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https://www.readbyqxmd.com/read/27922029/safety-of-eluxadoline-in-patients-with-irritable-bowel-syndrome-with-diarrhea
#1
Brooks D Cash, Brian E Lacy, Philip S Schoenfeld, Leonard S Dove, Paul S Covington
OBJECTIVES: Eluxadoline is a mixed μ-opioid receptor (OR) and κ-OR agonist and δ-OR antagonist, approved for the treatment of irritable bowel syndrome with diarrhea (IBS-D). This analysis evaluated the safety and tolerability of eluxadoline 75 and 100 mg twice daily (BID) in one Phase 2 (IBS-2001) and two Phase 3 (IBS-3001 and IBS-3002) studies. METHODS: Adults with IBS-D (Rome III criteria) were randomized to placebo or eluxadoline (75 or 100 mg) BID for 12 (IBS-2001), 26 (IBS-3002), or 52 (IBS-3001) weeks...
December 6, 2016: American Journal of Gastroenterology
https://www.readbyqxmd.com/read/27896372/opioid-receptor-agonists-may-favorably-affect-bone-mechanical-properties-in-rats-with-estrogen-deficiency-induced-osteoporosis
#2
Aleksandra Janas, Joanna Folwarczna
The results of epidemiological, clinical, and in vivo and in vitro experimental studies on the effect of opioid analgesics on bone are inconsistent. The aim of the present study was to investigate the effect of morphine (an agonist of opioid receptors), buprenorphine (a partial μ opioid receptor agonist and κ opioid receptor antagonist), and naloxone (an antagonist of opioid receptors) on the skeletal system of female rats in vivo. The experiments were carried out on 3-month-old Wistar rats, divided into two groups: nonovariectomized (intact; NOVX) rats and ovariectomized (OVX) rats...
November 28, 2016: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/27886263/nicotinic-and-opioid-receptor-regulation-of-striatal-dopamine-d2-receptor-mediated-transmission
#3
Aphroditi A Mamaligas, Yuan Cai, Christopher P Ford
In addition to dopamine neuron firing, cholinergic interneurons (ChIs) regulate dopamine release in the striatum via presynaptic nicotinic receptors (nAChRs) on dopamine axon terminals. Synchronous activity of ChIs is necessary to evoke dopamine release through this pathway. The frequency-dependence of disynaptic nicotinic modulation has led to the hypothesis that nAChRs act as a high-pass filter in the dopaminergic microcircuit. Here, we used optogenetics to selectively stimulate either ChIs or dopamine terminals directly in the striatum...
November 25, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27865836/g-protein-coupled-kinase-2-upregulation-causes-%C3%AE%C2%BA-opioid-receptor-desensitization-in-diabetic-heart
#4
Xiyao Chen, Shihao Zhao, Yunlong Xia, Zhenyu Xiong, Yueyang Li, Ling Tao, Fuyang Zhang, Xiaoming Wang
Activation of κ-opioid receptor (KOR) ameliorates myocardial ischemia/reperfusion (I/R) injury; however, cardioprotective effects of KOR stimulation disappear in type 1 diabetic subjects with hyperglycemia. The molecular mechanisms underlying this phenomenon remain unknown. Here we found that KOR expression was obviously downregulated and KOR agonism-induced contractile-regulatory/cardioprotective effects were significantly impaired in hearts isolated from streptozotocin (STZ) injection-induced diabetic mice...
November 16, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27849111/pharmacological-interventions-for-pruritus-in-adult-palliative-care-patients
#5
REVIEW
Waldemar Siemens, Carola Xander, Joerg J Meerpohl, Sabine Buroh, Gerd Antes, Guido Schwarzer, Gerhild Becker
BACKGROUND: This is an update of the original Cochrane review published in 2013 (Issue 6). Pruritus occurs in patients with disparate underlying diseases and is caused by different pathologic mechanisms. In palliative care patients, pruritus is not the most prevalent but is one of the most puzzling symptoms. It can cause considerable discomfort and affects patients' quality of life. OBJECTIVES: To assess the effects of different pharmacological treatments for preventing or treating pruritus in adult palliative care patients...
November 16, 2016: Cochrane Database of Systematic Reviews
https://www.readbyqxmd.com/read/27821345/n-18-f-fluoropropyljdtic-for-%C3%AE%C2%BA-opioid-receptor-pet-imaging-radiosynthesis-pre-clinical-evaluation-and-metabolic-investigation-in-comparison-with-parent-jdtic
#6
Sébastien Schmitt, Jérôme Delamare, Olivier Tirel, Fabien Fillesoye, Martine Dhilly, Cécile Perrio
INTRODUCTION: To image kappa opioid receptor (KOR) for preclinical studies, N-fluoropropylJDTic 9 derived from the best-established KOR antagonist JDTic, was labeled with fluorine-18. METHODS: Radiosynthesis of [(18)F]9 was achieved according to an automated two-step procedure from [(18)F]-fluoride. Peripheral and cerebral distributions were determined by ex vivo experiments and by PET imaging in mouse. Radiometabolism studies were performed both in vivo in mice and in vitro in mouse and human liver microsomes...
