The Impact of Nonpharmacological Interventions on Opioid Use for Chronic Noncancer Pain: A Scoping Review.

Despite the lack of evidence, opioids are still routinely used as a solution to long-term management for chronic noncancer pain (CNCP). Given the significant risks associated with long-term opioid use, including the increased number of unregulated opioid pills at large in the opioid ecosystem, opioid cessation or reduction may be the desired goal of the patient and clinician. Viable nonpharmacological interventions (NPIs) to complement and/or replace opioids for CNCP are needed. Comprehensive reviews that address the impact of NPIs to help adults with CNCP reduce opioid use safely are lacking. We conducted a literature search in PubMed, CINAHL, Embase, PsycINFO, and Scopus for studies published in English. The initial search was conducted in April 2021, and updated in January 2024. The literature search yielded 19,190 relevant articles. Thirty-nine studies met the eligibility criteria and underwent data extraction. Of these, nineteen (49%) were randomized controlled trials, eighteen (46%) were observational studies, and two (5%) were secondary analyses. Among adults with CNCP who use opioids for pain management, studies on mindfulness, yoga, educational programs, certain devices or digital technology, chiropractic, and combination NPIs suggest that they might be an effective approach for reducing both pain intensity and opioid use, but other NPIs did not show a significant effect (e.g., hypnosis, virtual reality). This review revealed there is a small to moderate body of literature demonstrating that some NPIs might be an effective and safe approach for reducing pain and opioid use, concurrently.

Kismet/CHD7/CHD8 affects gut microbiota, mechanics, and the gut-brain axis in Drosophila melanogaster.

The gut microbiome affects brain and neuronal development and may contribute to the pathophysiology of neurodevelopmental disorders. However, it is unclear how risk genes associated with such disorders affect gut physiology in a manner that could impact microbial colonization and how the mechanical properties of the gut tissue might play a role in gut-brain bidirectional communication. To address this, we used Drosophila melanogaster with a null mutation in the gene kismet, an ortholog of chromodomain helicase DNA-binding protein (CHD) family members CHD7 and CHD8. In humans, these are risk genes for neurodevelopmental disorders with co-occurring gastrointestinal symptoms. We found that kismet mutant flies have a significant increase in gastrointestinal transit time, indicating the functional homology of kismet with CHD7/CHD8 in vertebrates. Rheological characterization of dissected gut tissue revealed significant changes in the mechanics of kismet mutant gut elasticity, strain stiffening behavior, and tensile strength. Using 16S rRNA metagenomic sequencing, we also found that kismet mutants have reduced diversity and abundance of gut microbiota at every taxonomic level. To investigate the connection between the gut microbiome and behavior, we depleted gut microbiota in kismet mutant and control flies and quantified the flies' courtship behavior. Depletion of gut microbiota rescued courtship defects of kismet mutant flies, indicating a connection between gut microbiota and behavior. In striking contrast, depletion of the gut microbiome in the control strain reduced courtship activity, demonstrating that antibiotic treatment can have differential impacts on behavior and may depend on the status of microbial dysbiosis in the gut prior to depletion. We propose that Kismet influences multiple gastrointestinal phenotypes that contribute to the gut-microbiome-brain axis to influence behavior. We also suggest that gut tissue mechanics should be considered as an element in the gut-brain communication loop, both influenced by and potentially influencing the gut microbiome and neurodevelopment.

Bisphenol F affects neurodevelopmental gene expression, mushroom body development, and behavior in Drosophila melanogaster.

