236 research outputs found
BU10038 as a safe opioid analgesic with fewer side-effects after systemic and intrathecal administration in primates
Β© 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.Background: The marked increase in mis-use of prescription opioids has greatly affected our society. One potential solution is to develop improved analgesics which have agonist action at both mu opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) receptors. BU10038 is a recently identified bifunctional MOP/NOP partial agonist. The aim of this study was to determine the functional profile of systemic or spinal delivery of BU10038 in primates after acute and chronic administration. Methods: A series of behavioural and physiological assays have been established specifically to reflect the therapeutic (analgesia) and side-effects (abuse potential, respiratory depression, itch, physical dependence, and tolerance) of opioid analgesics in rhesus monkeys. Results: After systemic administration, BU10038 (0.001β0.01 mg kg β1 ) dose-dependently produced long-lasting antinociceptive and antihypersensitive effects. Unlike the MOP agonist oxycodone, BU10038 lacked reinforcing effects (i.e. little or no abuse liability), and BU10038 did not compromise the physiological functions of primates including respiration, cardiovascular activities, and body temperature at antinociceptive doses and a 10β30-fold higher dose (0.01β0.1 mg kg β1 ). After intrathecal administration, BU10038 (3 ΞΌg) exerted morphine-comparable antinociception and antihypersensitivity without itch scratching responses. Unlike morphine, BU10038 did not cause the development of physical dependence and tolerance after repeated and chronic administration. Conclusions: These in vivo findings demonstrate the translational potential of bifunctional MOP/NOP receptor agonists such as BU10038 as a safe, non-addictive analgesic with fewer side-effects in primates. This study strongly supports that bifunctional MOP/NOP agonists may provide improved analgesics and an alternative solution for the ongoing prescription opioid crisis.Peer reviewedFinal Published versio
Effects of dopamine D2/D3 receptor ligands on food-cocaine choice in socially housed male cynomolgus monkeys
Effects of Dopamine D2/D3 Receptor Ligands on Food-Cocaine Choice in Socially Housed Male Cynomolgus Monkeys
Effects of Chronic Methylphenidate on Cocaine Self-Administration under a Progressive-Ratio Schedule of Reinforcement in Rhesus Monkeys
Test purchase, synthesis and characterization of 3-fluorophenmetrazine (3-FPM) and differentiation from its ortho- and para-substituted isomers.
The knowledge captured in patent and scientific research literature stimulates new ideas and fosters new drug development efforts. Manufacturers and entrepreneurs dedicated to the sale of 'research chemicals' and/or new psychoactive substances (NPS) also make use of access to information to identify, prepare, and launch a range of new substances. One of the most recent compounds to appear on the NPS market is the phenmetrazine analog 3-fluorophenmetrazine (3-FPM) which represents one of many phenylmorpholines designed to explore treatment options in areas such as obesity and drug dependence. The anorectic drug analogs phenmetrazine and phendimetrazine, used as prescription medicines before they were withdrawn, feature amphetamine-like properties associated with monoamine release. Available data on 3-FPM suggest that the effects might show mechanistic overlaps. This study describes the synthesis and extensive analytical characterization of 3-FPM and its differentiation from synthesized ortho- and para- substituted isomers, 2-FPM and 4-FPM, respectively. This study was triggered by the purchase of five powdered samples advertised as 3-FPM by five different Internet vendors based in the United Kingdom. The analytical data obtained for the vendor samples were consistent with the synthesized 3-FPM standard and differentiation between all three isomers was possible. The presence of positional isomers and the absence of suitable reference material can cause difficulties in the day-to-day operation of forensic work and given the rate at which many of the newly emerging NPS appear on the market, a comprehensive approach is needed when attempting to decipher the identity of NPS arriving onto the drug market. Copyright Β© 2016 John Wiley & Sons, Ltd
Effects of chronic methylphenidate on cocaine self-administration under a progressive-ratio schedule of reinforcement in rhesus monkeys
ABSTRACT It has been hypothesized that drugs that serve as substrates for dopamine (DA) and norepinephrine (NE) transporters may be more suitable medications for cocaine dependence than drugs that inhibit DA and NE uptake by binding to transporters. Previous studies have shown that the DA/NE releaser d-amphetamine can decrease cocaine self-administration in preclinical and clinical studies. The present study examined the effects of methylphenidate (MPD), a DA uptake inhibitor, for its ability to decrease cocaine self-administration under conditions designed to reflect clinically relevant regimens of cocaine exposure and pharmacotherapy. Each morning, rhesus monkeys pressed a lever to receive food pellets under a fixed-ratio 50 schedule of reinforcement; cocaine was self-administered under a progressiveratio schedule of reinforcement in the evening. After cocaine (0.003-0.56 mg/kg per injection, i.v.) dose-response curves were determined, self-administration sessions were suspended and MPD (0.003-0.0056 mg/kg per hr, i.v. or 1.0-9.0 mg/kg p.o., b.i.d.) was administered for several weeks. A cocaine self-administration session was conducted every 7 days. When a MPD dose was reached that either persistently decreased cocaine self-administration or produced disruptive effects, the cocaine dose-effect curve was re-determined. In most cases, MPD treatment either produced behaviorally disruptive effects or increased cocaine selfadministration; it took several weeks for these effects to dissipate. These data are consistent with the largely negative results of clinical trials with MPD. In contrast to the positive effects with the monoamine releaser d-amphetamine under identical conditions, these results do not support use of monoamine uptake inhibitors like MPD as a medication for cocaine dependence
