Xylazine effects on opioid-induced brain hypoxia.

RATIONALE: Xylazine has emerged in recent years as an adulterant in an increasing number of opioid-positive overdose deaths in the United States. Although its exact role in opioid-induced overdose deaths is largely unknown, xylazine is known to depress vital functions and cause hypotension, bradycardia, hypothermia, and respiratory depression. OBJECTIVES: In this study, we examined the brain-specific hypothermic and hypoxic effects of xylazine and its mixtures with fentanyl and heroin in freely moving rats. RESULTS: In the temperature experiment, we found that intravenous xylazine at low, human-relevant doses (0.33, 1.0, 3.0 mg/kg) dose-dependently decreases locomotor activity and induces modest but prolonged brain and body hypothermia. In the electrochemical experiment, we found that xylazine at the same doses dose-dependently decreases nucleus accumbens oxygenation. In contrast to relatively weak and prolonged decreases induced by xylazine, intravenous fentanyl (20 µg/kg) and heroin (600 µg/kg) induce stronger biphasic brain oxygen responses, with the initial rapid and strong decrease, resulting from respiratory depression, followed by a slower, more prolonged increase reflecting a post-hypoxic compensatory phase, with fentanyl acting much quicker than heroin. The xylazine-fentanyl mixture eliminated the hyperoxic phase of oxygen response and prolonged brain hypoxia, suggesting xylazine-induced attenuation of the brain's compensatory mechanisms to counteract brain hypoxia. The xylazine-heroin mixture strongly potentiated the initial oxygen decrease, and the pattern lacked the hyperoxic portion of the biphasic oxygen response, suggesting more robust and prolonged brain hypoxia. CONCLUSIONS: These findings suggest that xylazine exacerbates the life-threatening effects of opioids, proposing worsened brain hypoxia as the mechanism contributing to xylazine-positive opioid-overdose deaths.

The pattern of brain oxygen response induced by intravenous fentanyl limits the time window of therapeutic efficacy of naloxone.

Opioids induce respiratory depression resulting in coma or even death during overdose. Naloxone, an opioid antagonist, is the gold standard reversal agent for opioid intoxication, but this treatment is often less successful for fentanyl. While low dosing is thought to be a factor limiting naloxone's efficacy, the timing between fentanyl exposure and initiation of naloxone treatment may be another important factor. Here, we used oxygen sensors coupled with amperometry to examine the pattern of oxygen responses in the brain and periphery induced by intravenous fentanyl in freely moving rats. At both doses (20 and 60 µg/kg), fentanyl induced a biphasic brain oxygen response-a rapid, strong, and relatively transient decrease (8-12 min) followed by a weaker and prolonged increase. In contrast, fentanyl induced stronger and more prolonged monophasic oxygen decreases in the periphery. When administered before fentanyl, intravenous naloxone (0.2 mg/kg) fully blocked the hypoxic effects of moderate-dose fentanyl in both the brain and periphery. However, when injected 10 min after fentanyl, when most of hypoxia had already ceased, naloxone had minimal effect on central and peripheral oxygen levels, but at a higher dose, it strongly attenuated hypoxic effects in the periphery with only a transient brain oxygen increase associated with behavioral awakening. Therefore, due to the rapid, strong but transient nature of fentanyl-induced brain hypoxia, the time window when naloxone can attenuate this effect is relatively short. This timing limitation is critical, making naloxone most effective when used quickly and less effective when used during the post-hypoxic comatose state after brain hypoxia has already ceased and harm for neural cells already done.

Basic metabolic and vascular effects of ketamine and its interaction with fentanyl.