Bisphenol F (BPF) is a potential neurotoxicant used as a replacement for bisphenol A (BPA) in polycarbonate plastics and epoxy resins. We investigated the neurodevelopmental impacts of BPF exposure using Drosophila melanogaster as a model. Our transcriptomic analysis indicated that developmental exposure to BPF caused the downregulation of neurodevelopmentally relevant genes, including those associated with synapse formation and neuronal projection. To investigate the functional outcome of BPF exposure, we evaluated neurodevelopmental impacts across two genetic strains of Drosophila- w1118 (control) and the Fragile X Syndrome (FXS) model-by examining both behavioral and neuronal phenotypes. We found that BPF exposure in w1118 Drosophila caused hypoactive larval locomotor activity, decreased time spent grooming by adults, reduced courtship activity, and increased the severity but not frequency of ß-lobe midline crossing defects by axons in the mushroom body. In contrast, although BPF reduced peristaltic contractions in FXS larvae, it had no impact on other larval locomotor phenotypes, grooming activity, or courtship activity. Strikingly, BPF exposure reduced both the severity and frequency of ß-lobe midline crossing defects in the mushroom body of FXS flies, a phenotype previously observed in FXS flies exposed to BPA. This data indicates that BPF can affect neurodevelopment and its impacts vary depending on genetic background. Further, BPF may elicit a gene-environment interaction with Drosophila fragile X messenger ribonucleoprotein 1 (dFmr1)-the ortholog of human FMR1, which causes fragile X syndrome and is the most common monogenetic cause of intellectual disability and autism spectrum disorder.

Biology Instructors See Value in Discussing Controversial Topics but Fear Personal and Professional Consequences.

Traditional biology curricula depict science as an objective field, overlooking the important influence that human values and biases have on what is studied and who can be a scientist. We can work to address this shortcoming by incorporating ideological awareness into the curriculum, which is an understanding of biases, stereotypes, and assumptions that shape contemporary and historical science. We surveyed a national sample of lower-level biology instructors to determine 1) why it is important for students to learn science, 2) the perceived educational value of ideological awareness in the classroom, and 3) hesitancies associated with ideological awareness implementation. We found that most instructors reported "understanding the world" as the main goal of science education. Despite the perceived value of ideological awareness, such as increasing student engagement and dispelling misconceptions, instructors were hesitant to implement ideological awareness modules due to potential personal and professional consequences.

Evaluating Learning and Memory in Drosophila melanogaster to Study the Neurodevelopmental Impacts of Toxicants.

Neurodevelopmental disorders are a heterogeneous group of behaviorally defined disorders with both genetic and environmental risk factors. Given that many neurodevelopmental disorders are characterized by impaired learning and/or intellectual abilities, behavioral paradigms that assess cognition in animal models have been effective tools in delineating underlying genetic variants that impact disease pathophysiology. For example, learning and memory paradigms in the common fruit fly Drosophila melanogaster have been successfully used to study risk genes and biological pathways associated with several neurodevelopmental disorders, including fragile X syndrome, autism spectrum disorder, and CHARGE syndrome. While these established Drosophila behavioral paradigms have historically been used to investigate genetic risk factors, they also have many other applications, including use in developmental neurotoxicology studies to determine environmental risk factors for neurodevelopmental disorders. There is, however, a deficit of step-by-step protocols that describe how to apply learning and memory assays in fruit flies to developmental neurotoxicology studies. Here, we describe two quantitative behavioral paradigms for Drosophila-predator-induced oviposition and courtship conditioning-that can be used to measure different forms of learning and memory in the context of a developmental neurotoxicology study. Non-associative learning and memory are measured here by examining female Drosophila oviposition behavior in response to endoparasitoid wasps, while associative learning and memory are measured in males using courtship conditioning. Our protocols outline procedures for oral toxicant exposure of developing fruit flies, culturing of endoparasitoid wasps, measuring Drosophila oviposition activity, and assessing conditioned courtship in order to identify the impact of toxicants on learning and memory in both females and males. As an example, we present the protocols using bisphenol A, a chemical utilized in the synthesis of polycarbonate plastics, to determine its impacts on learning and memory. These protocols are inexpensive and relatively simple to perform, and can be used by labs that are new to Drosophila behavioral research to evaluate how toxicant exposure influences learning and memory in male and female flies. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Preparation of toxicant-containing food and developmental exposure Basic Protocol 2: Predator-induced oviposition assay Support Protocol: Culture of Leptopilina heterotoma Basic Protocol 3: Conditioned courtship assay.

