Withdrawal Signs Research Articles

Predicting Heterogeneity in Patient Response to Morphine Treatment for Neonatal Opioid Withdrawal Syndrome.

Infants with neonatal opioid withdrawal syndrome (NOWS) commonly receive morphine treatment to manage their withdrawal signs. However, the effectiveness of this pharmacotherapy in managing the infants' withdrawal signs varies widely. We sought to understand how information available early in infant monitoring can anticipate this treatment response, focusing on early modified Finnegan Neonatal Abstinence Scoring System (FNASS) scores, polygenic risk for opioid dependence (polygenic risk score, PRS), and drug exposure. Using k-means clustering, we divided the 213 infants in our cohort into 3 groups based on their FNASS scores in the 12 hours before and after the initiation of pharmacotherapy. We found that these groups were pairwise significantly different for risk factors, including methadone exposure, and for in-hospital outcomes, including total morphine received, length of stay, and highest FNASS score. While PRS was not predictive of receipt of treatment, PRS was pairwise significantly different between a subset of the groups. Using tree-based machine learning methods, we then constructed network graphs of the relationships between these groups, FNASS scores, PRS, drug exposures, and in-hospital outcomes. The resulting networks also showed meaningful connection between early FNASS scores and PRS, as well as between both of those and later in-hospital outcomes. These analyses present clinicians with the opportunity to better anticipate infant withdrawal progression and prepare accordingly, whether with expedited morphine treatment or non-pharmacotherapeutic alternative treatments.

Differential roles of diacylglycerol lipase (DAGL) enzymes in nicotine withdrawal

Nicotine and tobacco-related deaths remains a leading cause of preventable death and disease in the United States. Several studies indicate that modulation of the endocannabinoid system, primarily of the endocannabinoid 2-Arachidonoylglycerol (2-AG), alters nicotinic dependence behaviors in rodents. This study, using transgenic knock-out (KO) mice, evaluated the role of the two 2-AG biosynthesis enzymes, (Diacylglycerol lipase-α) DAGL-α and DAGL-β in spontaneous nicotine withdrawal. DAGL-α deletion prevents somatic and affective signs of nicotine withdrawal, while DAGL-β deletion plays a role in hyperalgesia due to nicotine withdrawal. These results suggest a differential role of these enzymes in the various signs of nicotine withdrawal. Our behavioral findings relate to the distribution of these enzymes with DAGL-β being highly expressed in macrophages and DAGL-α in neurons. This study offers new potential targets for smoking cessation therapies.

Seeking the origins of psychic and social withdrawals: warning signs in the observations of young children

ABSTRACT The authors hypothesize that the child's psychic withdrawal is a potential precursor to the social withdrawal called ‘hikikomori’, a phenomenon frequently observed among adolescents and young adults. They also hypothesize a continuum between psychic withdrawal, social withdrawal and the ‘psychic retreats’ by John Steiner. The authors investigate very early psychic withdrawal and its potential link to the development of social withdrawal. Two observations collected using the Infant Observation and Young Child Observation method provided essential support. Children with premonitory signs of psychic withdrawal observed when they were very young were contacted years later for new observations. The aim was to test the hypothesis that the mental and social functioning mechanisms observed were maintained over time, hindering the children's lines of development. In both cases, it is shown that over the years, precursor signs of mental withdrawal can be traced in the non-spontaneous modes of interaction with peers, with an adaptation to the environment that, especially in a child, seems to rely on the family context and home to avoid contact with others. The article provides clues as to how psychic withdrawal fuels social withdrawal and can contribute to the construction of internal personality organizations that lead to self-reclusion called hikikomori.

