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https://www.readbyqxmd.com/read/28340145/human-abuse-potential-of-the-new-opioid-analgesic-molecule-nktr-181-compared-with-oxycodone
#1
Lynn Webster, Jack Henningfield, August R Buchhalter, Suresh Siddhanti, Lin Lu, Aleksandrs Odinecs, Carlo J Di Fonzo, Michael A Eldon
Objective.:  Evaluate the human abuse potential, pharmacokinetics, pharmacodynamics, and safety of NKTR-181, a novel mu-opioid agonist molecule, relative to oxycodone. Design.:  This randomized, single-center, double-blind, active- and placebo-controlled five-period crossover study enrolled healthy, adult, non-physically dependent recreational opioid users. Setting.:  Inpatient clinical research site. Subjects. : Forty-two randomized subjects (73...
March 10, 2017: Pain Medicine: the Official Journal of the American Academy of Pain Medicine
https://www.readbyqxmd.com/read/28333341/systemic-administration-of-sialorphin-attenuates-experimental-colitis-in-mice-via-interaction-with-mu-and-kappa-opioid-receptors
#2
M Salaga, A Mokrowiecka, D Jacenik, A I Cygankiewicz, E Malecka-Panas, R Kordek, W M Krajewska, M K Sobocinska, E Kamysz, J Fichna
Background and Aims: Pharmacological treatment and/or maintenance of remission in inflammatory bowel disease (IBD) is currently one of the biggest challenges in the field of gastroenterology. Here we aimed to assess the anti-inflammatory effect and the mechanism of action of sialorphin, the natural blocker of the endogenous opioid peptide-degrading enzymes neprilysin (NEP) and aminopeptidase N (APN), in the mouse models of IBD and the changes in the expression of these enzymes in IBD patients...
March 18, 2017: Journal of Crohn's & Colitis
https://www.readbyqxmd.com/read/28333316/convergent-balancing-selection-on-the-mu-opioid-receptor-in-primates
#3
Carolyn G Sweeney, Juliette M Rando, Helen N Panas, Gregory M Miller, Donna M Platt, Eric J Vallender
The mu opioid receptor is involved in many natural processes including stress response, pleasure, and pain. Mutations in the gene also have been associated with opiate and alcohol addictions as well as with responsivity to medication targeting these disorders. Two common and mutually exclusive polymorphisms have been identified in humans, A118G (N40D), found commonly in non-African populations, and C17T (V6A), found almost exclusively in African populations. While A118G has been studied extensively for associations and in functional assays, C17T is much less well understood...
March 15, 2017: Molecular Biology and Evolution
https://www.readbyqxmd.com/read/28318942/cyclic-mu-opioid-receptor-ligands-containing-multiple-n-methylated-amino-acid-residues
#4
Anna Adamska-Bartłomiejczyk, Anna Janecka, Márton Richárd Szabó, Maria Camilla Cerlesi, Girolamo Calo, Alicja Kluczyk, Csaba Tömböly, Attila Borics
In this study we report the in vitro activities of four cyclic opioid peptides with various sequence length/macrocycle size and N-methylamino acid residue content. N-Methylated amino acids were incorporated and cyclization was employed to enhance conformational rigidity to various extent. The effect of such modifications on ligand structure and binding properties were studied. The pentapeptide containing one endocyclic and one exocyclic N-methylated amino acid displayed the highest affinity to the mu-opioid receptor...
March 7, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28318893/design-and-characterization-of-opioid-ligands-based-on-cycle-in-macrocycle-scaffold
#5
Anna Adamska-Bartłomiejczyk, Rossella De Marco, Luca Gentilucci, Alicja Kluczyk, Anna Janecka
The study reports on a series of novel cyclopeptides based on the structure Tyr-[d-Lys-Phe-Phe-Asp]NH2, a mixed mu and kappa opioid receptor agonist with low nanomolar affinity, in which Phe(4) residue was substituted by cyclic amino acids, such as Pro or its six-membered surrogates, piperidine-2-, 3- or 4-carboxylic acids (Pip, Nip and Inp, respectively). All derivatives exhibited high mu- and moderate delta-opioid receptor affinity, and almost no binding to the kappa-opioid receptor. Conformational analysis suggested that the cis conformation of the peptide bond Phe(3)-Xaa(4) influences receptor selectivity through the control of the position of Phe(3) side chain...