Does Bisphenol A Confer Risk of Neurodevelopmental Disorders? What We Have Learned from Developmental Neurotoxicity Studies in Animal Models.

Substantial evidence indicates that bisphenol A (BPA), a ubiquitous environmental chemical used in the synthesis of polycarbonate plastics and epoxy resins, can impair brain development. Clinical and epidemiological studies exploring potential connections between BPA and neurodevelopmental disorders in humans have repeatedly identified correlations between early BPA exposure and developmental disorders, such as attention deficit/hyperactivity disorder and autism spectrum disorder. Investigations using invertebrate and vertebrate animal models have revealed that developmental exposure to BPA can impair multiple aspects of neuronal development, including neural stem cell proliferation and differentiation, synapse formation, and synaptic plasticity-neuronal phenotypes that are thought to underpin the fundamental changes in behavior-associated neurodevelopmental disorders. Consistent with neuronal phenotypes caused by BPA, behavioral analyses of BPA-treated animals have shown significant impacts on behavioral endophenotypes related to neurodevelopmental disorders, including altered locomotor activity, learning and memory deficits, and anxiety-like behavior. To contextualize the correlations between BPA and neurodevelopmental disorders in humans, this review summarizes the current literature on the developmental neurotoxicity of BPA in laboratory animals with an emphasis on neuronal phenotypes, molecular mechanisms, and behavioral outcomes. The collective works described here predominantly support the notion that gestational exposure to BPA should be regarded as a risk factor for neurodevelopmental disorders.

Bisphenol a affects neurodevelopmental gene expression, cognitive function, and neuromuscular synaptic morphology in Drosophila melanogaster.

Bisphenol A (BPA) is an environmentally prevalent endocrine disrupting chemical that can impact human health and may be an environmental risk factor for neurodevelopmental disorders. BPA has been associated with behavioral impairment in children and a variety of neurodevelopmental phenotypes in model organisms. We used Drosophila melanogaster to explore the consequences of developmental BPA exposure on gene expression, cognitive function, and synapse development. Our transcriptome analysis indicated neurodevelopmentally relevant genes were predominantly downregulated by BPA. Among the misregulated genes were those with roles in learning, memory, and synapse development, as well as orthologs of human genes associated with neurodevelopmental and neuropsychiatric disorders. To examine how gene expression data corresponded to behavioral and cellular phenotypes, we first used a predator-response behavioral paradigm and found that BPA disrupts visual perception. Further analysis using conditioned courtship suppression showed that BPA impairs associative learning. Finally, we examined synapse morphology within the larval neuromuscular junction and found that BPA significantly increased the number of axonal branches. Given that our findings align with studies of BPA in mammalian model organisms, this data indicates that BPA impairs neurodevelopmental pathways that are functionally conserved from invertebrates to mammals. Further, because Drosophila do not possess classic estrogen receptors or estrogen, this research suggests that BPA can impact neurodevelopment by molecular mechanisms distinct from its role as an estrogen mimic.

Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes.

The developing nervous system is remarkably sensitive to environmental signals, including disruptive toxins, such as polybrominated diphenyl ethers (PBDEs). PBDEs are an environmentally pervasive class of brominated flame retardants whose neurodevelopmental toxicity mechanisms remain largely unclear. Using dissociated cortical neurons from embryonic Rattus norvegicus, we found here that chronic exposure to 6-OH-BDE-47, one of the most prevalent hydroxylated PBDE metabolites, suppresses both spontaneous and evoked neuronal electrical activity. On the basis of our previous work on mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) (MEK) biology and our observation that 6-OH-BDE-47 is structurally similar to kinase inhibitors, we hypothesized that certain hydroxylated PBDEs mediate neurotoxicity, at least in part, by impairing the MEK-ERK axis of MAPK signal transduction. We tested this hypothesis on three experimental platforms: 1) in silico, where modeling ligand-protein docking suggested that 6-OH-BDE-47 is a promiscuous ATP-competitive kinase inhibitor; 2) in vitro in dissociated neurons, where 6-OH-BDE-47 and another specific hydroxylated BDE metabolite similarly impaired phosphorylation of MEK/ERK1/2 and activity-induced transcription of a neuronal immediate early gene; and 3) in vivo in Drosophila melanogaster, where developmental exposures to 6-OH-BDE-47 and a MAPK inhibitor resulted in offspring displaying similarly increased frequency of mushroom-body ß-lobe midline crossing, a metric of axonal guidance. Taken together, our results support that certain ortho-hydroxylated PBDE metabolites are promiscuous kinase inhibitors and can cause disruptions of critical neurodevelopmental processes, including neuronal electrical activity, pre-synaptic functions, MEK-ERK signaling, and axonal guidance.

