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Gregory N Ruegsegger, Jacob D Brown, M Cathleen Kovarik, Dennis K Miller, Frank W Booth
The mesolimbic dopamine and opioid systems are postulated to influence the central control of physical activity motivation. We utilized selectively bred rats for high (HVR) or low (LVR) voluntary running behavior to examine 1) inherent differences in mu-opioid receptor (Oprm1) expression and function in the nucleus accumbens (NAc), 2) if dopamine-related mRNAs, wheel-running, and food intake are differently influenced by intraperitoneal (i.p.) naltrexone injection in HVR and LVR rats, and 3) if dopamine is required for naltrexone-induced changes in running and feeding behavior in HVR rats...
October 12, 2016: Neuroscience
Jianguo Zhuang, Xiuping Gao, Franklin Gao, Fadi Xu
We tested the hypothesis that mu-opioid receptors (MORs) in the caudomedial nucleus tractus solitarius (cmNTS) are important for the ventilatory responses to stimulation of bronchopulmonary C-fibers (PCFs), the carotid body-mediated hypoxia, and hypercapnia independent of the carotid body. First, we used immunohistochemistry to map MORs distribution in the caudal medulla. Then we compared the effects of intra-cmNTS microinjection of DAMGO (a MOR agonist) with or without a combination of CTAP (a MOR antagonist) on the ventilatory responses to: 1) right atrial injection of capsaicin (to stimulation of PCFs) and 2) acute hypoxia (HVR, to stimulate the carotid body) in awake intact rats; and 3) hypercapnia (HCVR) in the carotid body ablated rats...
October 12, 2016: Respiratory Physiology & Neurobiology
Eiko Yokota, Yuko Koyanagi, Kiyofumi Yamamoto, Yoshiyuki Oi, Noriaki Koshikawa, Masayuki Kobayashi
The insular cortex (IC) plays a principal role in the regulation of pain processing. Although opioidergic agonists depress cortical excitatory synaptic transmission, little is known about opioidergic roles in inhibitory synaptic transmission. In the IC, the opioid receptors differentially regulate the excitatory propagation: agonists of the mu (MOR), delta (DOR), and kappa (KOR) exhibit suppressive, facilitative, and little effects, respectively. Thus, we aimed to examine the effects of opioid receptor agonists on unitary inhibitory postsynaptic currents (uIPSCs) in the IC...
October 7, 2016: Neuroscience
Laura C Sullivan, Teresa A Chavera, Raehannah J Jamshidi, Kelly A Berg, William P Clarke
Opioid receptors expressed by peripheral pain-sensing neurons are functionally inactive for antinociceptive signaling under most basal conditions, however, tissue damage or exposure to inflammatory mediators (e.g., bradykinin) converts these receptors from a non-responsive state to a functionally competent state. Here we tested the hypothesis that the basal, non-responsive state of the mu and delta opioid receptors (MOR and DOR, respectively) is the result of constitutive receptor activity that activates desensitization mechanisms, resulting in MOR and DOR receptor systems that are constitutively desensitized...
September 22, 2016: Journal of Pharmacology and Experimental Therapeutics
Gina F Marrone, Zhigang Lu, Grace Rossi, Ankita Narayan, Amanda Hunkele, Sarah Marx, Jin Xu, John Pintar, Susruta Majumdar, Ying-Xian Pan, Gavril W Pasternak
The mu opioid receptor gene undergoes extensive alternative splicing. Mu opioids can be divided into three classes based on the role of different groups of splice variants. Morphine and methadone require only full length seven transmembrane (7TM) variants for analgesia, whereas IBNtxA (3'-iodobenzyol-6β-naltrexamide) needs only truncated 6TM variants. A set of endomorphin analogs fall into a third group that requires both 6TM and 7TM splice variants. Unlike morphine, endomorphin 1 and 2, DAPP (Dmt,d-Ala-Phe-Phe-NH2), and IDAPP (3'-iodo-Dmt-d-Ala-Phe-Phe-NH2) analgesia was lost in an exon 11 knockout mouse lacking 6TM variants...
October 10, 2016: ACS Chemical Neuroscience
Pyung Sun Cho, Han Kyu Lee, Sang Hoon Lee, Jay Zoon Im, Sung Jun Jung
The analgesic mechanism of opioids is known to decrease the excitability of substantia gelatinosa (SG) neurons receiving the synaptic inputs from primary nociceptive afferent fiber by increasing inwardly rectifying K(+) current. In this study, we examined whether a µ-opioid agonist, [D-Ala2,N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO), affects the two-pore domain K(+) channel (K2P) current in rat SG neurons using a slice whole-cell patch clamp technique. Also we confirmed which subtypes of K2P channels were associated with DAMGO-induced currents, measuring the expression of K2P channel in whole spinal cord and SG region...