February 28, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28306605/hyperalgesic-priming-type-ii-induced-by-repeated-opioid-exposure-maintenance-mechanisms
#6
Dioneia Araldi, Luiz F Ferrari, Jon D Levine
We previously developed a model of opioid-induced neuroplasticity in the peripheral terminal of the nociceptor that could contribute to opioid-induced hyperalgesia, type II hyperalgesic priming. Repeated administration of mu-opioid receptor (MOR) agonists, such as DAMGO, at the peripheral terminal of the nociceptor, induces long-lasting plasticity expressed, prototypically as opioid-induced hyperalgesia and prolongation of prostaglandin-E2-induced hyperalgesia. In this study, we evaluated the mechanisms involved in the maintenance of type II priming...
March 14, 2017: Pain
https://www.readbyqxmd.com/read/28303899/the-behavioral-effects-of-the-antidepressant-tianeptine-require-the-mu-opioid-receptor
#7
Benjamin Adam Samuels, Katherine M Nautiyal, Andrew C Kruegel, Marjorie R Levinstein, Valerie M Magalong, Madalee M Gassaway, Steven G Grinnell, Jaena Han, Michael A Ansonoff, John E Pintar, Jonathan A Javitch, Dalibor Sames, René Hen
Depression is a debilitating chronic illness that affects around 350 million people worldwide. Current treatments, such as selective serotonin reuptake inhibitors (SSRIs), are not ideal because only a fraction of patients achieve remission. Tianeptine is an effective antidepressant with a previously unknown mechanism of action. We recently reported that tianeptine is a full agonist at the mu-opioid receptor (MOR). Here we demonstrate that the acute and chronic antidepressant-like behavioral effects of tianeptine in mice require MOR...
March 17, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28300398/novel-bivalent-ligands-based-on-the-sumanirole-pharmacophore-reveal-dopamine-d2-receptor-d2r-biased-agonism
#8
Alessandro Bonifazi, Hideaki Yano, Michael P Ellenberger, Ludovic Muller, Vivek Kumar, Mu-Fa Zou, Ning Sheng Cai, Adrian M Guerrero, Amina S Woods, Lei Shi, Amy Hauck Newman
The development of bivalent ligands has attracted interest as a way to potentially improve the selectivity and/or affinity for a specific receptor subtype. The ability to bind two distinct receptor binding sites simultaneously can allow the selective activation of specific G-protein dependent or β-arrestin-mediated cascade pathways. Herein, we developed an extended SAR study using sumanirole (1) as the primary pharmacophore. We found that substitutions in the N-1- and/or N-5-positions, physiochemical properties of those substituents, and secondary aromatic pharmacophores can enhance agonist efficacy for the cAMP inhibition mediated by Gi/o-proteins, while reducing or suppressing potency and efficacy toward β-arrestin recruitment...
March 16, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28267064/nerve-injury-induced-epigenetic-silencing-of-opioid-receptors-controlled-by-dnmt3a-in-primary-afferent-neurons
#9
Linlin Sun, Jian-Yuan Zhao, Xiyao Gu, Lingli Liang, Shaogen Wu, Kai Mo, Jian Feng, Weixiang Guo, Jun Zhang, Alex Bekker, Xinyu Zhao, Eric J Nestler, Yuan-Xiang Tao
Opioids are the gold standard for pharmacological treatment of neuropathic pain, but their analgesic effects are unsatisfactory in part due to nerve injury-induced downregulation of opioid receptors in dorsal root ganglia (DRG) neurons. How nerve injury drives such downregulation remains elusive. DNA methyltransferase-(DNMT-) triggered DNA methylation represses gene expression. We show here that blocking the nerve injury-induced increase in DRG DNMT3a (a de novo DNMT) rescued the expression of Oprm1 and Oprk1 mRNAs and their respective encoding mu opioid receptor (MOR) and kappa opioid receptor (KOR) proteins in the injured DRG...
March 4, 2017: Pain
https://www.readbyqxmd.com/read/28264976/a-pten-regulated-checkpoint-regulates-surface-delivery-of-delta-opioid-receptors
#10
Daniel J Shiwarski, Alycia Tipton, Melissa D Giraldo, Brigitte F Schmidt, Michael S Gold, Amynah A Pradhan, Manojkumar A Puthenveedu
The delta opioid receptor (δR) is a promising alternate target for pain management, because δR agonists show decreased abuse potential compared to current opioid analgesics that target the mu opioid receptor. A critical limitation in developing δR as an analgesic target, however, is that δR agonists show relatively low efficacy in vivo, requiring the use of high doses that often cause adverse effects such as convulsions. Here we tested whether intracellular retention of δR in sensory neurons contributes to this low δR agonist efficacy in vivo by limiting surface δR expression...