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry.

Mounting evidence indicates that Wnt signaling is relevant to pathophysiology of diverse mental illnesses including schizophrenia, bipolar disorder, and autism spectrum disorder. In the 35 years since Wnt ligands were first described, animal studies have richly explored how downstream Wnt signaling pathways affect an array of neurodevelopmental processes and how their disruption can lead to both neurological and behavioral phenotypes. Recently, human induced pluripotent stem cell (hiPSC) models have begun to contribute to this literature while pushing it in increasingly translational directions. Simultaneously, large-scale human genomic studies are providing evidence that sequence variation in Wnt signal pathway genes contributes to pathogenesis in several psychiatric disorders. This article reviews neurodevelopmental and postneurodevelopmental functions of Wnt signaling, highlighting mechanisms, whereby its disruption might contribute to psychiatric illness, and then reviews the most reliable recent genetic evidence supporting that mutations in Wnt pathway genes contribute to psychiatric illness. We are proponents of the notion that studies in animal and hiPSC models informed by the human genetic data combined with the deep knowledge base and tool kits generated over the last several decades of basic neurodevelopmental research will yield near-term tangible advances in neuropsychiatry.

Enhanced Glucose Transport, but not Phosphorylation Capacity, Ameliorates Lipopolysaccharide-Induced Impairments in Insulin-Stimulated Muscle Glucose Uptake.

Lipopolysaccharide (LPS) is known to impair insulin-stimulated muscle glucose uptake (MGU). We determined if increased glucose transport (GLUT4) or phosphorylation capacity (hexokinase II; HKII) could overcome the impairment in MGU. We used mice that overexpressed GLUT4 (GLUT4) or HKII (HK) in skeletal muscle. Studies were performed in conscious, chronically catheterized (carotid artery and jugular vein) mice. Mice received an intravenous bolus of either LPS (10 µg/g body weight) or vehicle (VEH). After 5 h, a hyperinsulinemic-euglycemic clamp was performed. As MGU is also dependent on cardiovascular function that is negatively affected by LPS, cardiac function was assessed using echocardiography. LPS decreased whole body glucose disposal and MGU in wild-type (WT) and HK mice. In contrast, the decrease was attenuated in GLUT4 mice. Although membrane-associated GLUT4 was increased in VEH-treated GLUT4 mice, LPS impaired membrane-associated GLUT4 in GLUT4 mice to the same level as LPS-treated WT mice. This suggested that overexpression of GLUT4 had further benefits beyond preserving transport activity. In fact, GLUT4 overexpression attenuated the LPS-induced decrease in cardiac function. The maintenance of MGU in GLUT4 mice following LPS was accompanied by sustained anaerobic glycolytic flux as suggested by increased muscle Pdk4 expression, and elevated lactate availability. Thus, enhanced glucose transport, but not phosphorylation capacity, ameliorates LPS-induced impairments in MGU. This benefit is mediated by long-term adaptations to the overexpression of GLUT4 that sustain muscle anaerobic glycolytic flux and cardiac function in response to LPS.

Liver, but not muscle, has an entrainable metabolic memory.

