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https://www.readbyqxmd.com/read/29029015/an-experimental-study-comparing-the-respiratory-effects-of-tapentadol-and-oxycodone-in-healthy-volunteers
#1
R van der Schrier, K Jonkman, M van Velzen, E Olofsen, A M Drewes, A Dahan, M Niesters
Background: There is a clinical need for potent opioids that produce little or no respiratory depression. In the current study we compared the respiratory effects of tapentadol, a mu-opioid receptor agonist and noradrenaline reuptake inhibitor, and oxycodone, a selective mu-opioid receptor agonist. We hypothesize that tapentadol 100 mg has a lesser effect on the control of breathing than oxycodone 20 mg. Methods: Fifteen healthy volunteers were randomized to receive oral tapentadol (100 and 150 mg), oxycodone 20 mg or placebo immediate release tablets in a crossover double-blind randomized design...
October 4, 2017: British Journal of Anaesthesia
https://www.readbyqxmd.com/read/28989282/spotlight-on-eluxadoline-for-the-treatment-of-patients-with-irritable-bowel-syndrome-with-diarrhea
#2
REVIEW
Konstantinos C Fragkos
BACKGROUND: Irritable bowel syndrome with diarrhea (IBS-D) has limited options for treatment currently, including mainly anti-motility medications, antispasmodics, and antidepressants. This review discusses the properties of a new drug, eluxadoline, a gut-targeting mu- and kappa-opioid receptor agonist and a delta-opioid receptor antagonist, and its efficacy and safety in patients with IBS-D. MATERIALS AND METHODS: A systematic review of the literature was undertaken to identify studies that had investigated eluxadoline as a treatment in IBS-D...
2017: Clinical and Experimental Gastroenterology
https://www.readbyqxmd.com/read/28891868/a-bivalent-ligand-that-activates-mu-opioid-receptor-and-antagonizes-mglur5-receptor-reduces-neuropathic-pain-in-mice
#3
Cristina D Peterson, Kelley F Kitto, Eyup Akgün, Mary M Lunzer, Maureen S Riedl, Lucy Vulchanova, George L Wilcox, Philip S Portoghese, Carolyn A Fairbanks
The mu opioid receptor (MOR) and metabotropic glutamate receptor 5 (mGluR5) are well-established pharmacological targets in the management of chronic pain. Both receptors are expressed in spinal cord. MMG22, a bivalent ligand containing two pharmacophores separated by 22 atoms that simultaneously activates MOR and antagonizes mGluR5 has been shown to produce potent reversal of tactile hypersensitivity in rodent models of LPS- and bone-cancer-induced chronic pain. The present study assessed whether intrathecal MMG22 also is effective in reducing pain of neuropathic origin...
September 1, 2017: Pain
https://www.readbyqxmd.com/read/28879802/anti-nociceptive-interactions-between-opioids-and-a-cannabinoid-receptor-2-agonist-in-inflammatory-pain
#4
Matthew B Yuill, David E Hale, Josée Guindon, Daniel J Morgan
The cannabinoid 1 receptor and cannabinoid 2 receptor can both be targeted in the treatment of pain; yet, they have some important differences. Cannabinoid 1 receptor is expressed at high levels in the central nervous system, whereas cannabinoid 2 receptor is found predominantly, although not exclusively, outside the central nervous system. The objective of this study was to investigate potential interactions between cannabinoid 2 receptor and the mu-opioid receptor in pathological pain. The low level of adverse side effects and lack of tolerance for cannabinoid 2 receptor agonists are attractive pharmacotherapeutic traits...
January 2017: Molecular Pain
https://www.readbyqxmd.com/read/28864212/14-o-methylmorphine-a-novel-selective-mu-opioid-receptor-agonist-with-high-efficacy-and-affinity
#5
Ferenc Zádor, Mihály Balogh, András Váradi, Zoltán S Zádori, Kornél Király, Edina Szűcs, Bence Varga, Bernadette Lázár, Sándor Hosztafi, Pál Riba, Sándor Benyhe, Susanna Fürst, Mahmoud Al-Khrasani
14-O-methyl (14-O-Me) group in morphine-6-O-sulfate (M6SU) or oxymorphone has been reported to be essential for enhanced affinity, potency and antinociceptive effect of these opioids. Herein we report on the pharmacological properties (potency, affinity and efficacy) of the new compound, 14-O-methylmorphine (14-O-MeM) in in vitro. Additionally, we also investigated the antinociceptive effect of the novel compound, as well as its inhibitory action on gastrointestinal transit in in vivo. The potency and efficacy of test compound were measured by [(35)S]GTPγS binding, isolated mouse vas deferens (MVD) and rat vas deferens (RVD) assays...