Distinctive roles of L-type calcium channels subtypes within the dorsal hippocampus in formation of morphine withdrawal-induced aversion in rats

Although the negative effects coming along with opiate withdrawal are in part modulated by L-type calcium channels (LTCCs), the distinctive physiological properties and functions of LTCCs subtypes suggest differential roles of subtypes during withdrawal. The present study aimed to examine the contributions of LTCC subtypes, Cav1.2 and Cav1.3, within the dorsal hippocampus (DH) in naloxone-precipitated morphine withdrawal using the conditioned place aversion (CPA) paradigm. Firstly, we injected the non-specific LTCCs antagonist verapamil into the DH of morphine-dependent rats before conditioning an environment with naloxone-precipitated withdrawal. Our results showed that verapamil blocked the acquisition of CPA. Then, to explore the molecular mechanisms of LTCCs subtypes during withdrawal, we measured the protein expression of Cav1.2 and Cav1.3 in morphine-dependent rats under different conditions. In morphine-dependent rats, conditioning with withdrawal increased Cav1.2 expression in the membrane, while only acute naloxone injection increased the membrane expression of Cav1.3. To further determine the causal roles of LTCCs subtypes in the withdrawal process, we used Cav1.2 siRNA or Cav1.3 shRNA to knock down the expression of subtypes and detected the effects on CPA and somatic withdrawal signs in morphine-dependent rats. Cav1.2 siRNA, but not Cav1.3 shRNA, inhibited the acquirement of CPA and relieved somatic withdrawal symptoms. Together, our findings reveal that Cav1.2, but not Cav1.3 plays an important role in mediating morphine withdrawal, suggesting this subtype may serve as a potential therapeutic target for the treatment of negative effects in opiate dependence.

Inhibition of dorsal raphe GABAergic neurons blocks hyperalgesia during heroin withdrawal

Opioid withdrawal signs, such as hyperalgesia, are manifestations of opioid use disorder that may contribute to opioid seeking and taking. We have previously identified an association between dorsal raphe (DR) neurons and the expression of hyperalgesia during spontaneous heroin withdrawal. Here, we found that chemogenetic inhibition of DR neurons decreased hyperalgesia during spontaneous heroin withdrawal in male and female C57/B6 mice. By neuroanatomy, we identified three major subtypes of DR neurons expressing μ-opioid receptors (MOR) that were activated in hyperalgesia during spontaneous withdrawal, those expressing vesicular GABA transporter (VGaT), glutamate transporter 3 (VGluT3), or co-expressing VGluT3 and tryptophan hydroxylase (TPH). In contrast, we identified a small population of DR-MOR neurons expressing solely TPH, which were not activated in hyperalgesia during spontaneous withdrawal. Collectively, these findings indicate a role of the DR in hyperalgesia during spontaneous heroin withdrawal mediated, in part, by the activation of local MOR-GABAergic, MOR-glutamatergic and MOR-co-releasing glutamatergic-serotonergic neurons. We found that specific chemogenetic inhibition of DR-VGaT neurons blocked hyperalgesia during spontaneous heroin withdrawal in male and female mice. Collectively, these findings indicate that DR-GABAergic neurons play a role in the expression of hyperalgesia during spontaneous heroin withdrawal.

Assessment of the physical dependence potential of difelikefalin: randomized placebo-controlled study in patients receiving hemodialysis.

Difelikefalin is a selective kappa opioid receptor agonist approved for treating moderate-to-severe pruritus in adults undergoing hemodialysis (HD). Difelikefalin is not a controlled substance under the Controlled Substances Act. This study assessed the potential for developing physical dependence on difelikefalin in patients undergoing HD. Eligible patients received open-label difelikefalin after each dialysis session for 3 weeks before entering a 2-week double-blind phase, when they were randomized to either continue difelikefalin or to switch to receiving placebo. Signs of physical withdrawal were assessed using the Clinical Opiate Withdrawal Scale (COWS), several patient-reported scales, and physiological measures. The primary endpoint was the between-group difference in mean maximum COWS total scores during the double-blind phase; the mean difference (placebo - difelikefalin) was compared against a pre-defined noninferiority limit (+4). Thirty-five patients (57.1% male; 91.4% Black or African American; median [range] age 58 [28-77] years) were included, of which 30 were randomized (placebo, n=14; difelikefalin, n=16). The least square mean difference in maximum COWS total scores was 0.52 (95% confidence interval [CI]: -0.56, 1.59). The upper CI limit (1.59) was below +4, indicating that patients who discontinued difelikefalin (placebo group) had similar withdrawal scores to patients who continued difelikefalin. Additional assessments supported the COWS results, showing no meaningful differences between groups in physiological measures or in patient-reported measures of sleep or physical withdrawal. These results demonstrate that abruptly discontinuing chronic difelikefalin treatment in patients undergoing HD does not produce signs or symptoms of physical withdrawal.

