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Opioid antagonism

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https://www.readbyqxmd.com/read/28502630/new-opioid-receptor-antagonist-naltrexone-14-o-sulfate-synthesis-and-pharmacology
#1
Ferenc Zádor, Kornél Király, András Váradi, Mihály Balogh, Ágnes Fehér, Dóra Kocsis, Anna I Erdei, Erzsébet Lackó, Zoltán S Zádori, Sándor Hosztafi, Béla Noszál, Pál Riba, Sándor Benyhe, Susanna Fürst, Mahmoud Al-Khrasani
Opioid antagonists, naloxone and naltrexone have long been used in clinical practice and research. In addition to their low selectivity, they easily pass through the blood-brain barrier. Quaternization of the amine group in these molecules, (e.g. methylnaltrexone) results in negligible CNS penetration. In addition, zwitterionic compounds have been reported to have limited CNS access. The current study, for the first time gives report on the synthesis and the in vitro [competition binding, G-protein activation, isolated mouse vas deferens (MVD) and mouse colon assay] pharmacology of the zwitterionic compound, naltrexone-14-O-sulfate...
May 11, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28485408/genetic-and-pharmacological-antagonism-of-nk1-receptor-prevents-opiate-abuse-potential
#2
A J Sandweiss, M I McIntosh, A Moutal, R Davidson-Knapp, J Hu, A K Giri, T Yamamoto, V J Hruby, R Khanna, T M Largent-Milnes, T W Vanderah
Development of an efficacious, non-addicting analgesic has been challenging. Discovery of novel mechanisms underlying addiction may present a solution. Here we target the neurokinin system, which is involved in both pain and addiction. Morphine exerts its rewarding actions, at least in part, by inhibiting GABAergic input onto substance P (SP) neurons in the ventral tegmental area (VTA), subsequently increasing SP release onto dopaminergic neurons. Genome editing of the neurokinin 1 receptor (NK1R) in the VTA renders morphine non-rewarding...
May 9, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28461466/oxytocin-under-opioid-antagonism-leads-to-supralinear-enhancement-of-social-attention
#3
Olga Dal Monte, Matthew Piva, Kevin M Anderson, Marios Tringides, Avram J Holmes, Steve W C Chang
To provide new preclinical evidence toward improving the efficacy of oxytocin (OT) in treating social dysfunction, we tested the benefit of administering OT under simultaneously induced opioid antagonism during dyadic gaze interactions in monkeys. OT coadministered with a μ-opioid receptor antagonist, naloxone, invoked a supralinear enhancement of prolonged and selective social attention, producing a stronger effect than the summed effects of each administered separately. These effects were consistently observed when averaging over entire sessions, as well as specifically following events of particular social importance, including mutual eye contact and mutual reward receipt...
May 1, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28442581/sigma-receptor-effects-of-n-substituted-benztropine-analogs-implications-for-antagonism-of-cocaine-self-administration
#4
Takato Hiranita, Weimin C Hong, Theresa Kopajtic, Jonathan L Katz
Several N-substituted benztropine (BZT) analogs are atypical dopamine transport inhibitors as they have affinity for the dopamine transporter (DAT), but have minimal cocaine-like pharmacological effects and can block numerous effects of cocaine including its self-administration. Among these compounds, N-methyl (AHN1-055), N-allyl (AHN2-005), and N-butyl (JHW007) analogs of 3α-[bis(4'-fluorophenyl)methoxy]-tropane were more potent in antagonizing self-administration of cocaine and d-methamphetamine than in decreasing food-maintained responding...
April 25, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28370746/low-dose-naltrexone-and-opioid-consumption-a-drug-utilization-cohort-study-based-on-data-from-the-norwegian-prescription-database
#5
Guttorm Raknes, Lars Småbrekke
PURPOSE: Low-dose naltrexone (LDN) is used in a wide range of conditions, including chronic pain and fibromyalgia. Because of the opioid antagonism of naltrexone, LDN users are probably often warned against concomitant use with opioids. In this study, based on data from the Norwegian prescription database, we examine changes in opioid consumption after starting LDN therapy. METHODS: We included all Norwegian patients (N = 3775) with at least one recorded LDN prescription in 2013 and at least one dispensed opioid prescription during the 365 days preceding the first LDN prescription...