November 5, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28844812/antidepressant-like-effects-of-3-carboxamido-seco-nalmefene-3cs-nalmefene-a-novel-opioid-receptor-modulator-in-a-rat-ifn-%C3%AE-induced-depression-model
#6
Charlotte K Callaghan, Jennifer Rouine, Reginald L Dean, Brian I Knapp, Jean M Bidlack, Daniel R Deaver, Shane M O'Mara
Patients receiving the cytokine immunotherapy, interferon-alpha (IFN-α) frequently present with neuropsychiatric consequences and cognitive impairments. Patients (25-80%) report symptoms of depression, including, anhedonia, irritability, fatigue and impaired motivation. Our lab has previously demonstrated treatment (170,000IU/kg sc, 3 times per week for 4weeks) of the pro-inflammatory cytokine, IFN-α, induced a depressive phenotype in rats in the forced swim test (FST). Here, we examine the biological mechanisms underlying behavioral changes induced by IFN-α, which may be reflective of mechanisms underlying inflammation associated depression...
August 24, 2017: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/28841920/ipsilateral-eeg-mu-rhythm-reflects-the-excitability-of-uncrossed-pathways-projecting-to-shoulder-muscles
#7
Keita Hasegawa, Shoko Kasuga, Kenichi Takasaki, Katsuhiro Mizuno, Meigen Liu, Junichi Ushiba
BACKGROUND: Motor planning, imagery or execution is associated with event-related desynchronization (ERD) of mu rhythm oscillations (8-13 Hz) recordable over sensorimotor areas using electroencephalography (EEG). It was shown that motor imagery involving distal muscles, e.g. finger movements, results in contralateral ERD correlating with increased excitability of the contralateral corticospinal tract (c-CST). Following the rationale that purposefully increasing c-CST excitability might facilitate motor recovery after stroke, ERD recently became an attractive target for brain-computer interface (BCI)-based neurorehabilitation training...
August 25, 2017: Journal of Neuroengineering and Rehabilitation
https://www.readbyqxmd.com/read/28836121/nerve-decompression-improves-spinal-synaptic-plasticity-of-opioid-receptors-for-pain-relief
#8
To-Jung Tseng, Ming-Ling Yang, Yu-Lin Hsieh, Miau-Hwa Ko, Sung-Tsang Hsieh
Nerve decompression is an essential therapeutic strategy for pain relief clinically; however, its potential mechanism remains poorly understood. Opioid analgesics acting on opioid receptors (OR) within the various regions of the nervous system have been used widely for pain management. We therefore hypothesized that nerve decompression in a neuropathic pain model of chronic constriction injury (CCI) improves the synaptic OR plasticity in the dorsal horn, which is in response to alleviate pain hypersensitivity...
August 23, 2017: Neurotoxicity Research
https://www.readbyqxmd.com/read/28830758/the-medicinal-chemistry-and-neuropharmacology-of-kratom-a-preliminary-discussion-of-a-promising-medicinal-plant-and-analysis-of-its-potential-for-abuse
#9
REVIEW
Andrew C Kruegel, Oliver Grundmann
The leaves of Mitragyna speciosa (commonly known as kratom), a tree endogenous to parts of Southeast Asia, have been used traditionally for their stimulant, mood-elevating, and analgesic effects and have recently attracted significant attention due to increased use in Western cultures as an alternative medicine. The plant's active alkaloid constituents, mitragynine and 7-hydroxymitragynine, have been shown to modulate opioid receptors, acting as partial agonists at mu-opioid receptors and competitive antagonists at kappa- and delta-opioid receptors...
August 19, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28830120/detection-of-carfentanil-by-lc-ms-ms-and-reports-of-associated-fatalities-in-the-usa
#10
Kevin G Shanks, George S Behonick
Carfentanil is a mu (μ) opioid receptor agonist and is estimated to be ~10,000 times more potent than morphine in animal (non-human) models. It is not approved for human use and is only used to immobilize large exotic animals in veterinary medicine. In mid-2016, carfentanil emerged as a contaminant in street heroin in the USA and was central to a large number of emergency department visits and deaths. We describe an analytical method for the detection and quantification of carfentanil in whole blood specimens via a protein precipitation extraction with acetonitrile and liquid chromatography with triple quadrupole mass spectrometry...