Suvorexant, an FDA-approved dual orexin receptor antagonist, reduces oxycodone self-administration and conditioned reinstatement in male and female rats.

Background: The Department of Health and Human Services reports that prescription pain reliever (e.g., oxycodone) misuse was initiated by 4,400 Americans each day in 2019. Amid the opioid crisis, effective strategies to prevent and treat prescription opioid use disorder (OUD) are pressing. In preclinical models, the orexin system is recruited by drugs of abuse, and blockade of orexin receptors (OX receptors) prevents drug-seeking behavior. The present study sought to determine whether repurposing suvorexant (SUV), a dual OX receptor antagonist marketed for the treatment of insomnia, can treat two features of prescription OUD: exaggerated consumption and relapse. Methods: Male and female Wistar rats were trained to self-administer oxycodone (0.15mg/kg, i. v., 8h/day) in the presence of a contextual/discriminative stimulus (SD) and the ability of SUV (0-20mg/kg, p. o.) to decrease oxycodone self-administration was tested. After self-administration testing, the rats underwent extinction training, after which we tested the ability of SUV (0 and 20mg/kg, p. o.) to prevent reinstatement of oxycodone seeking elicited by the SD. Results: The rats acquired oxycodone self-administration and intake was correlated with the signs of physical opioid withdrawal. Additionally, females self-administered approximately twice as much oxycodone as males. Although SUV had no overall effect on oxycodone self-administration, scrutiny of the 8-h time-course revealed that 20mg/kg SUV decreased oxycodone self-administration during the first hour in males and females. The oxycodone SD elicited strong reinstatement of oxycodone-seeking behavior that was significantly more robust in females. Suvorexant blocked oxycodone seeking in males and reduced it in females. Conclusions: These results support the targeting of OX receptors for the treatment for prescription OUD and repurposing SUV as pharmacotherapy for OUD.

L-theanine attenuates nicotine reward and withdrawal signs in mice

BackgroundL-theanine, 2-amino-4-(ethylcarbamoyl) butyric acid, an amino acid detected in green tea leaves, is used as a dietary supplement to attenuate stress and enhance mood and cognition. Furthermore, L-theanine induces anxiolytic effects in humans. Recently, L-theanine was reported to reduce morphine physical dependence in primates, suggesting the potential usefulness of L-theanine for drug dependence intervention. ObjectiveThe aim of this study is to determine whether L-theanine attenuates nicotine-withdrawal (somatic and affective signs) and nicotine reward in mice. We also investigated the effects of L-theanine on nicotinic receptors binding and function. MethodsICR male mice rendered dependent to nicotine through implanted subcutaneous osmotic minipumps for 14 days undertook precipitated nicotine withdrawal by mecamylamine on day 15. Anxiety-like behaviors using LDB, somatic signs observation and hot plate latency were assessed consecutively after treatment with L-theanine. Furthermore, we examined the effect of L-theanine on acute nicotine responses and nicotine conditioned reward in mice and on expressed nicotinic receptors in oocytes. Key findingsL-theanine reduced in a dose-dependent manner anxiety-like behavior, hyperalgesia and somatic signs during nicotine withdrawal. Also, L-theanine decreased the nicotine CPP, but it did not affect the acute responses of nicotine. Finally, L-theanine did not alter the binding or the function of expressed α4β2 and α7 nAChRs. ConclusionOur results support the potential of L-theanine as a promising candidate for treating nicotine dependence.

