- Modulation of serotonin transporter function by kappa-opioid receptor ligands. [Journal Article]
- NNeuropharmacology 2016 Oct 12; 113(Pt A):281-292
- Kappa opioid receptor (KOR) agonists produce dysphoria and psychotomimesis. While KOR agonists produce pro-depressant-like effects, KOR antagonists produce anti-depressant-like effects in rodent mode...
Kappa opioid receptor (KOR) agonists produce dysphoria and psychotomimesis. While KOR agonists produce pro-depressant-like effects, KOR antagonists produce anti-depressant-like effects in rodent models. The cellular mechanisms and downstream effector(s) by which KOR ligands produce these effects are not clear. KOR agonists modulate serotonin (5-HT) transmission in the brain regions implicated in mood and motivation regulation. Presynaptic serotonin transporter (SERT) activity is critical in the modulation of synaptic 5-HT and, subsequently, in mood disorders. Detailing the molecular events of KOR-linked SERT regulation is important for examining the postulated role of this protein in mood disorders. In this study, we used heterologous expression systems and native tissue preparations to determine the cellular signaling cascades linked to KOR-mediated SERT regulation. KOR agonists U69,593 and U50,488 produced a time and concentration dependent KOR antagonist-reversible decrease in SERT function. KOR-mediated functional down-regulation of SERT is sensitive to CaMKII and Akt inhibition. The U69,593-evoked decrease in SERT activity is associated with a decreased transport Vmax, reduced SERT cell surface expression, and increased SERT phosphorylation. Furthermore, KOR activation enhanced SERT internalization and decreased SERT delivery to the membrane. These data demonstrate that KOR activation decreases 5-HT uptake by altering SERT trafficking mechanisms and phosphorylation status to reduce the functional availability of surface SERT.
- Transgenerational attenuation of opioid self-administration as a consequence of adolescent morphine exposure. [Journal Article]
- NNeuropharmacology 2016 Oct 8; 113(Pt A):271-280
- The United States is in the midst of an opiate epidemic, with abuse of prescription and illegal opioids increasing steadily over the past decade. While it is clear that there is a genetic component t...
The United States is in the midst of an opiate epidemic, with abuse of prescription and illegal opioids increasing steadily over the past decade. While it is clear that there is a genetic component to opioid addiction, there is a significant portion of heritability that cannot be explained by genetics alone. The current study was designed to test the hypothesis that maternal exposure to opioids prior to pregnancy alters abuse liability in subsequent generations. Female adolescent Sprague Dawley rats were administered morphine at increasing doses (5-25 mg/kg, s.c.) or saline for 10 days (P30-39). During adulthood, animals were bred with drug-naïve colony males. Male and female adult offspring (F1 animals) were tested for morphine self-administration acquisition, progressive ratio, extinction, and reinstatement at three doses of morphine (0.25, 0.75, 1.25 mg/kg/infusion). Grandoffspring (F2 animals, from the maternal line) were also examined. Additionally, gene expression changes within the nucleus accumbens were examined with RNA deep sequencing (PacBio) and qPCR. There were dose- and sex-dependent effects on all phases of the self-administration paradigm that indicate decreased morphine reinforcement and attenuated relapse-like behavior. Additionally, genes related to synaptic plasticity, as well as myelin basic protein (MBP), were dysregulated. Some, but not all, effects persisted into the subsequent (F2) generation. The results demonstrate that even limited opioid exposure during adolescence can have lasting effects across multiple generations, which has implications for mechanisms of the transmission of drug abuse liability in humans.
- Naloxone blocks the aversive effects of electrical stimulation of the parabrachial complex in a place discrimination task. [Journal Article]
- NLNeurobiol Learn Mem 2016 Sep 19; 136:21-27
- The parabrachial complex is known to participate in various rewarding and aversive processes, including those related to the learning of taste or place discrimination and the motivational effects of ...
