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mu-opioid receptor

Rita Turnaturi, Carmela Parenti, Orazio Prezzavento, Agostino Marrazzo, Paschalina Pallaki, Zafiroula Georgoussi, Emanuele Amata, Lorella Pasquinucci
The opioid pharmacological profile of cis -(-)- N -normetazocine derivatives is deeply affected by the nature of their N -substituents. Here, our efforts were focused on the synthesis and pharmacological evaluation of novel derivatives of the lead LP1, a multitarget opioid analgesic compound featuring an N -phenylpropanamido substituent. LP1 derivatives 5a - d and 6a - d were characterized by flexible groups at the N -substituent that allow them to reposition themselves relative to cis -(-)- N -normetazocine nucleus, thus producing different pharmacological profiles at the mu, delta and kappa opioid receptors (MOR, DOR and KOR) in in vitro and in vivo assays...
March 16, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Samuel Obeng, Yunyun Yuan, Abdulmajeed Jali, Dana E Selley, Yan Zhang
Evidence has shown that downstream signaling by mu opioid receptor (MOR) agonists that recruit β-arrestin2 may lead to the development of tolerance. Also, it has been suggested that opioid receptor desensitization and cyclic AMP overshoot contributes to the development of tolerance and occurrence of withdrawal, respectively. Therefore, studies were conducted with 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3-carboxamido)morphinan (NAQ), a MOR selective partial agonist discovered in our laboratory, to characterize its effect on β-arrestin2 recruitment and precipitation of a cyclic AMP overshoot...
March 9, 2018: European Journal of Pharmacology
Meritxell Llorca-Torralba, Juan A Mico, Esther Berrocoso
The persistent activation of N-methyl-d-aspartate acid receptors (NMDARs) seems to be responsible for a series of changes in neurons associated with neuropathic pain, including the failure of opioids that act through mu-opioid receptors (MORs) to provide efficacious pain relief. As the noradrenergic locus coeruleus (LC) forms part of the endogenous analgesic system, we explored how intra-LC administration of morphine, a MORs agonist, alone or in combination with MK-801, a NMDARs antagonist, affects the sensorial and affective dimension of pain in a rat model of neuropathic pain; chronic constriction injury (CCI)...
March 7, 2018: Progress in Neuro-psychopharmacology & Biological Psychiatry
N Dietis, H Niwa, R Tose, J McDonald, V Ruggieri, M Filaferro, G Vitale, L Micheli, C Ghelardini, S Salvadori, G Calo, R Guerrini, D J Rowbotham, D G Lambert
BACKGROUND AND PURPOSE: Targeting more than one opioid receptor type simultaneously may have analgesic advantages in reduced side effect profile. We have evaluated the mixed MOP (μ, mu) agonist/DOP (δ, delta) antagonist UFP-505 in vitro and in vivo. EXPERIMENTAL APPROACH: We measured receptor density and function in single MOP, DOP and MOP/DOP double expression systems. GTPγ35 S binding, cAMP formation and arrestin recruitment were measured. Antinociceptive activity was measured in vivo using tail withdrawal and paw pressure tests following acute and chronic treatment...
March 10, 2018: British Journal of Pharmacology
Edward F Domino, Mika Hirasawa-Fujita
Introduction: The effects of smoking denicotinized (denic) and average nicotine (avnic) tobacco cigarettes were studied on brain mu opioid receptor binding by positron emission tomography with 11C carfentanil. The results indicated the importance of physiological and psychological effects induced by denic smoking. Methods: Regional mu opioid binding potential (non-displaceable binding potential, BPND) was measured in 20 adult male overnight abstinent chronic tobacco smokers...
March 5, 2018: Nicotine & Tobacco Research: Official Journal of the Society for Research on Nicotine and Tobacco
Justyna Piekielna-Ciesielska, Adriano Mollica, Stefano Pieretti, Jakub Fichna, Agata Szymaszkiewicz, Marta Zielińska, Radzisław Kordek, Anna Janecka
Opioid peptides and opiate drugs such as morphine, mediate their analgesic effects, but also undesired side effects, mostly through activation of the mu opioid receptor. However, delta- and kappa-opioid receptors can also contribute to the analgesic effects of opioids. Recent findings showed that simultaneous activation of multiple opioid receptors may result in additional analgesia with fewer side effects. Here, we evaluated the pharmacological profile of our formerly developed mixed mu/kappa-opioid receptor ligands, Dmt-c[D-Lys-Phe-Phe-Asp]NH2 (C-36) and Dmt-c[D-Lys-Phe-p-CF3 -Phe-Asp]NH2 (F-81)...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Nan Xie, Nicholas Matigian, Tharindu D Vithanage, Kye Gregory, Zeyad D Nassar, Peter J Cabot, Paul Nicholas Shaw, Carl Mj Kirkpatrick, Kim-Anh Lê Cao, David Sturgess, Marie-Odile Parat
PURPOSE: To investigate the potential interplay between opioid analgesia and tumour metastasis through modulation of μ opioid receptor (MOR), Toll-like receptor 4 (TLR4) activation, and matrix degradation potential. EXPERIMENTAL DESIGN: Plasma samples were collected from 60 patients undergoing elective lower limb joint replacement pre-operatively and at 3, 6 and 24 h after surgery; pain scores were documented at the same time points. Opioid administration was recorded and converted into morphine IV equivalents...