Ketamine is a short-acting general anesthetic with hallucinogenic, analgesic, and amnestic properties. In addition to its anesthetic use, ketamine is commonly abused in rave settings. While safe when used by medical professionals, uncontrolled recreational use of ketamine is dangerous, especially when mixed with other sedative drugs, including alcohol, benzodiazepines, and opioid drugs. Since synergistic antinociceptive interactions between opioids and ketamine were demonstrated in both preclinical and clinical studies, such an interaction could exist for the hypoxic effects of opioid drugs. Here, we focused on the basic physiological effects of ketamine as a recreational drug and its possible interactions with fentanyl-a highly potent opioid that induces strong respiratory depression and robust brain hypoxia. By using multi-site thermorecording in freely-moving rats, we showed that intravenous ketamine at a range of human relevant doses (3, 9, 27 mg/kg) dose-dependently increases locomotor activity and brain temperature, as assessed in the nucleus accumbens (NAc). By determining temperature differentials between the brain, temporal muscle, and skin, we showed that the brain hyperthermic effect of ketamine results from increased intracerebral heat production, an index of metabolic neural activation, and decreased heat loss due to peripheral vasoconstriction. By using oxygen sensors coupled with high-speed amperometry we showed that ketamine at the same doses increases NAc oxygen levels. Finally, co-administration of ketamine with intravenous fentanyl results in modest enhancement of fentanyl-induced brain hypoxia also enhancing the post-hypoxic oxygen increase. Therefore, in contrast to fentanyl, ketamine increases brain oxygenation but potentiates brain hypoxia induced by fentanyl.

Loperamide Abuse and Its Sequelae.

INTRODUCTION: Loperamide is an opioid available over the counter and in prescription form. Loperamide functions as a µ-agonist within the enteric nervous system to slow intestinal motility. Its antidiarrheal properties and primarily peripheral activity make loperamide an important tool in the management of inflammatory bowel disease. CASE REPORT: A 42-year-old man was found unconscious in cardiac arrest, and emergency medical personnel restored normal sinus rhythm. Family reported complaints of abdominal pain and that he "went through a lot" of loperamide. In the emergency department, the patient exhibited symptoms consistent with an opioid overdose. Mental status improved after administration of naloxone, an opioid antagonist. An electrocardiogram revealed a prolonged QTc interval, which progressed into Torsades de Pointes rhythm during admission. The patient succumbed from hypoxic brain injury, and there was evidence of acute pancreatitis at autopsy. Loperamide and desmethylloperamide (loperamide metabolite) were detected in blood samples. Cause of death was ruled loperamide toxicity. DISCUSSION: Because of reduced central nervous system activity and associated euphoria at therapeutic doses, loperamide abuse is rarely reported. This case demonstrates that an overdose on loperamide can occur in patients seeking symptom alleviation, and may mimic the presentation of opioid overdose.

Cocaine added to heroin fails to affect heroin-induced brain hypoxia.

Heroin and cocaine are both highly addictive drugs that cause unique physiological and behavioral effects. These drugs are often co-administered and cocaine has been found in ~20% of cases of opioid overdose death. Respiratory depression followed by brain hypoxia is the most dangerous effect of high-dose opioids that could result in coma and even death. Conversely, cocaine at optimal self-administering doses increases brain oxygen levels. Considering these differences, it is unclear what pattern of oxygen changes will occur when these drugs are co-administered. Here, we used high-speed amperometry with oxygen sensors to examine changes in oxygen concentrations in the nucleus accumbens (NAc) induced by intravenous (iv) cocaine, heroin, and their mixtures in freely-moving rats. Cocaine delivered at a range of doses, both below (0.25 mg/kg) and within the optimal range of self-administration (0.5 and 1.0 mg/kg) modestly increased NAc oxygen levels. In contrast, heroin increased oxygen levels at a low reinforcing dose (0.05 mg/kg), but induced a biphasic down-up change at higher reinforcing doses (0.1 and 0.2 mg/kg), and caused a strong monophasic oxygen decrease during overdose (0.6 mg/kg). When combined at moderate doses, cocaine (0.25, 0.5 mg/kg) slightly increased and prolonged oxygen increases induced by heroin alone (0.5 and 0.1 mg/kg), but oxygen decreases were identical when cocaine (1 mg/kg) was combined with heroin at large doses (0.2 and 0.6 mg/kg). Therefore, health dangers of speedball may result from de-compensation of vital functions due to diminished intra-brain oxygen inflow induced by high-dose heroin coupled with enhanced oxygen use induced by cocaine.

Respiratory depression and brain hypoxia induced by opioid drugs: Morphine, oxycodone, heroin, and fentanyl.