March 6, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28263712/synergistic-blockade-of-alcohol-escalation-drinking-in-mice-by-a-combination-of-novel-kappa-opioid-receptor-agonist-mesyl-salvinorin-b-and-naltrexone
#11
Yan Zhou, Rachel Saylor Cowley, Konrad Ben, Thomas E Prisinzano, Mary Jeanne Kreek
Mesyl Salvinorin B (MSB) is a potent selective kappa opioid receptor (KOP-r) agonist that has potential for development as an anti-psychostimulant agent with fewer side-effects (e.g., sedation, depression and dysphoria) than classic KOP-r agonists. However, no such study has been done on alcohol. We investigated whether MSB alone or in combination with naltrexone (mu-opioid receptor antagonist) altered voluntary alcohol drinking in both male and female mice. Mice, subjected to 3 weeks of chronic escalation drinking (CED) in a two-bottle choice paradigm with 24-h access every other day, developed rapid escalation of alcohol intake and high preference...
March 2, 2017: Brain Research
https://www.readbyqxmd.com/read/28226339/current-concepts-of-phenylpiperidine-derivatives-use-in-the-treatment-of-acute-and-chronic-pain
#12
Nidal Elbaridi, Alan D Kaye, Stephanie Choi, Richard D Urman
Phenylpiperidines are a chemical class of drugs with a phenyl moiety directly attached to piperidine. These agents have an important role in many aspects of medicine including anesthesia and pain medicine. After the development of meperidine, fentanyl, which is a second generation synthetic phenylpiperidine series opioid, was synthesized and introduced into clinical anesthesia practice as fentanyl citrate in 1968. Fentanyl-mediated or modulated responses involve action at the mu-opioid receptor as an agonist at the dorsal horn inhibiting ascending pain pathways in the rostral ventral medulla, increasing pain threshold, and producing both analgesic and sedative effects...
February 2017: Pain Physician
https://www.readbyqxmd.com/read/28217802/-comparison-of-agonists-induced-contraction-between-main-and-the-third-order-branches-of-pulmonary-arteries-in-rats
#13
Qiu-Hong Huang, Yun-Ping Mu, Fu-Rong Yan, Jie-Ling Zhu, Xiao-Ru Liu, Mo-Jun Lin
This study was designed to observe the differences between main pulmonary arteries and the third-order branches of pulmonary arteries in the contractile response to phenylephrine (Phen), endothelin-1 (ET-1) and potassium chloride (KCl). The vascular tension changes of main and the third-order branches of pulmonary arteries induced by KCl, ET-1 and Phen were recorded by traditional vascular tone detection methods and microvascular ring technique, respectively. The results showed that Phen could cause a significant contraction in main pulmonary arteries, but did not induce apparent contraction in the third-order branches of pulmonary arteries...
February 25, 2017: Sheng Li Xue Bao: [Acta Physiologica Sinica]
https://www.readbyqxmd.com/read/28215164/innovative-opioid-peptides-and-biased-agonism-novel-avenues-for-more-effective-and-safer-analgesics-to-treat-chronic-pain
#14
Andrea Bedini, Santi Mario Spampinato
Chronic pain is a clinically relevant and yet unsolved conditions that is poorly treated with the currently available drugs, thus highlighting the urgent need of innovative analgesics. Although opiates are not very effective in the treatment of inflammatory and neuropathic pain, developing novel opioid receptor peptide agonists, as well as modulating the opioid receptor-mediated responses in a ligand-specific fashion, may represent an innovative and promising strategy to identify more efficacious and safer antalgic drugs...
February 15, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28204957/insights-into-the-role-of-opioid-receptors-in-the-gi-tract-experimental-evidence-and-therapeutic-relevance
#15
James J Galligan, Catia Sternini
Opioid drugs are prescribed extensively for pain treatment but when used chronically they induce constipation that can progress to opioid-induced bowel dysfunction. Opioid drugs interact with three classes of opioid receptors: mu opioid receptors (MORs), delta opioid receptors (DOR), and kappa opioid receptors (KORs), but opioid drugs mostly target the MORs. Upon stimulation, opioid receptors couple to inhibitory Gi/Go proteins that activate or inhibit downstream effector proteins. MOR and DOR couple to inhibition of adenylate cyclase and voltage-gated Ca(2+) channels and to activation of K(+) channels resulting in reduced neuronal activity and neurotransmitter release...