March 29, 2017: Pharmacoepidemiology and Drug Safety
https://www.readbyqxmd.com/read/28365208/postoperative-hyperalgesia-a-clinically-applicable-narrative-review
#6
REVIEW
Avi A Weinbroum
Postoperative hyperalgesia (POH) is a condition characterized by signs and symptoms of pain despite the provision of conventional analgesia. In most cases, anesthesiologists are called upon soon after surgery, but occasionally it may occur as a late event. Persistent uncontrolled pain may transform into chronic or neuropathic pain. Correct diagnosis of POH is essential since similar phenomenon may exacerbate if misdiagnosed, while proper treatment is frequently achievable by pharmacological remedies. This review will describe the causes for POH and its bio-neuro-pharmacological basis, and clinical symptoms and signs directing the physician towards correct diagnosis of this paradoxical condition of pain, as well as modes capable of preventing POH from occurring...
June 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28363796/structure-constrained-endomorphin-analogs-display-differential-antinociceptive-mechanisms-in-mice-after-spinal-administration
#7
Yuan Wang, Jingjing Zhou, Xin Liu, Long Zhao, Zhaojuan Wang, Xianghui Zhang, Kezhou Wang, Linqing Wang, Rui Wang
We previously reported a series of novel endomorphin analogs with unnatural amino acid modifications. These analogs display good binding affinity and functional activity toward the μ opioid receptor (MOP). In the present study, we further investigated the spinal antinociceptive activity of these compounds. The analogs were potent in several nociceptive models. Opioid antagonists and antibodies against several endogenous opioid peptides were used to determine the mechanisms of action of these peptides. Intrathecal pretreatment with naloxone and β-funaltrexamine (β-FNA) effectively inhibited analog-induced analgesia, demonstrating that activity of the analogs is regulated primarily through MOP...
May 2017: Peptides
https://www.readbyqxmd.com/read/28336575/pharmacologic-profile-of-naloxegol-a-peripherally-acting-%C3%A2%C2%B5-opioid-receptor-antagonist-for-the-treatment-of-opioid-induced-constipation
#8
Eike Floettmann, Khanh Bui, Mark Sostek, Kemal Payza, Michael Eldon
Opioid-induced constipation (OIC) is a common side effect of opioid pharmacotherapy for the management of pain because opioid agonists bind to µ-opioid receptors in the enteric nervous system (ENS). Naloxegol, a polyethylene glycol derivative of naloxol, which is a derivative of naloxone and a peripherally acting µ-opioid receptor antagonist, targets the physiologic mechanisms that cause OIC. Pharmacologic measures of opioid activity and pharmacokinetic measures of central nervous system (CNS) penetration were employed to characterize the mechanism of action of naloxegol...
May 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28322978/delta-opioid-receptor-antagonism-leads-to-excessive-ethanol-consumption-in-mice-with-enhanced-activity-of-the-endogenous-opioid-system
#9
Piotr Poznanski, Anna Lesniak, Michal Korostynski, Klaudia Szklarczyk, Marzena Lazarczyk, Piotr Religa, Magdalena Bujalska-Zadrozny, Bogdan Sadowski, Mariusz Sacharczuk
The opioid system modulates the central reinforcing effects of ethanol and participates in the etiology of addiction. However, the pharmacotherapy of ethanol dependence targeted on the opioid system is little effective and varies due to individual patients' sensitivity. In the present study, we used two mouse lines with high (HA) and low (LA) activity of the endogenous opioid system to analyze the effect of opioid receptor blockade on ethanol drinking behavior. We found that LA and HA lines characterized by divergent magnitudes of swim stress-induced analgesia also differ in ethanol intake and preference...