Opioid drugs are important tools to alleviate pain of different origins, but they have strong addictive potential and their abuse at higher doses often results in serious health complications. Respiratory depression that leads to brain hypoxia is perhaps the most dangerous symptom of acute intoxication with opioids, and it could result in lethality. The development of substrate-specific sensors coupled with amperometry made it possible to directly evaluate physiological and drug-induced fluctuations in brain oxygen levels in awake, freely-moving rats. The goal of this review paper is to consider changes in brain oxygen levels induced by several opioid drugs (heroin, fentanyl, oxycodone, morphine). While some of these drugs are widely used in clinical practice, they all are abused, often at doses exceeding the clinical range and often resulting in serious health complications. First, we consider some basic knowledge regarding brain oxygen, its physiological fluctuations, and mechanisms involved in regulating its entry into brain tissue. Then, we present and discuss data on brain oxygen changes induced by each opioid drug within a wide range of doses, from low, behaviorally relevant, to high, likely to be self-administered by drug users. These data allowed us to compare the effects of these drugs on brain oxygen in terms of their potency, time-course, and their potential danger when used at high doses via rapid-onset administration routes. While most data discussed in this work were obtained in rats, we believe that these data have clear human relevance in addressing the alarming rise in lethality associated with the opioid abuse.

[Sustained upgaze in a patient who ingested high doses of bupropion. Report of one case]. / Supraversión de la mirada en intoxicación mortal por bupropión.

Upgaze or sustained elevation of the eyes, is an alteration of ocular motility initially described in hypoxic coma. We report a 65-year-old woman admitted with hypotension and alteration of sensorium due to the ingestion of 9.5 g of Bupropion. She presented two seizures of short duration, without epileptic activity on the EEG. She had a persistent asynchronous myoclonus in extremities, tachycardia and prolonged Q-t. She suffered a cardiac arrest caused by asystole, which recovered quickly in five minutes. At that moment, upgaze appeared, associated with a persistent ocular opening, which persisted for days, but finally disappeared, without remission of coma. A magnetic resonance imaging done at the eighth day, showed hyperintensity of the oval center and corpus callosum which disappeared in a new imaging study done 30 days later, where images of hypoxia in the basal nuclei and cortex appeared. The patient died forty seven days after admission. Up-gaze is an ominous oculomotor alteration linked to an important but incomplete damage in the cerebral cortex, a condition that perverts some sequences of the ocular opening, reversing the Bell phenomenon and producing eyelid retraction.

Supraversión de la mirada en intoxicación mortal por bupropión / Sustained upgaze in a patient who ingested high doses of bupropion: report of one case

Upgaze or sustained elevation of the eyes, is an alteration of ocular motility initially described in hypoxic coma. We report a 65-year-old woman admitted with hypotension and alteration of sensorium due to the ingestion of 9.5 g of Bupropion. She presented two seizures of short duration, without epileptic activity on the EEG. She had a persistent asynchronous myoclonus in extremities, tachycardia and prolonged Q-t. She suffered a cardiac arrest caused by asystole, which recovered quickly in five minutes. At that moment, upgaze appeared, associated with a persistent ocular opening, which persisted for days, but finally disappeared, without remission of coma. A magnetic resonance imaging done at the eighth day, showed hyperintensity of the oval center and corpus callosum which disappeared in a new imaging study done 30 days later, where images of hypoxia in the basal nuclei and cortex appeared. The patient died forty seven days after admission. Up-gaze is an ominous oculomotor alteration linked to an important but incomplete damage in the cerebral cortex, a condition that perverts some sequences of the ocular opening, reversing the Bell phenomenon and producing eyelid retraction.

Biomimetic synthesis and evaluation of histidine-derivative templated chiral mesoporous silica for improved oral delivery of the poorly water-soluble drug, nimodipine.

In this study, spherical shaped chiral mesoporous silica nanoparticles (CMS) was biomimetic synthesized using histidine derivatives (C16-L-histidine) as template via the sol-gel reaction and employed as poorly water-soluble drug nimodipine (NMP) carrier. Characteristics of CMS and its application as drug carrier were intensively investigated and compared with MCM41. Then NMP was respectively loaded into CMS and MCM41 with the drug: carrier weight ratio of 2:1. Structural features of NMP before and after drug loading were systemically characterized. The results demonstrated that hydrogen bonds were formed between NMP and carriers during the drug loading process. After drug loading, crystalline state of NMP effectively converted into modification L and amorphous state, and the first form turned out to be easily removed by washing. On the other hand, drug dissolution rate was significantly improved after drug loading, and the best result came from NMP-C3 sample. It was able to release 17.83% of drug within 60 min, which was 6.8-fold higher than the release amount of pure NMP. Undoubtedly, NMP-C3 presented the highest relative bioavailability (386.22%), and the best therapeutic effect. Meanwhile, CMS improved the brain distribution of NMP in vivo.

