Morphine Exposure Research Articles

Differential Patterns of Synaptic Plasticity in the Nucleus Accumbens Caused by Continuous and Interrupted Morphine Exposure.

Opioid exposure and withdrawal both cause adaptations in brain circuits that may contribute to abuse liability. These adaptations vary in magnitude and direction following different patterns of opioid exposure, but few studies have systematically manipulated the pattern of opioid administration while measuring neurobiological impact. In this study, we compared cellular and synaptic adaptations in the nucleus accumbens shell caused by morphine exposure that was either continuous or interrupted by daily bouts of naloxone-precipitated withdrawal. At the behavioral level, continuous morphine administration caused psychomotor tolerance, which was reversed when the continuity of morphine action was interrupted by naloxone-precipitated withdrawal. Using ex vivo slice electrophysiology in female and male mice, we investigated how these patterns of morphine administration altered intrinsic excitability and synaptic plasticity of medium spiny neurons (MSNs) expressing the D1 or D2 dopamine receptor. We found that morphine-evoked adaptations at excitatory synapses were predominately conserved between patterns of administration, but there were divergent effects on inhibitory synapses and the subsequent balance between excitatory and inhibitory synaptic input. Overall, our data suggest that continuous morphine administration produces adaptations that dampen the output of D1-MSNs, which are canonically thought to promote reward-related behaviors. Interruption of otherwise continuous morphine exposure does not dampen D1-MSN functional output to the same extent, which may enhance behavioral responses to subsequent opioid exposure. Our findings support the hypothesis that maintaining continuity of opioid administration could be an effective therapeutic strategy to minimize the vulnerability to opioid use disorders.SIGNIFICANCE STATEMENT Withdrawal plays a key role in the cycle of addiction to opioids like morphine. We studied how repeated cycles of naloxone-precipitated withdrawal from otherwise continuous opioid exposure can change brain function of the nucleus accumbens, which is an important brain region for reward and addiction. Different patterns of opioid exposure caused unique changes in communication between neurons in the nucleus accumbens, and the nature of these changes depended on the type of neuron being studied. The specific changes in communication between neurons caused by repeated cycles of withdrawal may increase vulnerability to opioid use disorders. This highlights the importance of reducing or preventing the experience of withdrawal during opioid treatment.

Quality Improvement Targeting Non-pharmacologic Care and As-needed Morphine Improves Outcomes in Neonatal Abstinence Syndrome.

We developed a protocol for NAS treatment emphasizing early transfer to general pediatric units, maximization of non-pharmacologic care, and use of as-needed morphine whenever pharmacologic treatment is required. Outcome metrics were the day of life at discharge and cumulative morphine exposure. As a process measure, we also monitored the day of life at transfer to general pediatric units. In addition, we utilized statistical process control charts to track changes in performance. Twenty-eight patients met the inclusion criteria for analysis over 24 months following project initiation. Day of life at discharge decreased by 61% (20.0 versus 7.89 days, P < 0.001), and cumulative morphine exposure decreased by 81% (13.66 versus 2.57 mg morphine, P ≤ 0.001). Day of life at transfer to general pediatric units decreased by 49% (11.13 versus 5.7 days, P = 0.002). There were no readmissions or other identified adverse events. We achieved significant improvements in NAS outcomes using improved non-pharmacologic care and as-needed morphine. Moreover, the improvement did not require transitioning to a new scoring system. These results support the efficacy and safety of as-needed morphine for NAS management.

Effect of early embryonic exposure to morphine on defects in the GABAergic system of day-old chicks

Embryonic morphine exposure (EME) leads to abnormal brain development and behavior in the offspring, and the functional alteration of γ-aminobutyric acid (GABA) system is considered to be one of the important mechanisms. To mimic the problem of susceptibility of human gestational drug abuse on addictive drugs in offspring, we administered morphine exposure on days 5–8 and 13–16 of chicken embryo development and examined the functions of GABA neurons and their receptors in postnatal chicks by neuroelectrophysiology, immunohistochemistry and behavioral methods. We found that morphine exposure during embryonic stages 5–8 (MorphineE5–8) significantly reduced the incidence of spontaneous inhibitory postsynaptic potentiation (IPSP) and the induction of evoked IPSP and the mean amplitude of GABAA agonist muscimol-induced response in the intermediate medial interstitial (IMM) region, compared to naïve controls or saline-exposed chicks. The results of immunocytochemistry further suggest that MorphineE5–8 decreased the synaptic density of GAD-expressing sites in the IMM, while increased the expression of the GABAA receptor subtype γ2 isoform. Behavioral results found that Morphine5–8 treatment de-inhibited morphine-induced psychomotor responses in postnatal chicks. Morphine exposure at embryonic stages 13–16 (MorphineE13–16) showed no significant changes in the above indicators compared to the saline group. Evidence suggests that early embryonic morphine exposure leads to defects in GABAergic function in the IMM, which in turn alters the responsiveness of postnatal chicks to addictive drugs. These results will help to understand the GABA mechanisms by which embryonic addictive drug exposure contributes to offspring susceptibility to addiction.