Social Withdrawal in Preschool Age: A Clinical Case in Intensive Psychoanalytic Psychotherapy.

In this work, we suggest that children's social withdrawal might be a precursor of Hikikomori, a phenomenon observed among adolescents and young adults. Hence, psychotherapy interventions with preschool children showing signs of social withdrawal might play a critical role in Hikikomori prevention. This paper presents the case of a five-year-old child treated with intensive psychoanalytic psychotherapy who began therapy due to his refusing to go to school and exhibiting isolating behavior from other children. Among other symptoms were regression, emotional tension, nightmares, and nocturnal and diurnal enuresis. Moreover, the relationship in the family was difficult, both between the parents and between the parent and the child. The intensive psychoanalytic treatment involved three weekly sessions for about a year, followed by six months with one weekly session. Besides illustrating the therapeutic process through clinical vignettes taken from the sessions, this paper also provides clues on how early social withdrawal can contribute to the construction of internal personality organizations that lead to social withdrawal up to self-reclusion (or Hikikomori).

Cannabidiol regulates behavioral and brain alterations induced by spontaneous alcohol withdrawal

The main goal of this study was to evaluate if the administration of cannabidiol (CBD) regulates behavioral and gene expression alterations induced by spontaneous alcohol withdrawal (SAW) in mice. Increasing doses of ethanol were administered to C57BL/6J male mice for 15 days (2.5, 3 and 3.5 g/kg/12 h, p. o.), and SAW was studied at 6, 12, 24, and 72 h after the last ethanol administration. The efficacy of acute CBD (10, 20, and 40 mg/kg, i. p.) to regulate behavioral changes induced by SAW was explored at 6 h. Gene expression analyses of cannabinoid receptors 1 (Cnr1) and 2 (Cnr2), mu-opioid receptor (Opmr1), and proopiomelanocortin (Pomc) in the nucleus accumbens (NAcc), and Pomc and tyrosine hydroxylase (Th) in the ventral tegmental area (VTA), were carried out by real time-PCR. Pearson correlation was used to identify potential associations between the gene expression data and the anxiety-like behaviors.Biostatistical studies suggest associations between gene expression data and the anxiogenic behaviors in mice exposed to the SAW model and treated with VEH and 40 mg/kg of CBD. Mice exposed to the SAW model showed significant somatic withdrawal signs, anxiety-like behaviors, and remarkable changes in the gene expression of all brain targets at 6 h. CBD dose-dependently normalized the behavioral, somatic withdrawal signs and anxiety-like behaviors and modulated gene expression changes in the NAcc, but not in the VTA.The results of this study suggest that CBD may regulate specific alcohol withdrawal-associated alterations. However, further studies are required to explore the possible mechanisms involved.

Verbal Behavior of Mothers With Opioid Use Disorder While Feeding Infants With Neonatal Opioid Withdrawal Syndrome.

An infant's cognitive development is highly dependent on early interactions with its primary caregiver, often its mother. Feeding, a frequent and early exchange between mothers and infants, is an important time for maternal-infant bonding. Mothers with opioid use disorder have been found to be more physically and verbally stimulating and more active during feeds than mothers with no opioid use. The purpose of this study was to describe the characteristics of verbal interactions mothers with opioid use disorder expressed while engaged in a feeding encounter with their infant undergoing treatment for neonatal opioid withdrawal syndrome to offer insight into maternal experiences and potential challenges of feeding infants experiencing withdrawal. A qualitative descriptive analysis of maternal verbalizations during the feeding was used in a secondary analysis using the Barnard Model as the theoretical framework for maternal-infant interaction. A theory-driven deductive approach was assumed to organize the identified subthemes within the concepts of the Barnard Model. Mothers frequently commented on hunger, satiation, and stress cues, while providing consolation, praise, and encouragement. Mothers expressed concerns regarding feeding volume and pace, and consequences related to feeding. It is crucial that clinicians remember that feeding is an important time for maternal-infant bonding. Further research into the feeding interactions of mother-infant dyads with opioid exposure is warranted. As infants may present with subacute signs of withdrawal, including persistent feeding difficulties for months, further investigation into feeding challenges dyads experience after discharge from the hospital is needed.

