Two Weeks of Continuous Opioid Treatment in an Adenine-Induced Mouse Model of Chronic Kidney Disease Exacerbates the Bone Inflammatory State and Increases Osteoclasts.

Patients with chronic kidney disease (CKD) report high pain levels, but reduced renal clearance eliminates many analgesic options; therefore, 30-50% of CKD patients have chronic opioid prescriptions. Opioid use in CKD is associated with higher fracture rates. Opioids may directly alter bone turnover directly through effects on bone cells and indirectly via increasing inflammation.

Perturbed neurochemical and microstructural organization in a mouse model of prenatal opioid exposure: A multi-modal magnetic resonance study.

Methadone-based treatment for pregnant women with opioid use disorder is quite prevalent in the clinical environment. A number of clinical and animal model-based studies have reported cognitive deficits in infants prenatally exposed to methadone-based opioid treatments. However, the long-term impact of prenatal opioid exposure (POE) on pathophysiological mechanisms that govern neurodevelopmental impairment is not well understood.

Perturbed neurochemical and microstructural organization in a mouse model of prenatal opioid exposure: a multi-modal magnetic resonance study.

Methadone-based treatment for pregnant women with opioid use disorder is quite prevalent in the clinical environment. A number of clinical and animal model-based studies have reported cognitive deficits in infants prenatally exposed to methadone-based opioid treatments. However, the long-term impact of prenatal opioid exposure (POE) on pathophysiological mechanisms that govern neurodevelopmental impairment is not well understood.

Alterations of brain microstructures in a mouse model of prenatal opioid exposure detected by diffusion MRI.

Growing opioid use among pregnant women is fueling a crisis of infants born with prenatal opioid exposure. A large body of research has been devoted to studying the management of opioid withdrawal during the neonatal period in these infants, but less substantive work has explored the long-term impact of prenatal opioid exposure on neurodevelopment. Using a translationally relevant mouse model of prenatal methadone exposure (PME), the aim of the study is to investigate the cerebral microstructural differences between the mice with PME and prenatal saline exposure (PSE).

The role of anterior insular cortex inputs to dorsolateral striatum in binge alcohol drinking.

How does binge drinking alcohol change synaptic function, and do these changes maintain binge consumption? The anterior insular cortex (AIC) and dorsolateral striatum (DLS) are brain regions implicated in alcohol use disorder. In male, but not female mice, we found that binge drinking alcohol produced glutamatergic synaptic adaptations selective to AIC inputs within the DLS. Photoexciting AIC→DLS circuitry in male mice during binge drinking decreased alcohol, but not water consumption and altered alcohol drinking mechanics.

Prenatal Opioid Exposure Impairs Endocannabinoid and Glutamate Transmission in the Dorsal Striatum.

The opioid crisis has contributed to a growing population of children exposed to opioids during fetal development; however, many of the long-term effects of opioid exposure on development are unknown. We previously demonstrated that opioids have deleterious effects on endocannabinoid plasticity at glutamate synapses in the dorsal striatum of adolescent rodents, but it is unclear whether prenatal opioid exposure produces similar neuroadaptations. Using a mouse model of prenatal methadone exposure (PME), we performed proteomics, phosphoproteomics, and patch-clamp electrophysiology in the dorsolateral striatum (DLS) and dorsomedial striatum (DMS) to examine synaptic functioning in adolescent PME offspring.

Prenatal opioid administration induces shared alterations to the maternal and offspring gut microbiome: A preliminary analysis.

Background While many studies have described the impact of prenatal opioid exposure on development, possible mechanisms for how opioids exert developmental impairments remain elusive. Emerging evidence indicates disruptions in the maternal gut microbiome can alter offspring development; however, no studies to date have examined the impact of maternal opioid treatment on maternal-offspring microbiome dysbiosis. Methods A mouse model of prenatal methadone exposure (PME) was employed to assess the impact of maternal opioid treatment on the microbiome of methadone-treated dams (MD) and their offspring.