Systems biology analyses reveal enhanced chronic morphine distortion of gut-brain interrelationships in simian human immunodeficiency virus infected rhesus macaques.

BackgroundCommonly used opioids, such as morphine have been implicated in augmented SIV/HIV persistence within the central nervous system (CNS). However, the extent of myeloid cell polarization and viral persistence in different brain regions remains unclear. Additionally, the additive effects of morphine on SIV/HIV dysregulation of gut-brain crosstalk remain underexplored. Therefore, studies focused on understanding how drugs of abuse such as morphine affect immune dynamics, viral persistence and gut-brain interrelationships are warranted.Materials and methodsFor a total of 9 weeks, rhesus macaques were ramped-up, and twice daily injections of either morphine (n = 4) or saline (n = 4) administered. This was later followed with infection with SHIVAD8EO variants. At necropsy, mononuclear cells were isolated from diverse brain [frontal lobe, cerebellum, medulla, putamen, hippocampus (HIP) and subventricular zone (SVZ)] and gut [lamina propria (LP) and muscularis (MUSC) of ascending colon, duodenum, and ileum] regions. Multiparametric flow cytometry was used to were profile for myeloid cell polarity/activation and results corroborated with indirect immunofluorescence assays. Simian human immunodeficiency virus (SHIV) DNA levels were measured with aid of the digital droplet polymerase chain reaction (PCR) assay. Luminex assays were then used to evaluate soluble plasma/CSF biomarker levels. Finally, changes in the fecal microbiome were evaluated using 16S rRNA on the Illumina NovaSeq platform.ResultsFlow Cytometry-based semi-supervised analysis revealed that morphine exposure led to exacerbated M1 (CD14/CD16)/M2 (CD163/CD206) polarization in activated microglia that spanned across diverse brain regions. This was accompanied by elevated SHIV DNA within the sites of neurogenesis–HIP and SVZ. HIP/SVZ CD16+ activated microglia positively correlated with SHIV DNA levels in the brain (r = 0.548, p = 0.042). Simultaneously, morphine dependence depleted butyrate-producing bacteria, including Ruminococcus (p = 0.05), Lachnospira (p = 0.068) genera and Roseburia_sp_831b (p = 0.068). Finally, morphine also altered the regulation of CNS inflammation by reducing the levels of IL1 Receptor antagonist (IL1Ra).ConclusionThese findings are suggestive that morphine promotes CNS inflammation by altering receptor modulation, increasing myeloid brain activation, distorting gut-brain crosstalk, and causing selective enhancement of SHIV persistence in sites of neurogenesis.

Normalization of the H3K9me2/H3K14ac-ΔFosB pathway in the nucleus accumbens underlying the reversal of morphine-induced behavioural and synaptic plasticity by Compound 511