September 26, 2016: Nuclear Medicine and Biology
https://www.readbyqxmd.com/read/27802429/kappa-opioid-agonist-u50-488h-mediated-protection-against-heart-failure-following-myocardial-ischemia-reperfusion-dual-roles-of-heme-oxygenase-1
#7
Guang Tong, Ben Zhang, Xuan Zhou, Jinbo Zhao, Zhongchan Sun, Ye Tao, Jianming Pei, Weida Zhang
BACKGROUNDS/AIMS: The selective κ-opioid agonist U50,488H protects heart from myocardial ischemia-reperfusion (MI/R) injury. We examined whether U50,488H is also beneficial for MI/R induced heart failure. METHODS: Anesthetized male Sprague-Dawley rats were subjected to 30 min of myocardial ischemia via left anterior descending coronary artery (LAD) occlusion, followed by 4 weeks of reperfusion. Infarct size was examined by Evans blue/triphenyl tetrazolium chloride (TTC) staining...
2016: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/27798836/structure-based-optimization-of-multifunctional-agonists-for-opioid-and-neuropeptide-ff-receptors-with-potent-non-tolerance-forming-analgesic-activities
#8
Zi-Long Wang, Jia-Xin Pan, Jing-Jing Song, Hong-Hai Tang, Hong-Ping Yu, Xu-Hui Li, Ning Li, Ting Zhang, Run Zhang, Meng-Na Zhang, Biao Xu, Quan Fang, Rui Wang
The opioid and neuropeptide FF pharmacophore-containing chimeric peptide 0 (BN-9) was recently developed and produced potent non-tolerance forming analgesia. In this study, eleven analogs of 0 were designed and synthesized. An in vitro cAMP assay demonstrated that these analogs behaved as multifunctional agonists at both opioid and NPFF receptors. In mouse tail-flick test, most of the analogs produced potent non-tolerance forming antinociception. Notably, 11 (DN-9) was 33-fold more potent than 0 at analgesic effects, which was mediated by μ- and κ-opioid receptors...
October 31, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27785643/activation-of-peripheral-%C3%AE%C2%BA-opioid-receptors-normalizes-caffeine-effects-modified-in-nicotine-dependent-rats-during-nicotine-withdrawal
#9
S K Sudakov, N G Bogdanova
The study examined the effect of peripheral (intragastric) ICI-204,448, an agonist of gastric κ-opioid receptors, on the psychostimulating and anxiolytic effects of caffeine in nicotinedependent rats at the stage of nicotine withdrawal. In these rats, the effects of caffeine (10 mg/kg) were perverted. In nicotine-dependent rats, caffeine produced an anxiolytic effect accompanied by pronounced stimulation of motor activity, in contrast to anxiogenic effect induced by caffeine in intact rats without nicotine dependence...
October 26, 2016: Bulletin of Experimental Biology and Medicine
https://www.readbyqxmd.com/read/27783050/morphine-protects-spinal-cord-astrocytes-from-glutamate-induced-apoptosis-via-reducing-endoplasmic-reticulum-stress
#10
Chao Zhang, Chendan Wang, Jianbo Ren, Xiangjie Guo, Keming Yun
Glutamate is not only a neurotransmitter but also an important neurotoxin in central nervous system (CNS). Chronic elevation of glutamate induces both neuronal and glial cell apoptosis. However, its effect on astrocytes is complex and still remains unclear. In this study, we investigated whether morphine, a common opioid ligand, could affect glutamate-induced apoptosis in astrocytes. Primary cultured astrocytes were incubated with glutamate in the presence/absence of morphine. It was found that morphine could reduce glutamate-induced apoptosis of astrocytes...
