroke model, we subjected 40 awake monkeys to middle cerebral artery (MCA) occlusion 2 weeks after the placement of a MCA ligature by a transorbital technique. Cerebral blood flow (CBF) was monitored with stereotactically placed H2 electrodes, and the neurological course was serially recorded. Infarct size was determined 2 weeks after MCA occlusion. Twenty animals served as control and received no naloxone; 10 of these underwent permanent occlusion, and 10 underwent 4-hour MCA occlusion. In 25 treatment animals, naloxone was administered in three different intravenous dosages: (a) naloxone, 2-mg/kg bolus 20 minutes postocclusion and 2 mg/kg/hour X 4 hours, in 10 animals with permanent MCA occlusion; (b) naloxone, 10-mg/kg bolus 20 minutes postocclusion and 10 mg/kg/hour X 4 hours, in 10 animals with 4-hour MCA occlusion; and (c) naloxone, 20-mg/kg bolus, in 5 animals with various neurological deficits. MCA occlusion typically produced a moderate deficit: hemiparesis, hemianopsia, and facial paresis. In most instances, naloxone in the 2- and 10-mg/kg dose regimens produced little or no change in the neurological function. CBF decreased after MCA occlusion and was unaffected by naloxone in most cases. Infarct size was not significantly different between the control and treated groups. However, the 20-mg/kg dose consistently produced a nonfunctional, transient increase in total body motor tone in normal and hemiparetic animals. Naloxone did not significantly improve useful neurological function, CBF, or infarct size in an experimental primate stroke model.

Topics: Animals; Brain Ischemia; Cerebral Infarction; Cerebrovascular Circulation; Cerebrovascular Disorders; Macaca fascicularis; Male; Models, Biological; Naloxone

Topics: Animals; Brain Ischemia; Cats; Naloxone

Topics: Animals; Brain Ischemia; Gerbillinae; Male; Naloxone; Pharmaceutical Vehicles; Solutions

Using unilateral carotid artery ligation in the gerbil as a model of cerebral ischemia, both nuclear magnetic resonance (NMR) imaging and a newly developed double-label autoradiographic technique have been employed to investigate the physiologic mechanism of opiate action during cerebral ischemia. While several parameters of the NMR image have been demonstrated to reflect focal cerebral ischemic lesions, neither 2 mg/kg naloxone nor 10 mg/kg morphine sulfate had an effect on any of the parameters of the NMR image at any time point during the 24 hr experiment. While no consistent changes could be measured in the metabolic rate immediately about the ischemic region, results from double-label 2-deoxyglucose autoradiographic studies indicate that there are marked focal increases in metabolic rate in several subcortical nuclei bilaterally following the administration of naloxone. While no significant change was noted in the thalamus or arcuate nucleus, naloxone produced a significant elevation in glucose metabolic rate in the substantia nigra, periaqueductal grey and the red nucleus. The significance of these effects are discussed and a mechanism for the beneficial effect of opiate antagonists on neurologic deficit following ischemic cerebral lesions is proposed.

Topics: Animals; Brain; Brain Ischemia; Gerbillinae; Glucose; Kinetics; Magnetic Resonance Spectroscopy; Male; Naloxone

Topics: Animals; Brain Ischemia; Disease Models, Animal; Gerbillinae; Humans; Naloxone

Topics: Aged; Brain Ischemia; Female; Humans; Naloxone; Seizures

Topics: Animals; Brain Ischemia; Cerebrovascular Disorders; Gerbillinae; Hemiplegia; Levorphanol; Male; Morphine; Naloxone; Receptors, Opioid

The effects of naloxone and thyrotropin releasing hormone (TRH) were compared in an incremental air embolization model of experimental stroke in dogs. Naloxone treatment significantly improved the cortical somatosensory evoked response and had a beneficial effect on local cerebral blood flow, whereas TRH treatment had no effect on these variables. These findings may implicate endorphins in the pathophysiology of stroke and indicate that naloxone may have a therapeutic role in this condition. Moreover, the lack of effect of TRH in this model, in contrast to its therapeutic effect in experimental spinal injury, indicates that the pathophysiologic responses to ischemic cerebral injury and traumatic spinal injury may differ.

Topics: Animals; Brain Ischemia; Cerebrovascular Circulation; Cerebrovascular Disorders; Disease Models, Animal; Dogs; Evoked Potentials, Somatosensory; Male; Naloxone; Spinal Cord Injuries; Thyrotropin-Releasing Hormone

The effects of naloxone or thyrotropin releasing hormone (TRH) upon neurologic outcome were evaluated in gerbil models of cerebral ischemia. Following temporary bilateral carotid occlusion, hypotension was transiently reversed by these endorphin antagonists. However, neither drug altered time to awaken, time to death, or the severity of neurologic signs (ptosis, movement, retracted paws, circling, righting reflexes, seizures, or opisthotonus) when evaluated by a blinded rater. Hot plate escape and roto-rod performance were also unaltered by naloxone or TRH; TRH, but not naloxone, increased respiratory rates. Thus, the transient improvement of cardiorespiratory function produced by these drugs is unrelated to the morbidity and mortality associated with temporary cerebral ischemia in the gerbil. Additional studies evaluating the effects of naloxone or TRH upon neurologic outcome following permanent unilateral carotid occlusion also failed to show any therapeutic effects of these drugs. Both morphine and TRH exacerbated the effects of ischemia. Of gerbils which developed neurologic impairment, the deficit was usually ipsilateral to the occluded carotid. Collectively, these results indicate that neither naloxone nor TRH prevents ischemic deficits in the gerbil. Further studies with different cerebral ischemia models in other species are required to clarify the possible therapeutic effects of these drugs in experimental stroke.

Topics: Animals; Arterial Occlusive Diseases; Brain Ischemia; Carotid Artery Diseases; Disease Models, Animal; Gerbillinae; Male; Motor Activity; Naloxone; Thyrotropin-Releasing Hormone

Stroke induced by a carotid occlusion in gerbils was reversed by intraperitoneal (i.p.) injection of naloxone (1 mg/kg) for up to 30 min. Placebo-treated stroked gerbils died in 48 hr; 40% of gerbils implanted with 10 mg naloxone pellets survived over 2 weeks without neurologic deficit. Intravenous (i.v.) injection of naloxone produced the same transient reversal of hemiplegia in 2 patients with neurologic deficit from cerebral ischemia. These findings suggest the involvement of endorphins and opiate receptors in the pathophysiology of stroke, and suggest the possible clinical use of opiate antagonists in humans in the acute phase of stroke.

Topics: Animals; Brain Ischemia; Gerbillinae; Hemiplegia; Humans; Male; Models, Biological; Naloxone

Topics: Animals; Brain Ischemia; Disease Models, Animal; Gerbillinae; Naloxone; Research Design

Topics: Aged; Brain Ischemia; Endorphins; Female; Humans; Naloxone