BackgroundAlthough opioid agonist-based treatments are considered the first-line treatment for opioid use disorders, nonopioid alternatives are urgently needed to combat the inevitable high relapse rates. Compound 511 is a formula derived from ancient traditional Chinese medical literature on opiate rehabilitation. Previously, we observed that Compound 511 could effectively prevent the acquisition of conditioned place preference (CPP) during early morphine exposure. However, its effects on drug-induced reinstatement remain unclear. PurposeThis study aims to estimate the potential of Compound 511 for the therapeutic intervention of opioid relapse in rodent models and explore the potential mechanisms underlying the observed actions. Study design/MethodsThe CPP and locomotor sensitization paradigm were established to evaluate the therapeutic effect of Compound 511 treatment on morphine-induced neuroadaptations, followed by immunofluorescence and western blot (WB) analysis of the synaptic markers PSD-95 and Syn-1. Furthermore, several addiction-associated transcription factors and epigenetic marks were examined by qPCR and WB, respectively. Furthermore, the key active ingredients and targets of Compound 511 were further excavated by network pharmacology approach and experimental validation. ResultsThe results proved that Compound 511 treatment during abstinence blunted both the reinstatement of morphine-evoked CPP and locomotor sensitization, accompanied by the normalization of morphine-induced postsynaptic plasticity in the nucleus accumbens (NAc). Additionally, Compound 511 was shown to exert a selectively repressive influence on morphine-induced hyperacetylation at H3K14 and a reduction in H3K9 dimethylation as well as ΔFosB activation and accumulation in the NAc. Finally, two herbal ingredients of Compound 511 and six putative targets involved in the regulation of histone modification were identified. ConclusionOur findings indicated that Compound 511 could block CPP reinstatement and locomotor sensitization predominantly via the reversal of morphine-induced postsynaptic plasticity through epigenetic mechanisms. Additionally, 1-methoxy-2,3-methylenedioxyxanthone and 1,7-dimethoxyxanthone may serve as key ingredients of Compound 511 by targeting specific epigenetic enzymes. This study provided an efficient nonopioid treatment against opioid addiction.

Neonatal Morphine Results in Long-Lasting Alterations to the Gut Microbiome in Adolescence and Adulthood in a Murine Model.

Despite the many advancements in the field of pain management, the use of intravenous opioids, such as morphine, in neonates is still a challenge for clinicians and researchers, as the available evidence concerning the long-term consequences of such an early exposure is limited. In particular, little is known concerning the long-term consequences of neonatal morphine exposure on the gut microbiome, which has been identified as a key modulator of health and diseases. Consequently, the purpose of this study was to investigate those long-term consequences of neonatal morphine on the gut microbiome. Newborn mice were exposed to either morphine (5 mg/kg/day) or saline for a duration of 7 ± 2 days. Fecal samples were collected during adolescence and adulthood to longitudinally assess the gut microbiome. DNA extracted from the stool samples were sent out for 16s rRNA sequencing. During adolescence, neonatal morphine resulted in a significant increase of α-diversity and an overall decrease in the abundance of several commensal genera. During adulthood, β-diversity revealed a significantly different microbial composition of the neonatally morphine-exposed mice than that of the controls. The results demonstrate that morphine exposure during this critical developmental period resulted in long-lasting changes, particularly a reduction in several commensal bacteria. Thus, an adjunct therapeutic intervention with probiotics could potentially be used along with opioids to manage pain while attenuating the long-term co-morbidities of neonatal morphine later in life.

Perinatal Morphine Exposure Leads to Sex-Dependent Executive Function Deficits and Microglial Changes in Mice.

Children exposed prenatally to opioids are at an increased risk for behavioral problems and executive function deficits. The prefrontal cortex (PFC) and amygdala (AMG) regulate executive function and social behavior and are sensitive to opioids prenatally. Opioids can bind to toll-like receptor 4 (TLR4) to activate microglia, which may be developmentally important for synaptic pruning. Therefore, we tested the effects of perinatal morphine exposure on executive function and social behavior in male and female mouse offspring, along with microglial-related and synaptic-related outcomes. Dams were injected once daily subcutaneously with saline (n = 8) or morphine (MO; 10 mg/kg; n = 12) throughout pregestation, gestation, and lactation until offspring were weaned on postnatal day 21 (P21). Male MO offspring had impairments in attention and accuracy in the five-choice serial reaction time task, while female MO offspring were less affected. Targeted gene expression analysis at P21 in the PFC identified alterations in microglial-related and TLR4-related genes, while immunohistochemical analysis in adult brains indicated decreased microglial Iba1 and phagocytic CD68 proteins in the PFC and AMG in males, but females had an increase. Further, both male and female MO offspring had increased social preference. Overall, these data demonstrate male vulnerability to executive function deficits in response to perinatal opioid exposure and evidence for disruptions in neuron–microglial signaling.

Development of anxiety-like behaviors during adolescence: Persistent effects of adolescent morphine exposure in male rats.