The parabrachial complex is known to participate in various rewarding and aversive processes, including those related to the learning of taste or place discrimination and the motivational effects of drugs of abuse, such as morphine. This study shows that electrical stimulation of the external lateral parabrachial (LPBe) subnucleus induces consistent place avoidance or place preference in three-compartment rectangular mazes. Administration of naloxone, an opiate antagonist, blocks both motivational effects induced by the intracranial electrical stimulation. Subsequent re-administration of the electrical stimulation was found to recover its aversive but not its rewarding effects after vehicle administration. These results are discussed in relation to different natural and artificial agents involved in the induction of avoidance and preference motivational processes, especially with regard to the opioid system.
- Prescription opioid abuse and misuse: gap between primary-care investigator assessment and actual extent of these behaviors among patients with chronic pain. [Journal Article]
- PMPostgrad Med 2016 Oct 26; :1-7
- CONCLUSIONS: A comparison of risk assessment across two studies indicates a tendency for investigators to assess patients as lower risk for opioid-related aberrant behaviors despite a significant proportion self-reporting aberrant behavior and/or presenting with illicit UDTs. These consistent findings underline the importance of appropriate implementation of objective measures and self-reporting tools when evaluating risk in patients.
- Cebranopadol: novel dual opioid/NOP receptor agonist analgesic. [Review]
- JCJ Clin Pharm Ther 2016 Oct 24
- CONCLUSIONS: Despite the medical need, a truly novel centrally acting analgesic has not been developed in many years. Cebranopadol represents a truly novel mechanistic approach. Its actual place in pain pharmacotherapy awaits the results of phase 3 clinical trials.
- Medication-Assisted Treatment Improves Child Permanency Outcomes for Opioid-Using Families in the Child Welfare System. [Journal Article]
- JSJ Subst Abuse Treat 2016; 71:63-67
- Parents who use opioids and are involved in the child welfare system are less likely to retain custody of their children than parents who use other drugs. No previous studies have described medicatio...
Parents who use opioids and are involved in the child welfare system are less likely to retain custody of their children than parents who use other drugs. No previous studies have described medication-assisted treatment (MAT) utilization and child permanency outcomes for this population. The Sobriety Treatment and Recovery Team (START) model is a child welfare-based intervention focused on families with co-occurring substance use and child abuse / neglect issues. This study examined the prevalence and correlates of MAT utilization among parents in the START program with a history of opioid use, and compared child outcomes for families who received MAT services to those who did not. Of the 596 individuals with a history of opioid use in the START program, 55 (9.2%) received MAT. Receipt of MAT services did not differ by gender, age, county of residence, or drug use, though individuals who identified as White were more likely to participate in MAT. In a multiple logistic regression model, additional months of MAT increased the odds of parents retaining custody of their children. To address barriers to MAT, results-focused educational interventions may be needed for the child welfare workforce, as well as programs to improve collaboration and decision-making between the child welfare workforce, court personnel, and drug addiction treatment providers.
- Cognitive Behavioral Therapy Improves Treatment Outcomes for Prescription Opioid Users in Primary Care Buprenorphine Treatment. [Journal Article]
- JSJ Subst Abuse Treat 2016; 71:54-57
- To determine whether treatment outcomes differed for prescription opioid and heroin use disorder patients, we conducted a secondary analysis of a 24-week (N=140) randomized trial of physician managem...
To determine whether treatment outcomes differed for prescription opioid and heroin use disorder patients, we conducted a secondary analysis of a 24-week (N=140) randomized trial of physician management (PM) or PM plus cognitive behavioral therapy (CBT) in primary care buprenorphine/naloxone treatment. Self-reported opioid use and urine toxicology analyses were obtained weekly. We examined baseline demographic differences between primary prescription opioid use patients (n=49) and primary heroin use patients (n=91) and evaluated whether treatment response differed by assigned condition. Compared to primary heroin use patients, primary prescription opioid use patients had marginally fewer years of opioid use, were less likely to have had a previous drug treatment or detoxification, and were less likely to report injection drug use. Although opioid abstinence only, and treatment retention did not differ by opioid use group, opioid category moderated the effect of CBT on urine samples negative for all drugs. Primary prescription opioid use patients assigned to PM-CBT had more than twice the mean number of weeks of abstinence for all drugs (7.6) than those assigned to PM only (3.6; p=.02), while primary heroin use patients did not differ by treatment. Findings suggest that examination of other factors that may predict response to behavioral interventions is warranted.