September 2016: Korean Journal of Physiology & Pharmacology
Barbora Melkes, Lucie Hejnova, Jiri Novotny
There are some indications that biased μ-opioid ligands may diversely affect μ-opioid receptor (MOR) properties. Here, we used confocal fluorescence recovery after photobleaching (FRAP) to study the regulation by different MOR agonists of receptor movement within the plasma membrane of HEK293 cells stably expressing a functional yellow fluorescent protein (YFP)-tagged μ-opioid receptor (MOR-YFP). We found that the lateral mobility of MOR-YFP was increased by (D-Ala(2),N-MePhe(4),Gly(5)-ol)-enkephalin (DAMGO) and to a lesser extent also by morphine but decreased by endomorphin-2...
September 6, 2016: Naunyn-Schmiedeberg's Archives of Pharmacology
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
Eva Tudurí, Daniel Beiroa, Johannes Stegbauer, Johan Fernø, Miguel López, Carlos Diéguez, Rubén Nogueiras
Pancreatic insulin-secreting β-cells express opioid receptors, whose activation by opioid peptides modulates hormone secretion. Opioid receptors are also expressed in multiple brain regions including the hypothalamus, where they play a role in feeding behavior and energy homeostasis, but their potential role in central regulation of glucose metabolism is unknown. Here, we investigate whether central opioid receptors participate in the regulation of insulin secretion and glucose homeostasis in vivo. C57BL/6J mice were acutely treated by intracerebroventricular (i...
November 2016: Neuropharmacology
Derik Hermann, Natalie Hirth, Matthias Reimold, Anil Batra, Michael N Smolka, Sabine Hoffmann, Falk Kiefer, Hamid R Noori, Wolfgang H Sommer, Gerald Reischl, Christian la Fougère, Karl Mann, Rainer Spanagel, Anita C Hansson
Blockade of the μ-opioid receptor (MOR) by naltrexone reduces relapse risk in a subpopulation of alcohol-dependent patients. Previous positron-emission-tomography (PET) studies using the MOR ligand [(11)C]carfentanil have found increased MOR availability in abstinent alcoholics, which may reflect either increased MOR expression or lower endogenous ligand concentration. To differentiate between both effects, we investigated two cohorts of alcoholic subjects using either post-mortem or clinical PET analysis...
August 11, 2016: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
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
Q-Schick Auh, Yang Hyun Chun, Ohannes K Melemedjian, Youping Zhang, Jin Y Ro
Activation of opioid and cannabinoid receptors expressed in nociceptors induces effective antihyperalgesia. In this study, we examined whether combinations of opioid and cannabinoid receptor agonists directed at the injured site would enhance therapeutic effectiveness. Behavioral pharmacology experiments were performed to compare the effects of DAMGO, a selective agonist for μ-opioid receptor (MOR), ACPA, a specific agonist for CB1, and combinations of DAMGO and ACPA in attenuating complete Freund's adjuvant (CFA)-induced mechanical hyperalgesia in the rat hindpaw...
July 2016: Brain Research Bulletin
Maciej Maciejczyk, Anika Lasota, Oliwia Frączak, Piotr Kosson, Aleksandra Misicka, Michał Nowakowski, Andrzej Ejchart, Aleksandra Olma
The synthesis of new dermorphin analogues is described. The (R)-alanine or phenylalanine residues of natural dermorphin were substituted by the corresponding α-methyl-β-azidoalanine or α-benzyl-β-azido(1-piperidinyl)alanine residues. The potency and selectivity of the new analogues were evaluated by a competitive receptor binding assay in rat brain using [(3) H]DAMGO (a μ ligand) and [(3) H]DELT (a δ ligand). The most active analogue in this series, Tyr-(R)-Ala-(R)-α-benzyl-β-azidoAla-Gly-Tyr-Pro-Ser-NH2 and its epimer were analysed by (1) H and (13) C NMR spectroscopy and restrained molecular dynamics simulations...
August 2016: Journal of Peptide Science: An Official Publication of the European Peptide Society
Elyssa B Margolis, Howard L Fields
Increased activity of lateral habenula (LHb) neurons is correlated with aversive states including pain, opioid abstinence, rodent models of depression, and failure to receive a predicted reward. Agonists at the mu opioid receptor (MOR) are among the most powerful rewarding and pain relieving drugs. Injection of the MOR agonist morphine directly into the habenula produces analgesia, raising the possibility that MOR acts locally within the LHb. Consequently, we examined the synaptic actions of MOR agonists in the LHb using whole cell patch clamp recording...