October 24, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27776274/discovery-structure-activity-relationship-studies-and-anti-nociceptive-effects-of-n-1-2-3-4-tetrahydro-1-isoquinolinylmethyl-benzamides-as-novel-opioid-receptor-agonists
#11
Sheng-Ren Chen, Yi-Yu Ke, Teng-Kuang Yeh, Shu-Yu Lin, Li-Chin Ou, Shu-Chun Chen, Wan-Ting Chang, Hsiao-Fu Chang, Zih-Huei Wu, Chih-Chien Hsieh, Ping-Yee Law, Horace H Loh, Chuan Shih, Yiu-Kay Lai, Shiu-Hwa Yeh, Shau-Hua Ueng
μ-Opioid receptor (MOR) agonists are analgesics used clinically for the treatment of moderate to severe pain, but their use is associated with severe adverse effects such as respiratory depression, constipation, tolerance, dependence, and rewarding effects. In this study, we identified N-({2-[(4-bromo-2-trifluoromethoxyphenyl)sulfonyl]-1,2,3,4-tetrahydro-1-isoquinolinyl}methyl)cyclohexanecarboxamide (1) as a novel opioid receptor agonist by high-throughput screening. Structural modifications made to 1 to improve potency and blood-brain-barrier (BBB) penetration resulted in compounds 45 and 46...
September 20, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27761113/ester-hydrolysis-differentially-reduces-aconitine-induced-anti-hypersensitivity-and-acute-neurotoxicity-involvement-of-spinal-microglial-dynorphin-expression-and-implications-for-aconitum-processing
#12
Teng-Fei Li, Nian Gong, Yong-Xiang Wang
Aconitines, including bulleyaconitine A, probably the most bioactive and abundant alkaloids in Aconitum plant, are a group of diester C19-diterpenoid alkaloids with one acetylester group attached to C8 of the diterpenoid skeleton and one benzoylester group to C14. Hydrolysis of both groups is involved in the processing of Aconitum, a traditional Chinese medicinal approach. We recently demonstrated that bulleyaconitine A produced anti-hypersensitivity, which was mediated by stimulation of spinal microglial dynorphin A expression...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27758012/total-synthesis-of-salvinorin%C3%A2-a
#13
Nathan J Line, Aaron C Burns, Sean C Butler, Jerry Casbohm, Craig J Forsyth
Salvinorin A (1) is natural hallucinogen that binds the human κ-opioid receptor. A total synthesis has been developed that parlays the stereochemistry of l-(+)-tartaric acid into that of (-)-1 via an unprecedented allylic dithiane intramolecular Diels-Alder reaction to obtain the trans-decalin scaffold. Tsuji allylation set the C9 quaternary center and a late-stage stereoselective chiral ligand-assisted addition of a 3-titanium furan upon a C12 aldehyde/C17 methyl ester established the furanyl lactone moiety...
October 18, 2016: Chemistry: a European Journal
https://www.readbyqxmd.com/read/27753159/efficacy-of-nalfurafine-hydrochloride-in-patients-with-chronic-liver-disease-with-refractory-pruritus-a-randomized-double-blind-trial
#14
Hiromitsu Kumada, Hiroshi Miyakawa, Taro Muramatsu, Naoki Ando, Takanori Oh, Kenji Takamori, Hidetomo Nakamoto
AIMS: Patients with chronic liver disease sometimes develop cholestasis, which induces severe whole-body pruritus that may disrupt daily activities and sleep. To determine the efficacy of nalfurafine hydrochloride (5 µg), which is a selective κ-opioid receptor agonist, in improving pruritus, we conducted a double-blind placebo-controlled study in patients with chronic liver disease with refractory pruritus. Nalfurafine hydrochloride at 2.5 µg was also used to evaluate the dose-response relationship...
October 18, 2016: Hepatology Research: the Official Journal of the Japan Society of Hepatology
https://www.readbyqxmd.com/read/27736318/norbni-blocks-the-adverse-effects-of-morphine-following-spinal-cord-injury
#15
Miriam Aceves, Eric Bancroft, Alejandro R Aceves, Michelle Hook
Opioids are frequently used for the treatment of pain following spinal cord injury (SCI). Unfortunately, we have shown that morphine administered in the acute phase of SCI results in significant, adverse secondary consequences including compromised locomotor and sensory recovery. Similarly, we showed that selective activation of the κ-opioid receptor (KOR), even at a dose 32-fold lower than morphine, is sufficient to attenuate recovery of locomotor function. In the current study, we tested whether activation of the KOR is necessary to produce morphine's adverse effects using nor-Binaltorphimine (norBNI), a selective KOR antagonist...
October 13, 2016: Journal of Neurotrauma
https://www.readbyqxmd.com/read/27700049/pharmacodynamic-relationships-between-duration-of-action-of-jdtic-like-kappa-opioid-receptor-antagonists-and-their-brain-and-plasma-pharmacokinetics-in-rats
#16
S Michael Owens, Gerald T Pollard, James L Howard, Timothy R Fennell, Rodney W Snyder, F Ivy Carroll
JDTic is a potent and selective κ-opioid receptor (KOR) antagonist that reverses U50,488-induced diuresis in rats. It partitions into brain with a duration of action lasting for weeks. In a search for KOR antagonists that do not accumulate in the brain, we compared single doses of five methylated JDTic analogs (RTI-97, -194, -212, -240, and -241) for reversal of U50,488 diuresis and pharmacokinetic (PK) properties. All six compounds showed potent and selective KOR antagonism in a [(35)S]GTPγS binding assay...