Epidemiological studies show the prevalence of opioid use, misuse and abuse in adolescents, which imposes social and economic accountability worldwide. Chronic opioid exposure, especially in adolescents, may have lasting effects on emotional behaviors that persist into adulthood. The current experiments were therefore designed to study the effects of sustained opioid exposure during adolescence on anxiety-like behaviors. Adolescent male Wistar rats underwent increasing doses of morphine for 10 days (PNDs 31-40). After that the open field test (OFT) and elevated plus maze (EPM) test were performed over a 4-week postmorphine treatment from adolescence to adulthood. Moreover, the weight of the animals was measured at these time points. We found that chronic adolescent morphine exposure reduces the weight gain during the period of morphine treatment and 4 weeks after that. It had no significant effect on the locomotor activity in the animals. Moreover, anxiolytic-like behavior was observed in the rats exposed to morphine during adolescence evaluated by OFT and EPM test. Thus, long-term exposure to morphine during adolescence has the profound potential of altering the anxiety-like behavior profile in the period from adolescence to adulthood. The maturation of the nervous system can be affected by drug abuse during the developmental window of adolescence and these effects may lead to behaviorally stable alterations.

Independent actions by HIV-1 Tat and morphine to increase recruitment of monocyte-derived macrophages into the brain in a region-specific manner

Despite advances in the treatment of human immunodeficiency virus (HIV), approximately one-half of people infected with HIV (PWH) experience neurocognitive impairment. Opioid use disorder (OUD) can exacerbate the cognitive and pathological changes seen in PWH. HIV increases inflammation and immune cell trafficking into the brain; however, less is known about how opioid use disorder affects the recruitment of immune cells. Accordingly, we examined the temporal consequences of HIV-1 Tat and/or morphine on the recruitment of endocytic cells (predominantly perivascular macrophages and microglia) in the dorsal striatum and hippocampus by infusing multi-colored, fluorescently labeled dextrans before and after exposure. To address this question, transgenic mice that conditionally expressed HIV-1 Tat (Tat+), or their control counterparts (Tat−), received three sequential intracerebroventricular (i.c.v.) infusions of Cascade Blue-, Alexa Fluor 488-, and Alexa Fluor 594-labeled dextrans, respectively infused 1 day before, 1-day after, or 13-days after morphine and/or Tat exposure. At the end of the study, the number of cells labeled with each fluorescent dextran were counted. The data demonstrated a significantly higher influx of newly-labeled cells into the perivascular space than into the parenchyma. In the striatum, Tat or morphine exposure increased the number of endocytic cells in the perivascular space, while only morphine increased the recruitment of endocytic cells into the parenchyma. In the hippocampus, morphine (but not Tat) increased the influx of dextran-labeled cells into the perivascular space, but there were too few labeled cells within the hippocampal parenchyma to analyze. Collectively, these data suggest that HIV-1 Tat and morphine act independently to increase the recruitment of endocytic cells into the brain in a region-specific manner.

Dynamic modulation of inhibition ability following repeated exposures to morphine in macaque monkey.

Deficits in cognitive control, particularly inhibition ability, play crucial roles in susceptibility, progress, and relapse to opioid addiction. However, it is unclear when and how such deficits develop and interact with repeated exposures to prescribed opioids. Using macaque monkey (Macaca mulatta), as an animal model with high translational merits in cognitive neuroscience, we tried to delineate alterations of inhibition ability in the course of repeated exposures to morphine. Monkeys were trained to perform stop-signal task and then we closely monitored their inhibition ability before exposure, after initial exposure, and following repeated exposures to morphine when they experienced abstinent periods. We also assessed morphine-induced conditioned place preference (CPP) in these monkeys to monitor the long-lasting effects of morphine on other behaviors. Compared to the baseline level, monkeys' inhibition ability was significantly enhanced after initial exposure to morphine (early phase); however, it became significantly attenuated after repeated exposures (late phase). These alterations occurred while monkeys consistently expressed the morphine-induced CPP over the course of morphine exposure. Our findings indicate that repeated and scheduled exposures to morphine, which is akin to its clinical and recreational use, lead to dynamic alterations in primates' cognitive control depending on the extent of exposure. Enhancement of inhibition after limited exposure might provide opportunities to intervene and prevent the progress and culmination of opioid addiction, which is characterized by disinhibited drug-seeking and consumption.