Altered Ratio of D1 and D2 Dopamine Receptors in Mouse Striatum Is Associated with Behavioral Sensitization to Cocaine
BACKGROUND: Drugs of abuse elevate brain dopamine levels, and, in vivo, chronic drug use is accompanied by a selective decrease in dopamine D2 receptor (D2R) availability in the brain. Such a decrease consequently alters the ratio of D1R:D2R signaling towards the D1R. Despite a plethora of behavioral studies dedicated to the understanding of the role of dopamine in addiction, a molecular mechanism responsible for the downregulation of the D2R, in vivo, in response to chronic drug use has yet to be identified. METHODS AND FINDINGS: ETHICS STATEMENT: All animal work was approved by the Gallo Center IACUC committee and was performed in our AAALAC approved facility. In this study, we used wild type (WT) and G protein coupled receptor associated sorting protein-1 (GASP-1) knock out (KO) mice to assess molecular changes that accompany cocaine sensitization. Here, we show that downregulation of D2Rs or upregulation of D1Rs is associated with a sensitized locomotor response to an acute injection of cocaine. Furthermore, we demonstrate that disruption of GASP-1, that targets D2Rs for degradation after endocytosis, prevents cocaine-induced downregulation of D2Rs. As a consequence, mice with a GASP-1 disruption show a reduction in the sensitized locomotor response to cocaine. CONCLUSIONS: Together, our data suggests that changes in the ratio of the D1:D2R could contribute to cocaine-induced behavioral plasticity and demonstrates a role of GASP-1 in regulating both the levels of the D2R and cocaine sensitization
Why Primate Models Matter
Research involving nonhuman primates (NHPs) has played a vital role in many of the medical and scientific advances of the past century. NHPs are used because of their similarity to humans in physiology, neuroanatomy, reproduction, development, cognition, and social complexity β yet it is these very similarities that make the use of NHPs in biomedical research a considered decision. As primate researchers, we feel an obligation and responsibility to present the facts concerning why primates are used in various areas of biomedical research. Recent decisions in the United States, including the phasing out of chimpanzees in research by the National Institutes of Health and the pending closure of the New England Primate Research Center, illustrate to us the critical importance of conveying why continued research with primates is needed. Here we review key areas in biomedicine where primate models have been, and continue to be, essential for advancing fundamental knowledge in biomedical and biological research
Effects of stimulation of mu opioid and nociceptin/orphanin FQ peptide (NOP) receptors on alcohol drinking in rhesus monkeys
A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates
Despite the critical need, no previous research has substantiated safe opioid analgesics without abuse liability in primates. Recent advances in medicinal chemistry have led to the development of ligands with mixed mu opioid peptide (MOP)/nociceptin-orphanin FQ peptide (NOP) receptor agonist activity to achieve this objective. BU08028 is a novel orvinol analog that displays a similar binding profile to buprenorphine with improved affinity and efficacy at NOP receptors. The aim of this preclinical study was to establish the functional profile of BU08028 in monkeys using clinically used MOP receptor agonists for side-by-side comparisons in various well-honed behavioral and physiological assays. Systemic BU08028 (0.001β0.01 mg/kg) produced potent long-lasting (i.e., >24 h) antinociceptive and antiallodynic effects, which were blocked by MOP or NOP receptor antagonists. More importantly, the reinforcing strength of BU08028 was significantly lower than that of cocaine, remifentanil, or buprenorphine in monkeys responding under a progressive-ratio schedule of drug self-administration. Unlike MOP receptor agonists, BU08028 at antinociceptive doses and βΌ10- to 30-fold higher doses did not cause respiratory depression or cardiovascular adverse events as measured by telemetry devices. After repeated administration, the monkeys developed acute physical dependence on morphine, as manifested by precipitated withdrawal signs, such as increased respiratory rate, heart rate, and blood pressure. In contrast, monkeys did not show physical dependence on BU08028. These in vivo findings in primates not only document the efficacy and tolerability profile of bifunctional MOP/NOP receptor agonists, but also provide a means of translating such ligands into therapies as safe and potentially abuse-free opioid analgesics
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