Low-grade inflammation during the glucocorticoid withdrawal phase in patients with Cushing's syndrome.

Endogenous Cushing's syndrome (CS) leads to profound immunosuppression. Successful surgery induces biochemical remission and reversal of immunosuppression, which is characterized by clinical signs of glucocorticoid withdrawal and associated with increased susceptibility to infections and thromboembolic complications. We hypothesized that the glucocorticoid withdrawal phase is characterized by low-grade inflammation that may be related to patient-relevant outcomes. In this retrospective observational study, we analyzed longitudinal data from 80 patients with CS prospectively enrolled in the German Cushing's registry between 2012 and 2021. All enrolled patients underwent successful surgery. In a second step, a case control study was performed in 25 of the patients with age-, gender- and BMI-matched control patients in whom hypercortisolism was excluded. Analyses included the inflammatory markers C-reactive protein and interleukin-6, as well as body composition, muscle function testing and quality of life questionnaires. The patients were studied during active CS and in the postoperative remission phase 1, 3, 6, 12 and 24 months after surgery. Compared to the preoperative phase and matched controls, patients with CS had increased systemic inflammatory markers in the early remission phase. One month following surgery, median (IQR) C-reactive protein was 0.48 mg/dL (0.14; 0.90) vs. 0.10 mg/dL (0.06; 0.39) during active CS (p ≤ 0.001). Similarly, interleukin-6 one month after surgery was 7.2 pg/mL (3.3; 11.7) vs. 1.7 pg/mL (1.5; 2.5) during active CS (p ≤ 0.001). Obesity and HbA1c were associated with increased inflammation levels. This proinflammatory state lasted until one year following surgery. Moreover, inflammatory markers during early remission showed an inverse correlation with long-term muscle function. The glucocorticoid withdrawal phase is associated with a low-grade inflammatory state, which is particularly pronounced in obese and hyperglycemic patients and related to lower muscle function.

Nicorandil reduces morphine withdrawal symptoms, potentiates morphine antinociception, and ameliorates liver fibrosis in rats

AimsChronic liver disease (CLD) is a serious medical condition affecting patients globally and pain management poses a unique challenge. ATP-sensitive potassium channels (KATP) are expressed in nociceptive neurons and hepatic cells. We tested the hypothesis whether morphine and nicorandil, KATP channel opener, alone and in combination possess hepatoprotective, antinociceptive effect and alter morphine physical dependence. Main methodsIntraperitoneal injection (i.p.) of carbon tetrachloride (CCl4) induced liver fibrosis in male Wistar rats. Nicorandil (15 mg/kg/day) was administered per os for two weeks. Morphine (3.8, 5, 10 mg/kg, i.p.) was administered prior to antinociception testing in tail flick and formalin tests. Morphine physical dependence following naloxone injection, fibrotic, oxidative stress markers, and liver histopathology were assessed. Key findingsMorphine alone, produced insignificant changes of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), hepatic hydroxyproline (Hyp), malondialdehyde (MDA), and superoxide dismutase (SOD) levels and exerted significant antinociception in the pain models. Nicorandil alone protected against liver damage (decreased serum ALT, AST, HA, hepatic Hyp, MDA, increased SOD levels, improved fibrosis scores). Nicorandil/morphine combination produced remarkable hepatoprotection and persistent analgesia compared to morphine alone as evidenced by reduced (EC50) of morphine. Nicorandil augmented morphine analgesia and markedly decreased withdrawal signs in morphine-dependent rats. SignificanceThe data showed for the first time, the hepatoprotection and augmented antinociception mediated by nicorandil/morphine combination in liver fibrosis via antioxidant and antifibrotic mechanisms. Nicorandil ameliorated withdrawal signs in morphine dependence in CLD. Thus, combining nicorandil/morphine provides a novel treatment strategy to ameliorate hepatic injury, potentiate antinociception and overcome morphine-induced physical dependence in liver fibrosis.