Anterior cingulate cortex metabolites and white matter microstructure: a multimodal study of emergent alcohol use disorder.

Multimodal imaging is increasingly used to address neuropathology associated with alcohol use disorder (AUD). Few studies have investigated relationships between metabolite concentrations and white matter (WM) integrity; currently, there are no such data in AUD. In this preliminary study, we used complementary neuroimaging techniques, magnetic resonance spectroscopy (MRS), and diffusion weighted imaging (DWI), to study AUD neurophysiology.

Prenatal methadone exposure disrupts behavioral development and alters motor neuron intrinsic properties and local circuitry.

Despite the rising prevalence of methadone treatment in pregnant women with opioid use disorder, the effects of methadone on neurobehavioral development remain unclear. We developed a translational mouse model of prenatal methadone exposure (PME) that resembles the typical pattern of opioid use by pregnant women who first use oxycodone then switch to methadone maintenance pharmacotherapy, and subsequently become pregnant while maintained on methadone. We investigated the effects of PME on physical development, sensorimotor behavior, and motor neuron properties using a multidisciplinary approach of physical, biochemical, and behavioral assessments along with brain slice electrophysiology and in vivo magnetic resonance imaging.

A multi-omic analysis of the dorsal striatum in an animal model of divergent genetic risk for alcohol use disorder.

The development of selectively bred high and low alcohol-preferring mice (HAP and LAP, respectively) has allowed for an assessment of the polygenetic risk for pathological alcohol consumption and phenotypes associated with alcohol use disorder (AUD). Accumulating evidence indicates that the dorsal striatum (DS) is a central node in the neurocircuitry underlying addictive processes. Therefore, knowledge of differential gene, protein, and phosphorylated protein expression in the DS of HAP and LAP mice may foster new insights into how aberrant DS functioning may contribute to AUD-related phenotypes.

Neuroimaging in infants with prenatal opioid exposure: Current evidence, recent developments and targets for future research.

Prenatal opioid exposure (POE) has shown to be a risk factor for adverse long-term cognitive and behavioral outcomes in offspring. However, the neural mechanisms of these outcomes remain poorly understood. While preclinical and human studies suggest that these outcomes may be due to opioid-mediated changes in the fetal and early postnatal brain, other maternal, social, and environmental factors are also shown to play a role.

Prenatal Opioid Exposure Enhances Responsiveness to Future Drug Reward and Alters Sensitivity to Pain: A Review of Preclinical Models and Contributing Mechanisms.

The opioid crisis has resulted in an unprecedented number of neonates born with prenatal opioid exposure (POE); however, the long-term effects of POE on offspring behavior and neurodevelopment remain relatively unknown. The advantages and disadvantages of the various preclinical POE models developed over the last several decades are discussed in the context of clinical and translational relevance. Although considerable and important variability exists among preclinical models of POE, the examination of these preclinical models has revealed that opioid exposure during the prenatal period contributes to maladaptive behavioral development as offspring mature including an altered responsiveness to rewarding drugs and increased pain response.

Mu opioid receptors on vGluT2-expressing glutamatergic neurons modulate opioid reward.

The role of Mu opioid receptor (MOR)-mediated regulation of GABA transmission in opioid reward is well established. Much less is known about MOR-mediated regulation of glutamate transmission in the brain and how this relates to drug reward. We previously found that MORs inhibit glutamate transmission at synapses that express the Type 2 vesicular glutamate transporter (vGluT2).

Adeno-Associated Viral Vectors in Neuroscience Research.

Adeno-associated viral vectors (AAVs) are increasingly useful preclinical tools in neuroscience research studies for interrogating cellular and neurocircuit functions and mapping brain connectivity. Clinically, AAVs are showing increasing promise as viable candidates for treating multiple neurological diseases. Here, we briefly review the utility of AAVs in mapping neurocircuits, manipulating neuronal function and gene expression, and activity labeling in preclinical research studies as well as AAV-based gene therapies for diseases of the nervous system.

