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κ opioid

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
Nathan Line, Aaron Burns, Sean Butler, Jerry Cashbolm, Craig J Forsyth
Salvinorin A (1) is natural product that in humans is a hallucinogen which binds the human κ-opioid receptor. A total synthesis has been developed that parlays 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
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
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
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
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...
October 1, 2016: Neurochemical Research
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
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
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
Wojciech Leppert, Jaroslaw Woron
Opioid-induced constipation (OIC) and other gastrointestinal (GI) symptoms of opioid-induced bowel dysfunction (OIBD) significantly deteriorate patients' quality of life and may lead to noncompliance with opioid schedule and undertreatment of pain. Although traditional oral laxatives are the first-line treatment of OIC, they do not address OIBD pathophysiology, and display numerous adverse effects. OIC treatment includes prokinetics (lubiprostone), opioid switch, and changing route of opioid administration...
September 2016: Therapeutic Advances in Gastroenterology
Manuel Pedro Pereira, Sonja Ständer
Pruritus is a symptom arising from a plethora of dermatological, neurological, and systemic conditions. The pathophysiological mechanisms involved in the transmission of acute and chronic pruritus are of high complexity and not yet fully understood. Recent research has enhanced the understanding of these mechanisms, enabling the development of novel drugs. Specifically, new therapies for inflammatory dermatoses, uremic pruritus, cholestatic pruritus, cutaneous T-cell lymphoma, and prurigo nodularis are being tested in ongoing randomized clinical trials...
2016: Current Problems in Dermatology
Juan Li, Xiaojie Liang, Yaguang Zhou, Shumiao Zhang, Fan Yang, Haitao Guo, Rong Fan, Na Feng, Min Jia, Yueming Wang, Mingchao Liu, Jianming Pei
Previously study showed κ-opioid receptor stimulation with exogenous κ-opioid receptor agonist elicited a protective effect against hypoxic pulmonary hypertension (HPH). However, the effect of endogenous κ-opioid receptor agonist dynorphin A on HPH remains unclear. This study was to determine the role of dynorphin in HPH. Hypoxia for 2 weeks induced HPH. Compared with the HPH group, the HPH + nor-BNI (a selective κ-opioid receptor antagonist) group showed a significant increase in mean pulmonary arterial pressure (mPAP)...
August 25, 2016: European Journal of Pharmacology
Elena Guerrieri, Marcel Bermudez, Gerhard Wolber, Ilona P Berzetei-Gurske, Helmut Schmidhammer, Mariana Spetea
The κ opioid (KOP) receptor crystal structure in an inactive state offers nowadays a valuable platform for inquiry into receptor function. We describe the synthesis, pharmacological evaluation and docking calculations of KOP receptor ligands from the class of diphenethylamines using an active-like structure of the KOP receptor attained by molecular dynamics simulations. The structure-activity relationships derived from computational studies was in accordance with pharmacological activities of targeted diphenethylamines at the KOP receptor established by competition binding and G protein activation in vitro assays...
October 1, 2016: Bioorganic & Medicinal Chemistry Letters
Xianwei Cui, Yun Li, Lei Yang, Lianghui You, Xing Wang, Chunmei Shi, Chenbo Ji, Xirong Guo
Breastfeeding is associated with a lower incidence of obesity, diabetes, and cardiovascular disease later in life. While macrosomic infants have a higher risk of developing obesity and other metabolic disorders. Breast milk may contain special nutrients to meet the different growth needs of different infants. Whether mothers make breast milk different to meet the requirement of macrosomic infants is still unknown. Here, we conducted a comparison between mothers delivering macrosomic and non-macrosomic infants in colostrum endogenous peptides...
August 23, 2016: Oncotarget
Katsuya Ohbuchi, Chika Miyagi, Yasuyuki Suzuki, Yasuharu Mizuhara, Keita Mizuno, Yuji Omiya, Masahiro Yamamoto, Eiji Warabi, Yuka Sudo, Akinobu Yokoyama, Kanako Miyano, Takatsugu Hirokawa, Yasuhito Uezono
Processed Aconiti tuber (PAT) is used to treat pain associated with various disorders. Although it has been demonstrated that the κ opioid receptor (KOR) signaling pathway is a mediator of the analgesic effect of PAT, active components affecting opioid signaling have not yet been identified. In this study, we explored candidate components of PAT by pharmacokinetic analysis and identified ignavine, which is a different structure from aconitine alkaloids. A receptor binding assay of opioid receptors showed that ignavine specifically binds the μ opioid receptor (MOR), not the KOR...