October 4, 2016: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/27696120/role-of-estradiol-in-the-regulation-of-prolactin-secretion-during-late-pregnancy
#17
Carlos Villegas-Gabutti, Gisela E Pennacchio, Graciela A Jahn, Marta Soaje
Estrogen action is necessary for evidencing the stimulatory action of mifepristone and naloxone on prolactin (PRL) secretion during late pregnancy. Our aim is to determine the mechanism mediating this facilitator action of estrogens. To investigate the hypothalamic mechanisms involved in estrogen actions in PRL secretion at the end of pregnancy, we measured the effect of pretreatment with the estrogen antagonist tamoxifen on the expression of tyrosine hydroxylase (TH), hormone receptors (ERα and β, PRs, PRLR(long)), and μ- and κ- opioid receptors (ORs) at mRNA (by semiquantitative RT-PCR) and protein (by western blot for TH, PRLR(long), ERα, PRs, μ- and ORs) levels in extracts of medial basal hypothalamus (MBH) and serum PRL, E2 and P4 levels (by RIA) in mifepristone- and naloxone-treated rats...
December 2016: Neurochemical Research
https://www.readbyqxmd.com/read/27647873/abuse-potential-and-pharmacodynamic-characteristics-of-oral-and-intranasal-eluxadoline-a-mixed-%C3%AE-and-%C3%AE%C2%BA-opioid-receptor-agonist-and-%C3%AE-opioid-receptor-antagonist
#18
Naama Levy-Cooperman, Gail McIntyre, Laura Bonifacio, Michael McDonnell, J Michael Davenport, Paul S Covington, Leonard S Dove, Edward M Sellers
Drugs with μ-opioid receptor (OR) activity can be associated with abuse and misuse. The peripherally acting mixed μ-OR and κ-OR agonist and δ-OR antagonist, eluxadoline, is approved in the US for the treatment of irritable bowel syndrome with diarrhea. In two separate crossover studies, we evaluated the oral and intranasal abuse potential of eluxadoline versus placebo and the active control oxycodone. Healthy recreational opioid users received eluxadoline 100, 300, and 1000 mg, oxycodone 30 and 60 mg, and placebo (oral study), or eluxadoline 100 and 200 mg, oxycodone 15 and 30 mg, and placebos matched to eluxadoline and oxycodone (intranasal study)...
September 19, 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27607020/versatile-picklocks-to-access-all-opioid-receptors-tuning-the-selectivity-and-functional-profile-of-the-cyclotetrapeptide-c-phe-d-pro-phe-trp-cj-15-208
#19
Rossella De Marco, Andrea Bedini, Santi Spampinato, Lorenzo Cavina, Edoardo Pirazzoli, Luca Gentilucci
Recently, the tryptophan-containing noncationizable opioid peptides emerged with atypical structure and unexpected in vivo activity. Herein, we describe analogs of the naturally occurring mixed κ/μ-ligand c[Phe-d-Pro-Phe-Trp] 1 (CJ-15,208). Receptor affinity, selectivity, and agonism/antagonism varied upon enlarging macrocycle size, giving the μ-agonist 9 or the δ-antagonist 10 characterized by low nanomolar affinity. In particular, the μ-agonist c[β-Ala-d-Pro-Phe-Trp] 9 was shown to elicit potent antinociception in a mouse model of visceral pain upon systemic administration...
October 13, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27588082/effects-of-the-%C3%AE%C2%BA-opioid-receptor-on-the-inhibition-of-100-hz-electroacupuncture-on-cocaine-induced-conditioned-place-preference
#20
Bingjun Hou
The administration of 100 Hz electroacupuncture has been demonstrated to suppress cocaine-induced conditioned place preference (CPP) in rats, and there is evidence that the κ-opioid receptor may have a role in cocaine addiction. The present study sought to explore the mechanisms underlying the inhibitory effects of 100 Hz electroacupuncture on cocaine-induced CPP in rats. A rat model of cocaine-induced CPP was used in the present study to investigate the following: i) Naloxone treatment (5 and 10 mg/kg) following 100 Hz electroacupuncture-mediated inhibition on cocaine-induced CPP, revealing that a high dose (10 mg/kg) of naloxone blocked the inhibitory effects of 100 Hz electroacupuncture on cocaine-induced CPP; ii) nor-binaltorphimine (nor-BNI) on 100 Hz electroacupuncture-mediated inhibition on cocaine-induced CPP, which indicated that administration of 10 µg/5 µl and 0...
September 2016: Experimental and Therapeutic Medicine
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