Hyperglycemia in the hospitalized setting is common, especially in patients that receive nutritional support either continuously or intermittently. As the liver and muscle are the major sites of glucose disposal, we hypothesized their metabolic adaptations are sensitive to the pattern of nutrient delivery. Chronically catheterized, well-controlled depancreatized dogs were placed on one of three isocaloric diets: regular chow diet once daily (Chow) or a simple nutrient diet (ND) that was given either once daily (ND-4) or infused continuously (ND-C). Intraportal insulin was infused to maintain euglycemia. After 5 days net hepatic (NHGU) and muscle (MGU) glucose uptake and oxidation were assessed at euglycemia (120 mg/dl) and hyperglycemia (200 mg/dl) in the presence of basal insulin. While hyperglycemia increased both NHGU and MGU in Chow, NHGU was amplified in both groups receiving ND. The increase was associated with enhanced activation of glycogen synthase, glucose oxidation and suppression of pyruvate dehydrogenase kinase-4 (PDK-4). Accelerated glucose-dependent muscle glucose uptake was only evident with ND-C. This was associated with a decrease in PDK-4 expression and an increase in AMP-activated protein kinase (AMPK) phosphorylation. Interestingly, ND-C markedly increased hepatic FGF-21 expression. Thus, augmentation of carbohydrate disposal in the liver, as opposed to the muscle, is not dependent on the pattern of nutrient delivery.

A liver Hif-2α-Irs2 pathway sensitizes hepatic insulin signaling and is modulated by Vegf inhibition.

Insulin initiates diverse hepatic metabolic responses, including gluconeogenic suppression and induction of glycogen synthesis and lipogenesis. The liver possesses a rich sinusoidal capillary network with a higher degree of hypoxia and lower gluconeogenesis in the perivenous zone as compared to the rest of the organ. Here, we show that diverse vascular endothelial growth factor (VEGF) inhibitors improved glucose tolerance in nondiabetic C57BL/6 and diabetic db/db mice, potentiating hepatic insulin signaling with lower gluconeogenic gene expression, higher glycogen storage and suppressed hepatic glucose production. VEGF inhibition induced hepatic hypoxia through sinusoidal vascular regression and sensitized liver insulin signaling through hypoxia-inducible factor-2α (Hif-2α, encoded by Epas1) stabilization. Notably, liver-specific constitutive activation of HIF-2α, but not HIF-1α, was sufficient to augment hepatic insulin signaling through direct and indirect induction of insulin receptor substrate-2 (Irs2), an essential insulin receptor adaptor protein. Further, liver Irs2 was both necessary and sufficient to mediate Hif-2α and Vegf inhibition effects on glucose tolerance and hepatic insulin signaling. These results demonstrate an unsuspected intersection between Hif-2α-mediated hypoxic signaling and hepatic insulin action through Irs2 induction, which can be co-opted by Vegf inhibitors to modulate glucose metabolism. These studies also indicate distinct roles in hepatic metabolism for Hif-1α, which promotes glycolysis, and Hif-2α, which suppresses gluconeogenesis, and suggest new treatment approaches for type 2 diabetes mellitus.

Wnt signaling in vertebrate neural development and function.

Members of the Wnt family of secreted signaling proteins influence many aspects of neural development and function. Wnts are required from neural induction and axis formation to axon guidance and synapse development, and even help modulate synapse activity. Wnt proteins activate a variety of downstream signaling pathways and can induce a similar variety of cellular responses, including gene transcription changes and cytoskeletal rearrangements. This review provides an introduction to Wnt signaling pathways and discusses current research on their roles in vertebrate neural development and function.

Disassociation of muscle insulin signaling and insulin-stimulated glucose uptake during endotoxemia.