2016: Scientific Reports
Johanna Uhari-Väänänen, Atso Raasmaja, Pia Bäckström, Ville Oinio, Mikko Airavaara, Petteri Piepponen, Kalervo Kiianmaa
BACKGROUND: The nucleus accumbens shell is a key brain area mediating the reinforcing effects of ethanol (EtOH). Previously, it has been shown that the density of μ-opioid receptors in the nucleus accumbens shell is higher in alcohol-preferring Alko Alcohol (AA) rats than in alcohol-avoiding Alko Non-Alcohol rats. In addition, EtOH releases opioid peptides in the nucleus accumbens and opioid receptor antagonists are able to modify EtOH intake, all suggesting an opioidergic mechanism in the control of EtOH consumption...
October 2016: Alcoholism, Clinical and Experimental Research
Chunhua Chen, Chunhua Xi, Xuan Liang, Jingyuan Ma, Diansan Su, Ted Abel, Renyu Liu
OBJECTIVES: Our previous studies indicated that highly selective κ opioid receptor agonists could protect the brain, indicating an important role of κ opioid receptor agonist in brain ischemia. In this study, we investigated the role and related mechanisms of κ opioid receptor agonists in brain ischemia in a middle cerebral artery occlusion mouse model. DESIGN: Animal model. SETTING: Laboratory. SUBJECTS: The middle cerebral artery occlusion model was established by 120 minutes of ischemia followed by 24-hour reperfusion in male adult mice...
August 5, 2016: Critical Care Medicine
John Broad, Damien Maurel, Victor W S Kung, Gareth A Hicks, Michael Schemann, Michael R Barnes, Terrence P Kenakin, Sébastien Granier, Gareth J Sanger
If activation of recombinant G protein-coupled receptors in host cells (by drugs or other ligands) has predictive value, similar data must be obtained with native receptors naturally expressed in tissues. Using mouse and human recombinant κ opioid receptors transfected into a host cell, two selectively-acting compounds (ICI204448, asimadoline) equi-effectively activated both receptors, assessed by measuring two different cell signalling pathways which were equally affected without evidence of bias. In mouse intestine, naturally expressing κ receptors within its nervous system, both compounds also equi-effectively activated the receptor, inhibiting nerve-mediated muscle contraction...
2016: Scientific Reports
Meng-Yun Dou, Hao Wu, Hai-Juan Zhu, Shi-Yun Jin, Ye Zhang, Shu-Fang He
Remifentanil preconditioning has been demonstrated to reduce myocardial ischemia reperfusion injury in rat hearts, while the mechanisms are not fully understood. This study investigated the protective effects of remifentanil against hypoxia-reoxygenation injury in adult rat cardiomyocytes and the mechanisms involving opioid receptors and downstream phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) and extracellular signal-regulated kinase (ERK) signaling pathways. Adult rat cardiomyocytes were pretreated with remifentanil at different concentrations and then subjected to 90min hypoxia followed by 120min reoxygenation...
October 15, 2016: European Journal of Pharmacology
Jamie H Rose, Anushree N Karkhanis, Björn Steiniger-Brach, Sara R Jones
The development of pharmacotherapeutics that reduce relapse to alcohol drinking in patients with alcohol dependence is of considerable research interest. Preclinical data support a role for nucleus accumbens (NAc) κ opioid receptors (KOR) in chronic intermittent ethanol (CIE) exposure-induced increases in ethanol intake. Nalmefene, a high-affinity KOR partial agonist, reduces drinking in at-risk patients and relapse drinking in rodents, potentially due to its effects on NAc KORs. However, the effects of nalmefene on accumbal dopamine transmission and KOR function are poorly understood...
2016: International Journal of Molecular Sciences
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