A common SNP in Chrna5 enhances morphine reward in female mice

The single nucleotide polymorphism (SNP) D398N (rs16969968) in CHRNA5, the gene encoding the α5 subunit of the nicotinic acetylcholine receptors (nAChR), has been associated with both nicotine and opiate dependence in human populations. Expression of this SNP on presynaptic VTA dopaminergic (DA) neurons is known to cause a reduction in calcium signaling, leading to alterations in transmitter signaling and altered responses to drugs of abuse. To examine the impact of the Chrna5 SNP on opiate reward and underlying dopaminergic mechanisms, mice harboring two copies of the risk-associated allele (Chrna5 A/A) at a location equivalent to human rs16969968 were generated via CRISPR/cas9 genome editing. We sought to determine whether Chrna5 A/A mice show differences in sensitivity to rewarding properties of morphine using the conditioned place preference paradigm. When mice were tested two weeks after conditioning, female Chrna5 A/A mice showed significantly enhanced preference for the morphine-paired chamber relative to WT females, suggesting that this genotype may enhance opioid reward specifically in females. In contrast, Chrna5 genotype had no effect on locomotor sensitization in male or female mice. Relative to WT females, peak amplitude of ACh-gated currents recorded from VTA DA neurons in Chrna5 A/A females was potentiated 1 day after conditioning with morphine. Increased FOS expression was also observed in Chrna5 A/A mice relative to WT mice following exposure to the morphine CPP chamber. We propose that impaired α5 nAChR subunit function alters DA neuron response following repeated morphine exposures, and that this early cellular response could contribute to enhanced opiate reward two weeks after conditioning.

Prefrontal Cortex Response to Prenatal Insult and Postnatal Opioid Exposure.

The influence of proinflammatory challenges, such as maternal immune activation (MIA) or postnatal exposure to drugs of abuse, on brain molecular pathways has been reported. On the other hand, the simultaneous effects of MIA and drugs of abuse have been less studied and sometimes offered inconsistent results. The effects of morphine exposure on a pig model of viral-elicited MIA were characterized in the prefrontal cortex of males and females using RNA-sequencing and gene network analysis. Interacting and main effects of morphine, MIA, and sex were detected in approximately 2000 genes (false discovery rate-adjusted p-value < 0.05). Among the enriched molecular categories (false discovery rate-adjusted p-value < 0.05 and −1.5 > normalized enrichment score > 1.5) were the cell adhesion molecule pathways associated with inflammation and neuronal development and the long-term depression pathway associated with synaptic strength. Gene networks that integrate gene connectivity and expression profiles displayed the impact of morphine-by-MIA interaction effects on the pathways. The cell adhesion molecules and long-term depression networks presented an antagonistic effect between morphine and MIA. The differential expression between the double-challenged group and the baseline saline-treated Controls was less extreme than the individual challenges. The previous findings advance the knowledge about the effects of prenatal MIA and postnatal morphine exposure on the prefrontal cortex pathways.

Multi-chemokine receptor antagonist RAP-103 inhibits opioid-derived respiratory depression, reduces opioid reinforcement and physical dependence, and normalizes opioid-induced dysregulation of mesolimbic chemokine receptors in rats

Chemokine-opioid crosstalk is a physiological crossroads for influencing therapeutic and adverse effects of opioids. Activation of chemokine receptors, especially CCR2, CCR5 and CXCR4, reduces opioid-induced analgesia by desensitizing OPRM1 receptors. Chemokine receptor antagonists (CRAs) enhance opioid analgesia, but knowledge about how CRAs impact adverse opioid effects remains limited. We examined effects of RAP-103, a multi-CRA orally active peptide analog of “DAPTA”, on opioid-derived dependence, reinforcement, and respiratory depression in male rats and on changes in chemokine and OPRM1 (µ opioid) receptor levels in mesolimbic substrates during opioid abstinence. In rats exposed to chronic morphine (75 mg pellet x 7 d), daily RAP-103 (1 mg/kg, IP) treatment reduced the severity of naloxone-precipitated withdrawal responses. For self-administration (SA) studies, RAP-103 (1 mg/kg, IP) reduced heroin acquisition (0.1 mg/kg/inf) and reinforcing efficacy (assessed by motivation on a progressive-ratio reinforcement schedule) but did not impact sucrose intake. RAP-103 (1–3 mg/kg, IP) also normalized the deficits in oxygen saturation and enhancement of respiratory rate caused by morphine (5 mg/kg, SC) exposure. Abstinence from chronic morphine elicited brain-region specific changes in chemokine receptor protein levels. CCR2 and CXCR4 were increased in the ventral tegmental area (VTA), whereas CCR2 and CCR5 were reduced in the nucleus accumbens (NAC). Effects of RAP-103 (1 mg/kg, IP) were focused in the NAC, where it normalized morphine-induced deficits in CCR2 and CCR5. These results identify CRAs as potential biphasic function opioid signaling modulators to enhance opioid analgesia and inhibit opioid-derived dependence and respiratory depression.