Ameliorative Effect of Trans-Sinapic Acid and its Protective Role in Cerebral Hypoxia in Aluminium Chloride Induced Dementia of Alzheimer's Type.

BACKGROUND: Trans-Sinapic Acid is a bioactive compound. Recent studies showed that it has a significant potential to attenuate various chemically induced Neurodegenerative toxicities. AIM: The present study investigates the potential of trans-Sinapic Acid as neuromodulator and its effect on release of Monoamine Oxidase (MAO-A, MAO-B), TNF-α, Acetylcholine esterase Enzyme, in cognitive dysfunctions associated with experimental dementia. Experiment: Aluminium chloride was administered at a dose of 175mg/kg, p.o. for a period of 25 days in rats and then divided into different groups, i.e. Treatment group, negative control and two groups of trans- Sinapic Acid, (at a dose of 30 and 60mg/kg, p.o.), where these groups treated and observed until the 35th day of experimental trial. Morris water Maze (MWM) and Photoactometer was used to access learning, memory and ambulatory movements on 5th, 16th, 26th and 36th day of experiment. Later, the animals were sacrificed for biochemical and histopahological studies. The oxidative stress was measured by estimating the levels of Glutathion (GSH), Superoxide dismutase (SOD), Nitrite, Catalase. Brain acetylcholine esterase (Ache) activity and Monoamine oxidase (MAO-A, MAO-B) were also estimated. The Brain level of TNF-α was measured as a marker of inflammation. RESULTS: Aluminium chloride (AlCl3) produced a marked decline in MWM performance and ambulatory movements' of animals, reflecting impairment of memory and learning. Trans-Sinapic Acid treatment significantly modulates AlCl3 induced memory deficits, biochemical and pathological alterations. The findings demonstrate that the memory restorative ability of trans-Sinapic Acid may be attributed to its anti-cholinesterase, anti-oxidative and anti-inflammatory potential.

Disruption of Interneuron Neurogenesis in Premature Newborns and Reversal with Estrogen Treatment.

Many Preterm-born children suffer from neurobehavioral disorders. Premature birth terminates the hypoxic in utero environment and supply of maternal hormones. As the production of interneurons continues until the end of pregnancy, we hypothesized that premature birth would disrupt interneuron production and that restoration of the hypoxic milieu or estrogen treatment might reverse interneuron generation. To test these hypotheses, we compared interneuronal progenitors in the medial ganglionic eminences (MGEs), lateral ganglionic eminences (LGEs), and caudal ganglionic eminences (CGEs) between preterm-born [born on embryonic day (E) 29; examined on postnatal day (D) 3 and D7] and term-born (born on E32; examined on D0 and D4) rabbits at equivalent postconceptional ages. We found that both total and cycling Nkx2.1+, Dlx2+, and Sox2+ cells were more abundant in the MGEs of preterm rabbits at D3 compared with term rabbits at D0, but not in D7 preterm relative to D4 term pups. Total Nkx2.1+ progenitors were also more numerous in the LGEs of preterm pups at D3 compared with term rabbits at D0. Dlx2+ cells in CGEs were comparable between preterm and term pups. Simulation of hypoxia by dimethyloxalylglycine treatment did not affect the number of interneuronal progenitors. However, estrogen treatment reduced the density of total and proliferating Nkx2.1+ and Dlx2+ cells in the MGEs and enhanced Ascl1 transcription factor. Estrogen treatment also reduced Ki67, c-Myc, and phosphorylation of retinoblastoma protein, suggesting inhibition of the G1-to-S phase transition. Hence, preterm birth disrupts interneuron neurogenesis in the MGE and estrogen treatment reverses interneuron neurogenesis in preterm newborns by cell-cycle inhibition and elevation of Ascl1. We speculate that estrogen replacement might partially restore neurogenesis in human premature infants.SIGNIFICANCE STATEMENT Prematurity results in developmental delays and neurobehavioral disorders, which might be ascribed to disturbances in the development of cortical interneurons. Here, we show that preterm birth disrupts interneuron neurogenesis in the medial ganglionic eminence (MGE) and, more importantly, that estrogen treatment reverses this perturbation in the population of interneuron progenitors in the MGE. The estrogen seems to restore neurogenesis by inhibiting the cell cycle and elevating Ascl1 expression. As preterm birth causes plasma estrogen level to drop 100-fold, the estrogen replacement in preterm infants is physiological. We speculate that estrogen replacement might ameliorate disruption in production of interneurons in human premature infants.