March 6, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
M E Sloan, T D Klepp, J L Gowin, J E Swan, H Sun, B L Stangl, V A Ramchandani
The endogenous opioid system may be involved in the development and maintenance of alcohol use disorder (AUD) and is a target for existing AUD pharmacotherapies. A functional polymorphism of the mu-opioid receptor gene (OPRM1 A118G, rs1799971) may alter the risk of developing AUD. Human laboratory studies have demonstrated that minor allele carriers self-administer more alcohol, show greater sensitivity to alcohol's effects, and exhibit increased alcohol-induced dopamine release. On the other hand, large genome-wide association studies and meta-analyses of candidate gene studies have not found an association between this genotype and alcohol dependence diagnosis...
February 2, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Yan Zhou, Rachel Crowley, Thomas Prisinzano, Mary Jeanne Kreek
Alcohol relapse plays a major role in alcohol dependence and is an important focus for the treatment of alcoholism. The alcohol deprivation effect (ADE) is a widely used paradigm in rodents to model the relapse episodes that occur in human alcoholics. Mesyl Salvinorin B (MSB) is a potent and selective kappa opioid receptor (KOP-r) full agonist, with fewer side effects (e.g., sedation or anhedonia) than classic KOP-r full agonists and a longer duration of action in mice than the structurally similar salvinorin A...
February 26, 2018: Neuroscience Letters
Yusuke Takagi, Etsuko Aruga
In 2010s, several opioids became available in Japan, including methadone, tapentadol and hydromorphone. Methadone was approved in September 2012 by Japanese regulatory authority. Since methadone is positioned as so-called "step 4 opioid" in Japan, it must be prescribed as alternative opioid switched from another of 60mg/day or greater equivalent dose of oral morphine. Diversity of pharmacokinetics among individuals and various drug interactions require close monitoring of adverse events. In spite of these cautions, unique characteristics such as inhibiting N-methyl-D-aspartate(NMDA)and in- ducing internalization/degradation of mu-delta opioid receptor heterodimers underline the value of methadone in opioid switching...
February 2018: Gan to Kagaku Ryoho. Cancer & Chemotherapy
Kornél Király, Márk Kozsurek, Erika Lukácsi, Benjamin Barta, Alán Alpár, Tamás Balázsa, Csaba Fekete, Judit Szabon, Zsuzsanna Helyes, Kata Bölcskei, Valéria Tékus, Zsuzsanna E Tóth, Károly Pap, Gábor Gerber, Zita Puskár
Altered pain sensations such as hyperalgesia and allodynia are characteristic features of various pain states, and remain difficult to treat. We have shown previously that spinal application of dipeptidyl peptidase 4 (DPP4) inhibitors induces strong antihyperalgesic effect during inflammatory pain. In this study we observed low level of DPP4 mRNA in the rat spinal dorsal horn in physiological conditions, which did not change significantly either in carrageenan-induced inflammatory or partial nerve ligation-generated neuropathic states...
February 22, 2018: Scientific Reports
Margaret I Davis, Jill R Crittenden, Austin Y Feng, David A Kupferschmidt, Alipi Naydenov, Nephi Stella, Ann M Graybiel, David M Lovinger
Presynaptic cannabinoid-1 receptors (CB1-R) bind endogenous and exogenous cannabinoids to modulate neurotransmitter release. CB1-Rs are expressed throughout the basal ganglia, including striatum and substantia nigra, where they play a role in learning and control of motivated actions. However, the pattern of CB1-R expression across different striatal compartments, microcircuits and efferent targets, and the contribution of different CB1-R-expressing neurons to this pattern, are unclear. We use a combination of conventional techniques and novel genetic models to evaluate CB1-R expression in striosome (patch) and matrix compartments of the striatum, and in nigral targets of striatal medium spiny projection neurons (MSNs)...
2018: PloS One
Jonathan E Harms, Audrey J Stone, Marc P Kaufman
Patients with peripheral artery disease show an exaggerated pressor response to mild exercise, an effect attributable to the exercise pressor reflex, whose afferent arm is comprised of the thinly myelinated group III and unmyelinated group IV afferents. Previously, we found that DAMGO, a μ opioid agonist injected into the femoral artery, attenuated the exaggerated exercise pressor reflex in rats with ligated femoral arteries, a preparation which simulates the blood flow patterns to muscle that is seen in patients with PAD...