February 16, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28192197/characterization-of-3-h-oxymorphone-binding-sites-in-mouse-brain-quantitative-autoradiography-in-opioid-receptor-knockout-mice
#16
Ji Hoon Yoo, Anna Borsodi, Géza Tóth, Sándor Benyhe, Robert Gaspar, Audrey Matifas, Brigitte L Kieffer, Athanasios Metaxas, Ian Kitchen, Alexis Bailey
Oxymorphone, one of oxycodone's metabolic products, is a potent opioid receptor agonist which is thought to contribute to the analgesic effect of its parent compound and may have high potential abuse liability. Nonetheless, the in vivo pharmacological binding profile of this drug is still unclear. This study uses mice lacking mu (MOP), kappa (KOP) or delta (DOP) opioid receptors as well as mice lacking all three opioid receptors to provide full characterisation of oxymorphone binding sites in the brain. Saturation binding studies using [(3)H]oxymorphone revealed high affinity binding sites in mouse brain displaying Kd of 1...
March 16, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28188737/genetic-variation-in-the-behavioral-effects-of-buprenorphine-in-female-mice-derived-from-a-murine-model-of-the-oprm1-a118g-polymorphism
#17
Caroline A Browne, Rebecca L Erickson, Julie A Blendy, Irwin Lucki
Pharmacogenetic studies have identified the non-synonymous single nucleotide polymorphism (A118G) in the human mu opioid receptor (MOR) gene (OPRM1) as a critical genetic variant capable of altering the efficacy of opioid therapeutics. To date few studies have explored the potential impact of the OPRM1 A118G polymorphism on the pharmacological effects of buprenorphine (BPN), a potent MOR partial agonist and kappa opioid receptor antagonist, which is approved by the FDA for the treatment of opioid addiction and chronic pain...
February 7, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28164119/sodium-ferulate-protects-against-angiotensin-ii-induced-cardiac-hypertrophy-in-mice-by-regulating-the-mapk-erk-and-jnk-pathways
#18
Bo Hu, Jian-Tao Song, Xian-Fei Ji, Zun-Qi Liu, Mu-Lin Cong, Dong-Xing Liu
Background and Objective. It has been reported that sodium ferulate (SF) has hematopoietic function against anemia and immune regulation, inflammatory reaction inhibition, inhibition of tumor cell proliferation, cardiovascular and cerebrovascular protection, and other functions. Thus, this study aimed to investigate the effects of SF on angiotensin II- (AngII-) induced cardiac hypertrophy in mice through the MAPK/ERK and JNK signaling pathways. Methods. Seventy-two male C57BL/6J mice were selected and divided into 6 groups: control group, PBS group, model group (AngII), model + low-dose SF group (AngII + 10 mg/kg SF), model + high-dose SF group (AngII + 40 mg/kg SF), and model + high-dose SF + agonist group (AngII + 40 mg/kg SCU + 10 mg/kg TBHQ)...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28158929/the-analgesic-and-anti-inflammatory-effects-of-salvinorin-a-analogue-%C3%AE-tetrahydropyran-salvinorin-b-in-mice
#19
K F Paton, N Kumar, R S Crowley, J L Harper, T E Prisinzano, B M Kivell
BACKGROUND: Drugs activating the mu opioid receptor are routinely used to treat severe acute and chronic pain. Unfortunately, side effects including nausea, constipation, respiratory depression, addiction and tolerance can limit clinical utility. In contrast, kappa opioid receptor (KOPr) agonists, such as Salvinorin A (SalA), have analgesic properties with little potential for abuse. METHODS: We evaluated SalA and the novel analogue β-tetrahydropyran Salvinorin B (β-THP SalB) for the ability to modulate pain and inflammation in vivo...
February 3, 2017: European Journal of Pain: EJP
https://www.readbyqxmd.com/read/28153853/epigenetic-activation-of-mu-opioid-receptor-mor-gene-via-increased-expression-and-function-of-mitogen-and-stress-activated-protein-kinase-1-msk1
#20
Yadav Wagley, Ping-Yee Law, Li-Na Wei, Horace H Loh
Since the discovery of mu opioid receptor (MOR) gene two decades ago, various regulatory factors have been shown to interact with the MOR promoter and modulate transcript levels. However, the majority of early transcriptional studies on MOR gene have not addressed how intracellular signaling pathways mediate extracellular modulators. In this study, we demonstrate that MOR epigenetic regulation requires multiple co-ordinated signals converged at the MOR promoter, involving mitogen-activated protein kinase (MAPK) activation and mitogen-and stress-activated protein kinase (MSK1) - similar ranges of intracellular signaling pathways that are activated by opioid agonists...
February 2, 2017: Molecular Pharmacology
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