2016: PloS One
Annika Lindqvist, Markus Fridén, Margareta Hammarlund-Udenaes
The use of nanocarriers is an intriguing solution to increase the brain delivery of novel therapeutics. The aim of this paper was to use pharmacokinetic analysis and simulations to identify key factors that determine the effective drug concentration-time profile at the target site in the brain. Model building and simulations were based on experimental data obtained from the administration of the opioid peptide DAMGO in glutathione tagged PEGylated liposomes to rats. Different pharmacokinetic models were investigated to explore the mechanisms of increased brain delivery...
September 20, 2016: European Journal of Pharmaceutical Sciences
Joslyn Lay, Simona E Carbone, Jesse J DiCello, Nigel W Bunnett, Meritxell Canals, Daniel P Poole
The μ-opioid receptor (MOR) is a major regulator of gastrointestinal motility and secretion and mediates opiate-induced bowel dysfunction. Although MOR is of physiological and therapeutic importance to gut function, the cellular and subcellular distribution and regulation of MOR within the enteric nervous system are largely undefined. Herein, we defined the neurochemical coding of MOR-expressing neurons in the guinea pig gut and examined the effects of opioids on MOR trafficking and regulation. MOR expression was restricted to subsets of enteric neurons...
August 1, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
Ki Seok Lee, Youping Zhang, Jamila Asgar, Q-Schick Auh, Man-Kyo Chung, Jin Y Ro
The involvement of testosterone in pain, inflammation, and analgesia has been reported, but the role of androgen receptor (AR), a steroid receptor for testosterone, is not well understood. We have previously shown that peripheral inflammation upregulates μ-opioid receptor (MOR) in rat trigeminal ganglia (TG) in a testosterone-dependent manner. In this study, we hypothesized that testosterone regulates MOR expression via transcriptional activities of AR in TG. We first examined whether AR is co-expressed with MOR in TG neurons...
September 7, 2016: Neuroscience
Dwight A Williams, Yi Zheng, Bethany G David, Yunyun Yuan, Saheem A Zaidi, David L Stevens, Krista L Scoggins, Dana E Selley, William L Dewey, Hamid I Akbarali, Yan Zhang
The 6β-N-heterocyclic naltrexamine derivative, NAP, has been demonstrated to be a peripherally selective mu opioid receptor modulator. To further improve peripheral selectivity of this highly potent ligand, its pyridal ring was quaterinized with benzyl bromide to produce BNAP. In radioligand binding assay, the Ki of BNAP for MOR was 0.76 ± 0.09 nM and was >900-fold more selective for MOR than DOR. The Ki for KOR was 3.46 ± 0.05 nM. In [(35)S]GTPγS ligand stimulated assay, BNAP showed low agonist efficacy with 14...
August 17, 2016: ACS Chemical Neuroscience
Eiko Yokota, Yuko Koyanagi, Hiroko Nakamura, Eri Horinuki, Yoshiyuki Oi, Masayuki Kobayashi
The insular cortex (IC) contributes to nociceptive information processing. IC neurons express opioid receptors, including the mu (MOR), kappa (KOR), and delta (DOR) subtypes. Opioidergic agonists suppress excitatory synaptic transmission in the cerebral cortex. In addition, morphine injection into the IC reduces responses to noxious thermal stimuli. However, the mechanisms of the opioid-dependent modulation of cortical excitation at the macroscopic level, which bridge the cellular and behavioral findings, have remained unknown...
August 15, 2016: Neuroscience Letters
Lorella Pasquinucci, Rita Turnaturi, Giuseppina Aricò, Carmela Parenti, Paschalina Pallaki, Zafiroula Georgoussi, Simone Ronsisvalle
The benzomorphan scaffold has great potential as lead structure and the nature of the N-substituent is able to influence affinity, potency, and efficacy at all three opioid receptors. Building upon these considerations, we synthesized a new series of LP1 analogues by introducing naphthyl or heteroaromatic rings in propanamide side chain of its N-substituent (9-15). In vitro competition-binding assays in HEK293 cells stably expressing MOR, DOR or KOR showed that in compound 9 the 1-naphthyl ring led to the retention of MOR affinity (Ki(MOR)=38±4nM) displaying good selectivity versus DOR and KOR...
June 15, 2016: Bioorganic & Medicinal Chemistry
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