Opioid Withdrawal Abruptly Disrupts Amygdala Circuit Function by Reducing Peptide Actions.

While the physical signs of opioid withdrawal are most readily observable, withdrawal insidiously drives relapse and contributes to compulsive drug use, by disrupting emotional learning circuits. How these circuits become disrupted during withdrawal is poorly understood. Because amygdala neurons mediate relapse, and are highly opioid sensitive, we hypothesized that opioid withdrawal would induce adaptations in these neurons, opening a window of disrupted emotional learning circuit function. Under normal physiological conditions, synaptic transmission between the basolateral amygdala (BLA) and the neighboring main island (Im) of GABAergic intercalated cells (ITCs) is strongly inhibited by endogenous opioids. Using patch-clamp electrophysiology in brain slices prepared from male rats, we reveal that opioid withdrawal abruptly reduces the ability of these peptides to inhibit neurotransmission, a direct consequence of a protein kinase A (PKA)-driven increase in the synaptic activity of peptidases. Reduced peptide control of neurotransmission in the amygdala shifts the excitatory/inhibitory balance of inputs onto accumbens-projecting amygdala cells involved in relapse. These findings provide novel insights into how peptidases control synaptic activity within the amygdala and presents restoration of endogenous peptide activity during withdrawal as a viable option to mitigate withdrawal-induced disruptions in emotional learning circuits and rescue the relapse behaviors exhibited during opioid withdrawal and beyond into abstinence.SIGNIFICANCE STATEMENT We find that opioid withdrawal dials down inhibitory neuropeptide activity in the amygdala. This disrupts both GABAergic and glutamatergic transmission through amygdala circuits, including reward-related outputs to the nucleus accumbens. This likely disrupts peptide-dependent emotional learning processes in the amygdala during withdrawal and may direct behavior toward compulsive drug use.

Identification of candidate genes for nicotine withdrawal in C57BL/6J×DBA/2J recombinant inbred mice.

Nicotine is the reinforcing ingredient in tobacco. Following chronic exposure, sudden cessation of nicotine use produces negative symptoms of withdrawal that contribute to dependence. The molecular mechanisms underlying nicotine withdrawal behaviors, however, are poorly understood. Using recombinant inbred mice, chronic nicotine was delivered by minipump and withdrawal induced using mecamylamine. Somatic signs of withdrawal, and anxiety-like behavior using elevated plus maze, were then assessed. Interval mapping was used to identify associations between genetic variation and withdrawal behaviors, and with basal gene expression. Differential gene expression following nicotine exposure and withdrawal was also assessed in progenitor mice using microarrays. Quantitative trait loci mapping identified chromosome intervals with significant genetic associations to somatic signs of withdrawal or withdrawal-induced anxiety-like behavior. Using bioinformatics, and association with basal gene expression in nucleus accumbens, we implicated Rb1, Bnip3l, Pnma2, Itm2b, and Kif13b as candidate genes for somatic signs of withdrawal, and Galr1, which showed trans-regulation from a region of chromosome 14 that was associated with somatic signs of withdrawal. Candidate genes within the chromosome 9 region associated with anxiety-like withdrawal behavior included Dixdc1, Ncam1, and Sorl1. Bioinformatics identified six genes that were also significantly associated with nicotine or alcohol traits in recent human genome-wide association studies. Withdrawal-associated somatic signs and anxiety-like behavior had strong non-overlapping genetic associations, respectively, with regions of chromosome 14 and chromosome 9. Genetic, behavioral and gene expression correlations, and bioinformatics analysis identified several candidate genes that may represent novel molecular targets for modulating nicotine withdrawal symptoms.

A review of the genomics of neonatal abstinence syndrome.