Delayed-onset MRI findings in acute chorea related to anoxic brain injury.

Anoxic brain injury can manifest with various abnormal movements. We describe acute chorea in a young patient with anoxic brain injury due to chlordiazepoxide toxicity who had delayed radiographic lesions in bilateral globus pallidus. Although brain MRI 8days after the anoxic event was unremarkable, repeat brain MRI 15days after the event showed T2 hyperintensities and enhancement within the bilateral globus pallidi. It is possible that MRI brain findings of bilateral basal ganglia lesions may appear later than onset of chorea in anoxic brain injury. However, given the normal brain MRI in between, other etiologies cannot be excluded entirely.

Metyrapone prevents acute glucose hypermetabolism and short-term brain damage induced by intrahippocampal administration of 4-aminopyridine in rats.

Intracerebral administration of the potassium channel blocker 4-aminopyridine (4-AP) triggers neuronal depolarization and intense acute seizure activity followed by neuronal damage. We have recently shown that, in the lithium-pilocarpine rat model of status epilepticus (SE), a single administration of metyrapone, an inhibitor of the 11ß-hydroxylase enzyme, had protective properties of preventive nature against signs of brain damage and neuroinflammation. Herein, our aim was to investigate to which extent, pretreatment with metyrapone (150 mg/kg, i.p.) was also able to prevent eventual changes in the acute brain metabolism and short-term neuronal damage induced by intrahippocampal injection of 4-AP (7 µg/5 µl). To this end, regional brain metabolism was assessed by 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) positron emission tomography (PET) during the ictal period. Three days later, markers of neuronal death and hippocampal integrity and apoptosis (Nissl staining, NeuN and active caspase-3 immunohistochemistry), neurodegeneration (Fluoro-Jade C labeling), astrogliosis (glial fibrillary acidic protein (GFAP) immunohistochemistry) and microglia-mediated neuroinflammation (in vitro [18F]GE180 autoradiography) were evaluated. 4-AP administration acutely triggered marked brain hypermetabolism within and around the site of injection as well as short-term signs of brain damage and inflammation. Most important, metyrapone pretreatment was able to reduce ictal hypermetabolism as well as all the markers of brain damage except microglia-mediated neuroinflammation. Overall, our study corroborates the neuroprotective effects of metyrapone against multiple signs of brain damage caused by seizures triggered by 4-AP. Ultimately, our data add up to the consistent protective effect of metyrapone pretreatment reported in other models of neurological disorders of different etiology.

Fentanyl-Induced Brain Hypoxia Triggers Brain Hyperglycemia and Biphasic Changes in Brain Temperature.

Fentanyl is a potent synthetic opioid used extensively in humans for general anesthesia and analgesia. Fentanyl has emerged as a recreational drug, often in combination with heroin, and can result in lethality during overdose. Fentanyl is well characterized as an anesthetic, but the basic physiological effects of fentanyl in the brain when taken as a drug of abuse are largely unknown. We used high-speed amperometry in freely moving rats to examine the effects of intravenous fentanyl at doses within the range of possible human intake (3-40 µg/kg) on oxygen and glucose levels in nucleus accumbens (NAc). Fentanyl induced a rapid, dose-dependent decrease in NAc oxygen followed by a more delayed and prolonged increase in NAc glucose. Fentanyl induced similar oxygen decreases in the basolateral amygdala, indicating that brain hypoxia could be a generalized phenomenon. We used oxygen recordings in the subcutaneous space to confirm that fentanyl-induced brain hypoxia results from decreases in blood oxygen levels caused by drug-induced respiratory depression. Temperature recordings in the NAc, muscle, and skin showed that fentanyl induces biphasic changes in brain temperature, with an initial decrease that results primarily from peripheral vasodilation, and a subsequent increase driven by metabolic brain activation. The initial vasodilation appears caused by respiratory depression-induced hypoxia and a subsequent rise in CO2 that drives fentanyl-induced increases in NAc glucose. Together, these data suggest that fentanyl-induced respiratory depression triggers brain hypoxia and subsequent hyperglycemia, both of which precede slower changes in brain temperature and metabolic brain activity.