July 1, 2017: Journal of Analytical Toxicology
https://www.readbyqxmd.com/read/28826482/anti-nociceptive-action-of-peripheral-mu-opioid-receptors-by-g-beta-gamma-protein-mediated-inhibition-of-trpm3-channels
#11
Sandeep Dembla, Marc Behrendt, Florian Mohr, Christian Goecke, Julia Sondermann, Franziska M Schneider, Marlene Schmidt, Julia Stab, Raissa Enzeroth, Michael G Leitner, Paulina Nuñez-Badinez, Jochen Schwenk, Bernd Nürnberg, Alejandro Cohen, Stephan E Philipp, Wolfgang Greffrath, Moritz Bünemann, Dominik Oliver, Eleonora Zakharian, Manuela Schmidt, Johannes Oberwinkler
Opioids, agonists of µ-opioid receptors (µORs), are the strongest pain killers clinically available. Their action includes a strong central component, which also causes important adverse effects. However, µORs are also found on the peripheral endings of nociceptors and their activation there produces meaningful analgesia. The cellular mechanisms downstream of peripheral µORs are not well understood. Here, we show in neurons of murine dorsal root ganglia that pro-nociceptive TRPM3 channels, present in the peripheral parts of nociceptors, are strongly inhibited by µOR activation, much more than other TRP channels in the same compartment, like TRPV1 and TRPA1...
August 15, 2017: ELife
https://www.readbyqxmd.com/read/28821664/differential-desensitization-observed-at-multiple-effectors-of-somatic-%C3%AE-opioid-receptors-underlies-sustained-agonist-mediated-inhibition-of-proopiomelanocortin-neuron-activity
#12
Philip D Fox, Shane T Hentges
Activation of somatic μ-opioid receptors (MORs) in hypothalamic proopiomelanocortin (POMC) neurons leads to the activation of G-protein-coupled inward rectifier potassium (GIRK) channels and hyperpolarization, but in response to continued signaling MORs undergo acute desensitization resulting in robust reduction in the peak GIRK current after minutes of agonist exposure. We hypothesized that the attenuation of the GIRK current would lead to a recovery of neuronal excitability whereby desensitization of the receptor would lead to a new steady state of POMC neuron activity reflecting the sustained GIRK current observed after the initial decline from peak with continued agonist exposure...
September 6, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28807672/pharmacological-characterization-of-novel-synthetic-opioids-nso-found-in-the-recreational-drug-marketplace
#13
REVIEW
Michael H Baumann, Susruta Majumdar, Valerie Le Rouzic, Amanda Hunkele, Rajendra Uprety, Xi Ping Huang, Jin Xu, Bryan L Roth, Ying-Xian Pan, Gavril W Pasternak
Novel synthetic opioids (NSO) are increasingly encountered in illicit heroin and counterfeit pain pills. Many NSO are resurrected from older biomedical literature or patent applications, so limited information is available about their biological effects. Here we examined the pharmacology of three structurally-distinct NSO found in the recreational drug market: N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenylbutyramide (butyrylfentanyl), 3,4-dichloro-N-[(1R,2R)-2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) and 1-cyclohexyl-4-(1,2-diphenylethyl)piperazine (MT-45)...
August 11, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28798303/understanding-the-molecular-basis-of-agonist-antagonist-mechanism-of-human-mu-opioid-receptor-through-gaussian-accelerated-molecular-dynamics-method
#14
Yeng-Tseng Wang, Yang-Hsiang Chan
The most powerful analgesic and addictive properties of opiate alkaloids are mediated by the μ opioid receptor (MOR). The MOR has been extensively investigated as a drug target in the twentieth century, with numerous compounds of varying efficacy being identified. We employed molecular dynamics and Gaussian accelerated molecular dynamics techniques to identify the binding mechanisms of MORs to BU72 (agonist) and β-funaltrexamine (antagonist). Our approach theoretically suggests that the 34 residues (Lys209-Phe221 and Ile301-Cys321) of the MORs were the key regions enabling the two compounds to bind to the active site of the MORs...
August 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28796483/placement-of-hydroxy-moiety-on-pendant-of-peptidomimetic-scaffold-modulates-mu-and-kappa-opioid-receptor-efficacy
#15
Aubrie A Harland, Irina D Pogozheva, Nicholas W Griggs, Tyler J Trask, John R Traynor, Henry I Mosberg
In an effort to expand the structure-activity relationship (SAR) studies of a series of mixed-efficacy opioid ligands, peptidomimetics that incorporate methoxy and hydroxy groups around a benzyl or 2-methylindanyl pendant on a tetrahydroquinoline (THQ) core of the peptidomimetics were evaluated. Compounds containing a methoxy or hydroxy moiety in the o- or m- positions increased binding affinity to the kappa opioid receptor (KOR), whereas compounds containing methoxy or hydroxy groups in the p- position decreased KOR affinity and reduced or eliminated efficacy at the mu opioid receptor (MOR)...