Neonatal abstinence syndrome (NAS) is a constellation of signs of withdrawal occurring after birth following in utero exposure to licit or illicit opioids. Despite significant research and public health efforts, NAS remains challenging to diagnose, predict, and manage due to highly variable expression. Biomarker discovery in the field of NAS is crucial for stratifying risk, allocating resources, monitoring longitudinal outcomes, and identifying novel therapeutics. There is considerable interest in identifying important genetic and epigenetic markers of NAS severity and outcome that can guide medical decision making, research efforts, and public policy. A number of recent studies have suggested that genetic and epigenetic changes are associated with NAS severity, including evidence of neurodevelopmental instability. This review will provide an overview of the role of genetics and epigenetics in short and longer-term NAS outcomes. We will also describe novel research efforts using polygenic risk scores for NAS risk stratification and salivary gene expression to understand neurobehavioral modulation. Finally, emerging research focused on neuroinflammation from prenatal opioid exposure may elucidate novel mechanisms that could lead to development of future novel therapeutics.

Endomorphin analog ZH853 shows low reward, tolerance, and affective-motivational signs of withdrawal, while inhibiting opioid withdrawal and seeking

Currently available μ-opioid receptor agonist pharmacotherapies for opioid use disorder possess adverse effects limiting their use and, despite treatment, rates of relapse remain high. We previously showed that endomorphin analog ZH853 had no effect in rodent models that predict abuse liability in humans. Here we extended these findings by examining dependence liability and reinforcing properties in female rats and male rats with previous opioid exposure. The potential use of ZH853 in managing opioid use disorder was evaluated by examining its effect on opioid-seeking behavior and withdrawal. We found that ZH853 did not induce locomotor activation in male and female mice and was not self-administered by female rats. Relative to morphine, ZH853 led to similar somatic signs of withdrawal, but low affective-motivational signs of withdrawal, and absent changes in ventral tegmental area K(+)-Cl(−) co-transporter expression associated with reward dysregulation. The low abuse liability of ZH853 was further supported in oxycodone self-administering male rats, where ZH853 substitution extinguished opioid-seeking behavior. ZH853 priming also did not reinstate morphine conditioned place preference. Lastly, ZH853 inhibited oxycodone-seeking behavior during relapse after forced abstinence and decreased the expression of morphine withdrawal. These findings suggest the potential use of ZH853 as a safer opioid medication for long-term treatment of pain and opioid use disorder.

Complicated opioid withdrawal presenting with delirium

Unlike alcohol or benzodiazepine withdrawal, delirium is extremely uncommon during opioid withdrawal. We describe a case of smack addiction and opioid withdrawal in which led to delirium during withdrawal management. There is no prior history of substance misuse and no relevant personal or family background. It is discussed if delirium could be a withdrawal sign in opioid dependence. Yawning, sweating, lacrimation, rhinorrhea, anxiety, restlessness, insomnia, dilated pupils, piloerection, chills, tachycardia, hypertension, nausea/vomiting, crampy abdominal pains, diarrhea, and muscle aches and pains are some of the withdrawal symptoms that are typically associated with opioid abuse.

From Natural Behavior to Drug Screening: Invertebrates as Models to Study Mechanisms Associated with Alcohol Use Disorders.