Chronic Low Dose Morphine Does Not Alter Two In Vitro BBB Models.

The blood–brain barrier (BBB) mediates cellular and molecular passage between the central nervous system (CNS) and peripheral circulation. Compromised BBB integrity has been linked to neurocognitive deficits in multiple diseases and various infections, including those associated with HIV-1 infection. Understanding the impact of exposure to pharmaceuticals, such as those utilized for pain management by patients suffering from CNS disease, on BBB regulation and function is clinically important. In this study, we modelled two different BBB systems; a primary human co-culture and a cell line monoculture. These systems were both exposed to three daily repeat doses of morphine and examined for alterations to BBB integrity via permeability, PBMC transmigration, and chemokine gradient changes. We did not find any significant changes to either BBB system with repeat morphine dosing, suggesting that repeat morphine exposure may not play a significant role in BBB changes.

Progressive Degeneration and Adaptive Excitability in Dopamine D1 and D2 Receptor-Expressing Striatal Neurons Exposed to HIV-1 Tat and Morphine.

The striatum is especially vulnerable to HIV-1 infection, with medium spiny neurons (MSNs) exhibiting marked synaptodendritic damage that can be exacerbated by opioid use disorder. Despite known structural defects in MSNs co-exposed to HIV-1 Tat and opioids, the pathophysiological sequelae of sustained HIV-1 exposure and acute comorbid effects of opioids on dopamine D1 and D2 receptor-expressing (D1 and D2) MSNs are unknown. To address this question, Drd1-tdTomato- or Drd2-eGFP-expressing reporter and conditional HIV-1 Tat transgenic mice were interbred. MSNs in ex vivo slices from male mice were assessed by whole-cell patch-clamp electrophysiology and filled with biocytin to explore the functional and structural effects of progressive Tat and acute morphine exposure. Although the excitability of both D1 and D2 MSNs increased following 48h of Tat exposure, D1 MSN firing rates decreased below control (Tat-) levels following 2weeks and 1month of Tat exposure but returned to control levels after 2months. D2 neurons continued to display Tat-dependent increases in excitability at 2weeks, but also returned to control levels following 1 and 2months of Tat induction. Acute morphine exposure increased D1 MSN excitability irrespective of the duration of Tat exposure, while D2 MSNs were variably affected. That D1 and D2 MSN excitability would return to control levels was unexpected since both subpopulations displayed significant synaptodendritic degeneration and pathologic phospho-tau-Thr205 accumulation following 2months of Tat induction. Thus, despite frank morphologic damage, D1 and D2 MSNs uniquely adapt to sustained Tat and acute morphine insults.

Prenatal exposure to morphine enhances excitability in locus coeruleus neurons.

Opioid abuse during pregnancy may have noteworthy effects on the child's behavioral, emotional and cognitive progression. In this study, we assessed the effect of prenatal exposure to morphine on electrophysiological features of locus coeruleus (LC) noradrenergic neurons which is involved in modulating cognitive performance. Pregnant dams were randomly divided into two groups, that is a prenatal saline treated and prenatal morphine-treated group. To this end, ongestational days 11-18, either morphine or saline (twice daily, s.c.) was administered to pregnant dams. Whole-cell patch-clamp recordings were conducted on LC neurons of male offspring. The evoked firing rate, instantaneous frequency and action potentials half-width, and also input resistance of LC neurons significantly increased in the prenatal morphine group compared to the saline group. Moreover, action potentials decay slope, after hyperpolarization amplitude, rheobase current, and first spike latency were diminished in LC neurons following prenatal exposure to morphine. In addition, resting membrane potential, rise slope, and amplitude of action potentials were not changed by prenatal morphine exposure. Together, the current findings show a significant enhancement in excitability of the LC neurons following prenatal morphine exposure, which may affect the release of norepinephrine to other brain regions and/or cognitive performances of the offspring.

Prenatal Morphine Exposure Differentially Alters Addictive and Emotional Behavior in Adolescent and Adult Rats in a Sex-Specific Manner.