The Penrose Effect and its acceleration by the war on drugs: a crisis of untranslated neuroscience and untreated addiction and mental illness.

In 1939, British psychiatrist Lionel Penrose described an inverse relationship between mental health treatment infrastructure and criminal incarcerations. This relationship, later termed the 'Penrose Effect', has proven remarkably predictive of modern trends which have manifested as reciprocal components, referred to as 'deinstitutionalization' and 'mass incarceration'. In this review, we consider how a third dynamic-the criminalization of addiction via the 'War on Drugs', although unanticipated by Penrose, has likely amplified the Penrose Effect over the last 30 years, with devastating social, economic, and healthcare consequences.

The science of medicine and the art of medicine: A student perspective on the U.S. medical education system.

This personal view about the overemphasis placed on United States Medical Licensing Examination scores and how the U.S. undergraduate medical education system currently assesses medical student competency is based on my personal experience as both a medical student and a hospitalized patient.

Alterations in White Matter Microstructure and Connectivity in Young Adults with Alcohol Use Disorder.

Background: Magnetic resonance imaging (MRI) studies have shown differences in volume and structure in the brains of individuals with alcohol use disorder (AUD). Most research has focused on neuropathological effects of alcohol that appear after years of chronic alcohol misuse. However, few studies have investigated white matter (WM) microstructure and diffusion MRI-based (DWI) connectivity during early stages of AUD.

Pharmacokinetic data of synthetic cathinones in female Sprague-Dawley rats.

The synthetic cathinones methylone, butylone, and pentylone differ from each other through the one carbon lengthening of the α-alkyl chain: methylone (-CH3), butylone (-CH2CH3), and pentylone (-CH2CH2CH3) while 3,4-methylenedioxymethamphetamine (MDMA) differs from methylone by a single oxygen atom. Studies with MDMA, suggests that there may be male and female pharmacokinetic and pharmacodynamic differences. In the present study, we present the plasma pharmacokinetic data relative to a 20 mg/kg, subcutaneous doses of methylone, butylone and pentylone in female Sprague-Dawley rats.

Impact of common clandestine structural modifications on synthetic cathinone "bath salt" pharmacokinetics.

Since 2009, the synthetic cathinones ("bath salts") have risen in popularity as drugs of abuse. However, there are a paucity of studies that have determined the impact of functional group modifications in the synthetic cathinone chemical structures on plasma and central nervous system (CNS) pharmacokinetics. In the present study, we investigated the in vivo plasma and CNS pharmacokinetics of three synthetic cathinones whose structures differ by lengthening of the α-alkyl chain: methylone (-CH), butylone (-CHCH), and pentylone (-CHCHCH).

Cooling down the bath salts: Carvedilol attenuation of methylone and mephedrone mediated hyperthermia.

The use of the synthetic cathinones ("bath salts"), methylone and mephedrone, has been associated with the development of life-threatening hyperthermia. To date, no direct pharmacological intervention to mitigate the hyperthermia induced by synthetic cathinones has been identified. Here, we investigated the effects of the non-selective α and β adrenergic receptor antagonist carvedilol (5mg/kg ip) on established hyperthermia mediated by methylone and mephedrone (30mg/kg sc) in Sprague-Dawley rats.

Impact of Functional Group Modifications on Designer Phenethylamine Induced Hyperthermia.

The popularity of designer phenethylamines such as synthetic cathinones ("bath salts") has led to increased reports of life-threatening hyperthermia. The diversity of chemical modifications has resulted in the toxicological profile of most synthetic cathinones being mostly uncharacterized. Here, we investigated the thermogenic effects of six recently identified designer phenethylamines (4-methylmethamphetamine, methylone, mephedrone, butylone, pentylone, and MDPV) and compared these effects to the established thermogenic agent 3,4-methylenedioxymethamphetamine (MDMA).