February 21, 2018: Journal of Neurophysiology
Dionéia Araldi, Luiz F Ferrari, Jon D Levine
Repeated stimulation of mu-opioid receptors (MORs), by an MOR-selective agonist DAMGO induces type II priming, a form of nociceptor neuroplasticity, which has 2 components: opioid-induced hyperalgesia (OIH) and prolongation of prostaglandin-E2 (PGE2)-induced hyperalgesia. We report that intrathecal antisense knockdown of the MOR in nociceptors, prevented the induction of both components of type II priming. Type II priming was also eliminated by SSP-saporin, which destroys the peptidergic class of nociceptors...
January 11, 2018: Pain
Belin G Teklezgi, Annapurna Pamreddy, Sooraj Baijnath, Hendrik G Kruger, Tricia Naicker, Nirmala D Gopal, Thavendran Govender
Opioid addiction is a serious public health concern with severe health and social implications; therefore, extensive therapeutic efforts are required to keep users drug free. The two main pharmacological interventions, in the treatment of addiction, involve management with methadone an mu (μ)-opioid agonist and treatment with naltrexone, μ-opioid, kappa (κ)-opioid and delta (δ)-opioid antagonist. MET and NAL are believed to help individuals to derive maximum benefit from treatment and undergo a full recovery...
February 14, 2018: Addiction Biology
Sevasti Gaspari, Immanuel Purushothaman, Valeria Cogliani, Farhana Sakloth, Rachael L Neve, David Howland, Robert H Ring, Elliott M Ross, Li Shen, Venetia Zachariou
Regulator of G protein signaling z1 (RGSz1), a member of the RGS family of proteins, is present in several networks expressing mu opioid receptors (MOPRs). By using genetic mouse models for global or brain region-targeted manipulations of RGSz1 expression, we demonstrated that the suppression of RGSz1 function increases the analgesic efficacy of MOPR agonists in male and female mice and delays the development of morphine tolerance while decreasing the sensitivity to rewarding and locomotor activating effects...
February 12, 2018: Proceedings of the National Academy of Sciences of the United States of America
Dioneia Araldi, Eugen V Khomula, Luiz F Ferrari, Jon D Levine
Systemic fentanyl induces hyperalgesic priming, long-lasting neuroplasticity in nociceptor function characterized by prolongation of inflammatory mediator hyperalgesia. To evaluate priming at both nociceptor terminals, we studied, in male Sprague--Dawley rats, the effect of local administration of agents that reverse Type I (protein translation) or Type II (combination of Src and mitogen-activated protein kinase [MAPK]) priming. While at the central terminal, priming induced by systemic, intradermal or intrathecal fentanyl was reversed by the combination of Src and MAPK inhibitors, at the peripheral terminal it was reversed by the protein translation inhibitor...
February 5, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Gavril W Pasternak
Opioids continue to play a major role in medicine, but not without problems. Side effects limit their utility medically, while the potential of addiction has had a major societal impact. Pharmacologists have been trying to develop opioids lacking side effects since the first derivative, heroin, was synthesized in the 1870s. The identification of opioid receptors about 40 years ago opened up new insights into our understanding of opioid action, fueled by the molecular biology revolution of the 1980s and 1990s...
2018: Advances in Pharmacology
H Halawi, P Vijayvargiya, I Busciglio, I Oduyebo, D Khemani, M Ryks, D Rhoten, D Burton, L A Szarka, A Acosta, M Camilleri
BACKGROUND: Nausea, vomiting, and constipation (OIC) are common adverse effects of acute or chronic opioid use. Naloxegol (25 mg) is an approved peripherally active mu-opiate opioid receptor antagonist. AIM: To compare the effects on pan-gut transit of treatment with codeine, naloxegol, or combination in healthy volunteers. METHODS: We conducted a randomized, double-blind, placebo-controlled, single-center, parallel-group study in 72 healthy opioid-naïve adults, randomized to: codeine (30 mg q...
February 6, 2018: Neurogastroenterology and Motility: the Official Journal of the European Gastrointestinal Motility Society
Mark A Smith, Gaylen E Fronk, Jean M Abel, Ryan T Lacy, Sarah E Bills, Wendy J Lynch
RATIONALE: Preclinical studies consistently report that aerobic exercise decreases drug self-administration and other forms of drug-seeking behavior; however, relatively few studies have examined other types of physical activity. OBJECTIVES: The purpose of the present study was to examine the effects of resistance exercise (i.e., strength training) on heroin self-administration and mRNA expression of genes known to mediate opioid reinforcement and addictive behavior in the nucleus accumbens (NAc) of heroin-exposed rats...
February 2, 2018: Psychopharmacology
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