August 10, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28745394/opioids-for-chronic-non-cancer-pain-in-children-and-adolescents
#16
REVIEW
Tess E Cooper, Emma Fisher, Andrew L Gray, Elliot Krane, Navil Sethna, Miranda Al van Tilburg, Boris Zernikow, Philip J Wiffen
BACKGROUND: Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past, pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time, and relief of pain is now seen as importantWe designed a suite of seven reviews on chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol as priority areas) in order to review the evidence for children's pain utilising pharmacological interventions in children and adolescents...
July 26, 2017: Cochrane Database of Systematic Reviews
https://www.readbyqxmd.com/read/28743488/mu-opioid-receptor-biased-ligands-a-safer-and-painless-discovery-of-analgesics
#17
REVIEW
Abraham Madariaga-Mazón, Andrés F Marmolejo-Valencia, Yangmei Li, Lawrence Toll, Richard A Houghten, Karina Martinez-Mayorga
Biased activation of G-protein-coupled receptors (GPCRs) is shifting drug discovery efforts and appears promising for the development of safer drugs. The most effective analgesics to treat acute pain are agonists of the μ opioid receptor (μ-OR), a member of the GPCR superfamily. However, the analgesic use of opioid drugs, such as morphine, is hindered by adverse effects. Only a few μ-OR agonists have been reported to selectively activate the Gi over β-arrestin signaling pathway, resulting in lower gastrointestinal dysfunction and respiratory suppression...
July 22, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28727837/differing-roles-for-short-chain-fatty-acids-and-gpr43-agonism-in-the-regulation-of-intestinal-barrier-function-and-immune-responses
#18
Warren N D'Souza, Jason Douangpanya, Sharon Mu, Peter Jaeckel, Ming Zhang, Joseph R Maxwell, James B Rottman, Katja Labitzke, Angela Willee, Holger Beckmann, Yingcai Wang, Yang Li, Ralf Schwandner, James A Johnston, Jennifer E Towne, Hailing Hsu
Inflammatory bowel disease (IBD) is associated with a loss of intestinal barrier function and dysregulated immune responses. It has been shown that short chain fatty acids (SCFAs) are protective in IBD and that GPR43 mediates the protective effects of SCFAs. In this study, we investigated the effects of SCFAs in comparison to highly specific GPR43 agonists on human intestinal epithelial and immune cells. Our results confirm that SCFAs are enhancers of barrier function in intestinal epithelial cells. Additionally, SCFAs also displayed potent immunoregulatory properties based upon the ability to inhibit LPS-induced cytokine production in PBMC, and human T cell proliferation and cytokine production...
2017: PloS One
https://www.readbyqxmd.com/read/28699350/analgesic-properties-of-opioid-nk1-multitarget-ligands-with-distinct-in-vitro-profiles-in-naive-and-chronic-constriction-injury-mice
#19
Joanna Starnowska, Roberto Costante, Karel Guillemyn, Katarzyna Popiolek-Barczyk, Nga N Chung, Carole Lemieux, Attila Keresztes, Joost Van Duppen, Adriano Mollica, John Streicher, Jozef Vanden Broeck, Peter W Schiller, Dirk Tourwé, Joanna Mika, Steven Ballet, Barbara Przewlocka
The lower efficacy of opioids in neuropathic pain may be due to the increased activity of pronociceptive systems such as substance P. We present evidence to support this hypothesis in this work from the spinal cord in a neuropathic pain model in mice. Biochemical analysis confirmed the elevated mRNA and protein level of pronociceptive substance P, the major endogenous ligand of the neurokinin-1 (NK1) receptor, in the lumbar spinal cord of chronic constriction injury (CCI)-mice. To improve opioid efficacy in neuropathic pain, novel compounds containing opioid agonist and neurokinin 1 (NK1) receptor antagonist pharmacophores were designed...
July 26, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28674470/eluxadoline-viberzi-a-mu-opioid-receptor-agonist-for-the-treatment-of-irritable-bowel-syndrome-with-diarrhea
#20
Fraidy Maltz, Brooke Fidler
Eluxadoline (Viberzi) for the treatment of irritable bowel syndrome with diarrhea.
July 2017: P & T: a Peer-reviewed Journal for Formulary Management
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