Lipopolysaccharide (LPS) elicits a strong immune response, which leads to the release of inflammatory cytokines. Increased cytokine production has been shown to impair insulin-mediated glucose disposal. LPS can alter other factors, such as muscle blood flow and insulin signaling in the myocyte, that can influence glucose disposal. We hypothesize that LPS induced impairments in cardiovascular function contribute to the associated impairments in insulin action in vivo. Male wild-type C57BL/6J mice had a catheter implanted in the jugular vein for infusions and the carotid artery for sampling 5 days prior to the hyperinsulinemic-euglycemic clamp. Mice were treated with vehicle, low- (1 ug/gBW) or high-dose (10 ug/gBW) LPS 4 hours prior to the clamp. Muscle glucose uptake (MGU) was assessed using [2-(14)C] deoxyglucose. While both low- and high-dose LPS inhibited insulin-stimulated MGU compared to vehicle-treated mice, the impairment was more significant with the high-dose treatment (∼25% in soleus and ∼70% in both gastrocnemius and vastus lateralis). Interestingly, insulin signaling through the PI3-kinase pathway in the muscle was not affected by this treatment suggesting that the decrease in MGU is not directly due to impairments in muscle insulin action. Echocardiography demonstrated that high-dose LPS treatment significantly decreased stroke volume (∼30%), heart rate (∼35%), and cardiac output (∼50%). These observations were not seen with vehicle or low-dose LPS treatment. High-dose LPS treatment also significantly decreased muscle blood flow (∼70%) and whole body oxygen consumption (∼50%). Thus, in vivo acute endotoxemia does not impair insulin signaling through the PI3-kinase pathway in skeletal muscle and decreased tissue blood flow likely plays a central role in the impairment of glucose uptake in the muscle.

Secreted Wingless-interacting molecule (Swim) promotes long-range signaling by maintaining Wingless solubility.

Lipid-modified Wnt/Wingless (Wg) proteins can signal to their target cells in a short- or long-range manner. How these hydrophobic proteins travel through the extracellular environment remains an outstanding question. Here, we report on a Wg binding protein, Secreted Wg-interacting molecule (Swim), that facilitates Wg diffusion through the extracellular matrix. Swim, a putative member of the Lipocalin family of extracellular transport proteins, binds to Wg with nanomolar affinity in a lipid-dependent manner. In quantitative signaling assays, Swim is sufficient to maintain the solubility and activity of purified Wg. In Drosophila, swim RNAi phenotypes resemble wg loss-of-function phenotypes in long-range signaling. We propose that Swim is a cofactor that promotes long-range Wg signaling in vivo by maintaining the solubility of Wg.

Metabolic response to endotoxin in vivo in the conscious mouse: role of interleukin-6.

Inflammation and insulin resistance are characteristics of endotoxemia. Although the role of interleukin (IL)-6 in insulin-resistant states has been characterized, little is known of its role in the metabolic response to inflammation. To study the role of IL-6, conscious chronically catheterized mice were used. Five days before being studied, catheters were implanted in the carotid artery and jugular vein. After a 5-hour fast, Escherichia coli (250 µg per mouse) lipopolysaccharide (LPS) was injected in IL-6⁻/⁻ (KO, n = 13) and IL-6+/+ (WT, n = 10) littermates. The IL-6 response to LPS was simulated in an additional group of KO mice (KO + IL-6, n = 10). Interleukin-6 increased in WT (15 ± 0.7 ng/mL) 4 hours after LPS and was undetectable in KO. Interleukin-6 replacement in the KO restored circulating IL-6 to levels observed in the WT group (14 ± 0.3 ng/mL). Tumor necrosis factor-α increased more rapidly in WT than in both KO and KO + IL-6 mice. The KO mice exhibited a more profound glucose excursion 30 minutes after LPS injection and no apparent hypoglycemia at 4 hours (95 ± 5 vs 70 ± 8 mg/dL, KO vs WT), despite having a blunted glucagon and epinephrine response. Glucose levels in KO + IL-6 mice, while decreased (93 ± 4 mg/dL) at 4 hours, remained higher than those in WT mice. In summary, the absence of IL-6 protected against LPS-induced hypoglycemia. Acute restoration of the IL-6 response to LPS did not potentiate hypoglycemia but partially restored the glucagon response. Thus, although IL-6 promotes glucose intolerance in insulin-resistant states, IL-6 promotes hypoglycemia during acute inflammation.