Humans consume ethanol-containing beverages, which may cause an uncontrollable or difficult-to-control intake of ethanol-containing liquids and may result in alcohol use disorders. How the transition at the molecular level from "normal" ethanol-associated behaviors to addictive behaviors occurs is still unknown. One problem is that the components contributing to normal ethanol intake and their underlying molecular adaptations, especially in neurons that regulate behavior, are not clear. The fruit fly Drosophila melanogaster and the earthworm Caenorhabditis elegans show behavioral similarities to humans such as signs of intoxication, tolerance, and withdrawal. Underlying the phenotypic similarities, invertebrates and vertebrates share mechanistic similarities. For example in Drosophila melanogaster, the dopaminergic neurotransmitter system regulates the positive reinforcing properties of ethanol and in Caenorhabditis elegans, serotonergic neurons regulate feeding behavior. Since these mechanisms are fundamental molecular mechanisms and are highly conserved, invertebrates are good models for uncovering the basic principles of neuronal adaptation underlying the behavioral response to ethanol. This review will focus on the following aspects that might shed light on the mechanisms underlying normal ethanol-associated behaviors. First, the current status of what is required at the behavioral and cellular level to respond to naturally occurring levels of ethanol is summarized. Low levels of ethanol delay the development and activate compensatory mechanisms that in turn might be beneficial for some aspects of the animal's physiology. Repeated exposure to ethanol however might change brain structures involved in mediating learning and memory processes. The smell of ethanol is already a key component in the environment that is able to elicit behavioral changes and molecular programs. Minimal networks have been identified that regulate normal ethanol consumption. Other environmental factors that influence ethanol-induced behaviors include the diet, dietary supplements, and the microbiome. Second, the molecular mechanisms underlying neuronal adaptation to the cellular stressor ethanol are discussed. Components of the heat shock and oxidative stress pathways regulate adaptive responses to low levels of ethanol and in turn change behavior. The adaptive potential of the brain cells is challenged when the organism encounters additional cellular stressors caused by aging, endosymbionts or environmental toxins or excessive ethanol intake. Finally, to underline the conserved nature of these mechanisms between invertebrates and higher organisms, recent approaches to identify drug targets for ethanol-induced behaviors are provided. Already approved drugs regulate ethanol-induced behaviors and they do so in part by interfering with cellular stress pathways. In addition, invertebrates have been used to identify new compounds targeting molecules involved in the regulation in ethanol withdrawal-like symptoms. This review primarily highlights the advances of the last 5years concerning Drosophila melanogaster, but also provides intriguing examples of Caenorhabditis elegans and Apis mellifera in support.

Effects of Dextromethorphan on Nicotine-Induced Reward, Behavioral Sensitization, Withdrawal Signs, and Drug Seeking-Related Behavior in Rats.

Tobacco products are addictive, with nicotine serving as the major addictive ingredient. Chronic tobacco use or chronic administration of nicotine alone results in both physiological and psychological dependence. Our previous studies indicated that dextromethorphan (DM) could effectively attenuate the dependence of morphine and methamphetamine. Thus, we further investigated the possible effects of DM on nicotine dependence. Conditioned place preference (CPP) test was used to examine nicotine-induced rewarding effects as well as the drug-seeking-related behavior in rats. Nicotine dependence was induced by continuous subcutaneous infusion of nicotine via an osmotic minipump for 7 days and abstinence was initiated by removal of the pump. Withdrawal signs were observed and quantified. Locomotor activity was measured to determine the behavioral sensitization induced by nicotine. To investigate the activity of mesolimbic dopaminergic neuronal activity in correlation with the effects of nicotine, the animals were sacrificed and the nucleus accumbens (NAc), dorsal striatum (DS), and medial prefrontal cortex (mPFC) were dissected and used to determine the contents of dopamine (DA) and its metabolites using high-performance liquid chromatography (HPLC). Our results showed that DM could suppress nicotine-induced rewarding effect and drug-seeking-related behavior. In addition, co-administration and post-treatment of DM could both attenuate nicotine withdrawal signs. Moreover, DM could suppress nicotine-induced behavioral sensitization. Neurochemical experiments show that co-administration and post-treatment of DM abolished nicotine-induced increase of the DA turnover rate in the mPFC, but not in the NAc and DS. The results suggest that DM has a great therapeutic potential in the treatment of nicotine dependence. Our results showed that DM could suppress nicotine-induced rewarding effect and drug-seeking-related behavior. In addition, co-administration and post-treatment of DM could both attenuate nicotine withdrawal signs. Moreover, DM could suppress nicotine-induced behavioral sensitization. Neurochemical experiments show that co-administration and post-treatment of DM abolished nicotine-induced increase of the DA turnover rate in the mPFC, but not in the NAc and DS. These results suggest that DM has a great therapeutic potential in the treatment of nicotine dependence.