AB-CHMINACA-induced sudden death from non-cardiogenic pulmonary edema.

CONTEXT: Despite widespread use of diverse synthetic cannabinoid (sCB) compounds, the pathophysiology associated with intoxication with many sCB compounds, including AB-CHMINACA, is poorly understood, as is their metabolism and distribution into blood and organs. CASE DETAILS: A young man died shortly after ingesting an herb product containing sCB compounds. Toxicological analyses of blood samples revealed high levels of AB-CHMINACA (7.61 ± 0.59 ng/mL) and its metabolites (M2, 56.73 ± 4.16 ng/mL; M4, 2.29 ± 0.14 ng/mL) and trace amounts of 5-fluoro-AMB, FUB-PB-22, and AB-FUBINACA. The autopsy revealed severe pulmonary edema, and histology showed air bubbles in the alveolar effusion, suggesting rapid progression of edema. Low blood levels of N-terminal pro-brain natriuretic peptide excluded cardiogenic pulmonary edema. Histological examination revealed diffuse neuronal (brain) and myocardial (sub-endocardial) hyper-eosinophilia, indicating hypoxic encephalopathy and systemic hypoxemia, respectively. CONCLUSIONS: The findings show that AB-CHMINACA induced rapid progression of pulmonary edema resulting in hypoxic encephalopathy and systemic hypoxemia, possibly through severe seizures. The high blood ratio of the M2 metabolite to the parent compound, AB-CHMINACA, demonstrates rapid metabolism. This highlights the usefulness of quantification of M2 in diagnosing AB-CHMINACA intoxication.

Heroin Contaminated with Fentanyl Dramatically Enhances Brain Hypoxia and Induces Brain Hypothermia.

While opioid abuse is an established medical and public health issue, the increased availability of highly potent synthetic opioids, such as fentanyl, has given rise to acute health complications, including a comatose state and death during drug overdose. Since respiratory depression that leads to acute hypoxia is the most dangerous complication of opioid drug use, we examined the effects of intravenous heroin and heroin contaminated with 10% fentanyl on oxygen levels in the nucleus accumbens (NAc) monitored using high-speed amperometry in freely moving rats. Additionally, we examined the effects of heroin, fentanyl, and their mixture on locomotion and temperatures in the NAc, temporal muscle, and skin. Both fentanyl and heroin at human-relevant doses (400 and 40 µg/kg, respectively) induced rapid, strong and transient decreases in NAc oxygen, indicative of brain hypoxia. When the heroin-fentanyl mixture was injected, the NAc hypoxic response was greatly potentiated in its duration, suggesting sustained hypoxia. In contrast to modest, monophasic brain temperature increases caused by heroin alone, the heroin-fentanyl mixture induced a biphasic temperature response, with a prominent postinjection decrease resulting from peripheral vasodilation. This hypothermic effect, albeit much smaller and more transient, was typical of fentanyl injected alone. Our findings indicate that accidental use of fentanyl instead of heroin, or even a relatively minor contamination of "street heroin" with fentanyl, poses great danger for acute health complications, including a comatose state and death.

Detection of butane gas inhalation at 16days after hypoxic encephalopathy: A case report.

In Japan, there are increasing reports of death by poisoning following butane abuse. To determine the specific cause of death in such cases, it is important to confirm the presence of fuel gas components in the body, although careful analysis is required because of their volatile properties. In most reported cases, the subject died suddenly during or immediately after butane aspiration. Thus, the butane concentration in the samples from the deceased should be relatively high. Herein, we present a case of an 18-year-old man found with cardiopulmonary arrest, who then exhibited hypoxic encephalopathy for 16days in a hospital. At autopsy, we detected hypoxic encephalopathy, pneumonia, and ischemia-reperfusion injury of the myocardium, while the cause of cardiac arrest remained unclear. Toxicological analysis was then performed for fuel gas components in several specimens collected at autopsy. Results showed that n-butane and isobutane were detected in the adipose tissue at 16days after inhalation, indicating a role of butane gas inhalation as the cause of death. These data suggest that adipose tissue may be the most appropriate analysis sample to be collected at postmortem in cases where involvement of volatile and fat-soluble gas inhalation is suspected.