The effects of prenatal opioid exposure in adult animals has been widely studied, but little is known about the effects of prenatal opioid on adolescents. Most of the risk behaviors associated with drug abuse are initiated during adolescence. The developmental state of the adolescent brain makes it vulnerable to initiate drug use and susceptible to drug-induced brain changes. In this study, pregnant rats were subcutaneously injected with an increasing dose of morphine (5mg/kg, 7mg/kg, 10mg/kg) for 9 days since the gestation day 11. The effects of prenatal morphine (PNM) on learning and memory, anxiety- and depressive- like behavior, morphine induced conditioned place preference (CPP) as well as locomotor sensitization were tested in both adolescent and adult rats. The results showed that: (1) PNM decreased anxiety-like behavior in both adolescent and adult female rats, but not males; (2) PNM decreased depressive-like behavior in adolescent but increased depressive -like behavior in adult females; (3) PNM increased low dose morphine induced locomotor sensitization in females; (4) PNM decreased tyrosine hydroxylase (TH) expression in the prefrontal cortex but decreased dopamine D1 receptor expression in the nucleus-accumbens (NAc) in female rats. These results suggested that PNM altered the emotional and addictive behavior mainly in female rats, with female rats being less anxiety and depressive during adolescence, but more depressive in adult, and more sensitive to low dose morphine induced locomotor activity sensitization, which might be mediated in part by the differential expression of the TH, dopamine D1 receptors in the female brain.

HIV-1 Tat reduces apical dendritic spine density throughout the trisynaptic pathway in the hippocampus of male transgenic mice

Nearly one-third of persons infected with HIV-1 (PWH) develop HIV-associated neurocognitive disorders (HAND), which can be exacerbated by exposure to opioids. The impact of opioids on HIV-induced alterations in neuronal plasticity is less well understood. Both morphine exposure and HIV have been shown to disrupt synaptic growth and stability in the hippocampus suggesting a potential site of convergence for their deleterious effects. In the present study, we examined the density of dendritic spines in CA1 and CA3 pyramidal neurons, and granule neurons within the dentate gyrus representing the hippocampal trisynaptic pathway after short-term exposure to the HIV transactivator of transcription (Tat) protein and morphine. We exposed inducible male, HIV-1 Tat transgenic mice to escalating doses of morphine (10–40 mg/kg, b.i.d.) and examined synaptodendritic structure in Golgi-impregnated hippocampal neurons. HIV-1 Tat, but not morphine, systematically reduced the density of apical, but not basilar, dendrites of CA1 and CA3 pyramidal neurons, and granule neuronal apical dendrites, suggesting the coordinated loss of specific synaptic interconnections throughout the hippocampal trisynaptic pathway.

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

Neurodegeneration Within the Amygdala Is Differentially Induced by Opioid and HIV-1 Tat Exposure

Opioid use disorder (OUD) is a critical problem that contributes to the spread of HIV and may intrinsically worsen neuroHIV. Despite the advent of combined antiretroviral therapies (cART), about half of persons infected with HIV (PWH) experience cognitive and emotional deficits that can be exacerbated by opioid abuse. HIV-1 Tat is expressed in the central nervous system (CNS) of PWH on cART and is thought to contribute to neuroHIV. The amygdala regulates emotion and memories associated with fear and stress and is important in addiction behavior. Notwithstanding its importance in emotional saliency, the effects of HIV and opioids in the amygdala are underexplored. To assess Tat- and morphine-induced neuropathology within the amygdala, male Tat transgenic mice were exposed to Tat for 8 weeks and administered saline and/or escalating doses of morphine twice daily (s.c.) during the last 2 weeks of Tat exposure. Eight weeks of Tat exposure decreased the acoustic startle response and the dendritic spine density in the basolateral amygdala, but not the central nucleus of the amygdala. In contrast, repeated exposure to morphine alone, but not Tat, increased the acoustic startle response and whole amygdalar levels of amyloid-β (Aβ) monomers and oligomers and tau phosphorylation at Ser396, but not neurofilament light chain levels. Co-exposure to Tat and morphine decreased habituation and prepulse inhibition to the acoustic startle response and potentiated the morphine-induced increase in Aβ monomers. Together, our findings indicate that sustained Tat and morphine exposure differentially promote synaptodendritic degeneration within the amygdala and alter sensorimotor processing.