- Exploration of bivalent ligands targeting putative mu opioid receptor and chemokine receptor CCR5 dimerization. [Journal Article]
- BMBioorg Med Chem 2016 Nov 15; 24(22):5969-5987
- Modern antiretroviral therapies have provided HIV-1 infected patients longer lifespans and better quality of life. However, several neurological complications are now being seen in these patients due...
Modern antiretroviral therapies have provided HIV-1 infected patients longer lifespans and better quality of life. However, several neurological complications are now being seen in these patients due to HIV-1 associated injury of neurons by infected microglia and astrocytes. In addition, these effects can be further exacerbated with opiate use and abuse. One possible mechanism for such potentiation effects of opiates is the interaction of the mu opioid receptor (MOR) with the chemokine receptor CCR5 (CCR5), a known HIV-1 co-receptor, to form MOR-CCR5 heterodimer. In an attempt to understand this putative interaction and its relevance to neuroAIDS, we designed and synthesized a series of bivalent ligands targeting the putative CCR5-MOR heterodimer. To understand how these bivalent ligands may interact with the heterodimer, biological studies including calcium mobilization inhibition, binding affinity, HIV-1 invasion, and cell fusion assays were applied. In particular, HIV-1 infection assays using human peripheral blood mononuclear cells, macrophages, and astrocytes revealed a notable synergy in activity for one particular bivalent ligand. Further, a molecular model of the putative CCR5-MOR heterodimer was constructed, docked with the bivalent ligand, and molecular dynamics simulations of the complex was performed in a membrane-water system to help understand the biological observation.
- Morphine-induced locomotor sensitization produces structural plasticity in the mesocorticolimbic system dependent on CB1-R activity. [Journal Article]
- ABAddict Biol 2016; 21(6):1113-1126
- Changes in structural plasticity produced by the chronic exposure to drugs of abuse, such as alterations in dendritic spine densities, participate in the development of maladaptive learning processes...
Changes in structural plasticity produced by the chronic exposure to drugs of abuse, such as alterations in dendritic spine densities, participate in the development of maladaptive learning processes leading to drug addiction. Understanding the neurobiological mechanisms involved in these aberrant changes is crucial to clarify the neurobiological substrate of addiction. Drug-induced locomotor sensitization has been widely accepted as a useful animal model to study these mechanisms related to drug addiction. We have evaluated the changes in structural plasticity in the mesocorticolimbic system involved in morphine-induced locomotor sensitization. The role of the cannabinoid receptor type 1 (CB1-R) in these neuroplastic alterations has also been studied using CB1-R-deficient (CB1-R KO) mice. Structural plasticity changes promoted by morphine are a highly dynamic phenomenon that evolves during the entire time course of the behavioral sensitization in wild-type (WT) animals. The different phases of the sensitization process were related to specific changes in connectivity between neurons revealed by modifications in dendritic spines in specific areas of the mesocorticolimbic system. Moreover, the lack of morphine-induced locomotor sensitization in CB1-R KO mice was accompanied by abnormal alterations in structural plasticity in the same mesocorticolimbic areas. These specific structural plasticity changes mediated by CB1-R activity seem necessary for the normal progression of morphine-induced locomotor sensitization and could play a critical role in the addictive process.
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- Delay discounting in opioid use disorder: Differences between heroin and prescription opioid users. [Journal Article]
- DADrug Alcohol Depend 2016 Oct 17; 169:68-72
- CONCLUSIONS: Adults with opioid dependence who exclusively used prescription opioids had lower delay discounting relative to those who used heroin. This finding contributes further to the literature suggesting that heroin use is associated with greater clinical severity among those with opioid use disorder.