Intravenous Heroin Induces Rapid Brain Hypoxia and Hyperglycemia that Precede Brain Metabolic Response.

Heroin use and overdose have increased in recent years as people transition from abusing prescription opiates to using the cheaper street drug. Despite a long history of research, many physiological effects of heroin and their underlying mechanisms remain unknown. Here, we used high-speed amperometry to examine the effects of intravenous heroin on oxygen and glucose levels in the nucleus accumbens (NAc) in freely-moving rats. Heroin within the dose range of human drug use and rat self-administration (100-200 µg/kg) induced a rapid, strong, but transient drop in NAc oxygen that was followed by a slower and more prolonged rise in glucose. Using oxygen recordings in the subcutaneous space, a densely-vascularized site with no metabolic activity, we confirmed that heroin-induced brain hypoxia results from decreased blood oxygen, presumably due to drug-induced respiratory depression. Respiratory depression and the associated rise in CO2 levels appear to drive tonic increases in NAc glucose via local vasodilation. Heroin-induced changes in oxygen and glucose were rapid and preceded the slow and prolonged increase in brain temperature and were independent of enhanced intra-brain heat production, an index of metabolic activation. A very high heroin dose (3.2 mg/kg), corresponding to doses used by experienced drug users in overdose conditions, caused strong and prolonged brain hypoxia and hyperglycemia coupled with robust initial hypothermia that preceded an extended hyperthermic response. Our data suggest heroin-induced respiratory depression as a trigger for brain hypoxia, which leads to hyperglycemia, both of which appear independent of subsequent changes in brain temperature and metabolic neural activity.

Codeine and opioid metabolism: implications and alternatives for pediatric pain management.

PURPOSE OF REVIEW: Use of perioperative opioids for surgical pain management of children presents clinical challenges because of concerns of serious adverse effects including life-threatening respiratory depression. This is especially true for children with history of obstructive sleep apnea. This review will explore current knowledge of clinically relevant factors and genetic polymorphisms that affect opioid metabolism and postoperative outcomes in children. RECENT FINDINGS: Within the past several years, an increasing number of case reports have illustrated clinically important respiratory depression, anoxic brain injuries and even death among children receiving appropriate weight-based dosages of codeine and other opioids for analgesia at home setting particularly following tonsillectomy. Several national and international organizations have issued advisories on use of codeine in pediatrics, based on cytochrome P450 family 2 subfamily D type 6 (CYP2D6) pharmacogenetics. We have discussed the pros and cons of alternatives to codeine for pain management. SUMMARY: Although routine preoperative genotyping to identify children at risk and personalized opioid use for pediatric perioperative pain management is still a distant reality, current known implications of CYP2D6 pharmacogenetics on codeine use shows that pharmacogenetics has the potential to guide anesthesia providers on perioperative opioid selection and dosing to maximize efficacy and safety.

Maternal administration of nanomaterials elicits hemoglobin upregulation in the neonatal brain of non-human primates.

To investigate the influence of nanomaterial exposure during fetal development, diesel exhaust particles (DEPs), carbon black (CB), or titanium dioxide (TiO2) was injected intradermally to pregnant rhesus macaques. The hippocampus and cerebellum of newborn infants were then examined. DNA microarray and quantitative real-time RT-PCR, western blot, and immunohistochemical analyses were used to measure the expression of the hemoglobin genes, HBA, HBB, and HBG. Of the nanomaterials tested, DEP elicited the greatest increase in mRNA and protein levels of hemoglobin genes in the brain tissues. Strong signal of HbA protein was detected in the pyramidal cell layer, the polymorphic cell layer and in the alveus of the hippocampi of the DEP-treated animals. The altered gene expression was likely due to responses to oxidative or nitrosative stress and/or hypoxia in the fetal/neonatal brain. Since excessive hemoglobin is reportedly neurotoxic, the vulnerability of developing brains by long-term upregulation of hemoglobin should be considered. Maternal exposure to nanomaterials may increase the risk of brain dysfunction in offspring.