May 15, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28316587/characterization-of-the-antinociceptive-mechanisms-of-khat-extract-catha-edulis-in-mice
#10
Elham A Afify, Huda M Alkreathy, Ahmed S Ali, Hassan A Alfaifi, Lateef M Khan
This study investigated the antinociceptive mechanisms of khat extract (100, 200, and 400 mg/kg, i.p.) in four pain models: two thermic (hot plate, tail-flick) and two chemical (acetic acid, formalin) models. Male mice were pretreated intraperitoneally (i.p.) with the opioid receptor blocker naloxone (5 mg/kg), the cholinergic antagonist atropine (2 mg/kg), the selective α1 blocker prazosin (1 mg/kg), the dopamine D2 antagonist haloperidol (1.5 mg/kg), or the GABAA receptor antagonist, bicuculline (1 mg/kg) 15 minutes prior to i...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/28315268/sigma-1-receptor-antagonists-a-new-class-of-neuromodulatory-analgesics
#11
Cristina Sánchez-Fernández, José Manuel Entrena, José Manuel Baeyens, Enrique José Cobos
The sigma-1 receptor is a unique ligand-operated chaperone present in key areas for pain control, in both the peripheral and central nervous system. Sigma-1 receptors interact with a variety of protein targets to modify their function. These targets include several G-protein-coupled receptors such as the μ-opioid receptor, and ion channels such as the N-methyl-D-aspartate receptor (NMDAR). Sigma-1 antagonists modify the chaperoning activity of sigma-1 receptor by increasing opioid signaling and decreasing NMDAR responses, consequently enhancing opioid antinociception and decreasing the sensory hypersensitivity that characterizes pathological pain conditions...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28315267/pharmacological-modulation-of-the-sigma-1-receptor-and-the-treatment-of-pain
#12
Manuel Merlos, Javier Burgueño, Enrique Portillo-Salido, Carlos Ramón Plata-Salamán, José Miguel Vela
There is a critical need for new analgesics acting through new mechanisms of action, which could increase the efficacy with respect to existing therapies and reduce their unwanted effects. Current preclinical evidence supports the modulatory role of sigma-1 receptors (σ1R) in nociception, mainly based on the pain-attenuated phenotype of σ1R knockout mice and on the antinociceptive effect exerted by σ1R antagonists on pains of different etiologies. σ1R is highly expressed in different pain areas of the CNS and the periphery (particularly dorsal root ganglia), and interacts and modulates the functionality of different receptors and ion channels ...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28280516/evaluation-of-analgesic-activity-of-papaver-libanoticum-extract-in-mice-involvement-of-opioids-receptors
#13
Mohamad Ali Hijazi, Ahmed El-Mallah, Maha Aboul-Ela, Abdalla Ellakany
Papaver libanoticum is an endemic plant to Lebanese region (family Papaveraceae) that has not been investigated before. The present study aimed to explore the analgesic activity of dried ethanolic extract of Papaver libanoticum (PLE) using tail flick, hot plate, and acetic acid induced writhing models in mice. The involvement of opioid receptors in the analgesic mechanism was investigated using naloxone antagonism. Results demonstrated that PLE exhibited a potent dose dependent analgesic activity in all tested models for analgesia...
2017: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/28230181/dezocine-exhibits-antihypersensitivity-activities-in-neuropathy-through-spinal-%C3%AE-opioid-receptor-activation-and-norepinephrine-reuptake-inhibition
#14
Yong-Xiang Wang, Xiao-Fang Mao, Teng-Fei Li, Nian Gong, Ma-Zhong Zhang
Dezocine is the number one opioid painkiller prescribed and sold in China, occupying 44% of the nation's opioid analgesics market today and far ahead of the gold-standard morphine. We discovered the mechanisms underlying dezocine antihypersensitivity activity and assessed their implications to antihypersensitivity tolerance. Dezocine, given subcutaneously in spinal nerve-ligated neuropathic rats, time- and dose-dependently produced mechanical antiallodynia and thermal antihyperalgesia, significantly increased ipsilateral spinal norepinephrine and serotonin levels, and induced less antiallodynic tolerance than morphine...
February 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28216001/loperamide-inhibits-sodium-channels-to-alleviate-inflammatory-hyperalgesia
#15
Ying Wu, Beiyan Zou, Lingli Liang, Min Li, Yuan-Xiang Tao, Haibo Yu, Xiaoliang Wang, Min Li
Previous studies demonstrated that Loperamide, originally known as an anti-diarrheal drug, is a promising analgesic agent primarily targeting mu-opioid receptors. However some evidences suggested that non-opioid mechanisms may be contributing to its analgesic effect. In the present study, Loperamide was identified as a Nav1.7 blocker in a pilot screen. In HEK293 cells expressing Nav1.7 sodium channels, Loperamide blocked the resting state of Nav1.7 channels (IC50 = 1.86 ± 0.11 μM) dose-dependently and reversibly...
February 16, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28132914/acquisition-and-expression-of-fat-conditioned-flavor-preferences-are-differentially-affected-by-nmda-receptor-antagonism-in-balb-c-and-swr-mice
#16
Tamar T Kraft, Donald Huang, Sam LaMagna, Deena Warshaw, Elona Natanova, Anthony Sclafani, Richard J Bodnar
Conditioned flavor preferences are elicited by fat (Intralipid) in inbred mouse strains with BALB/c and SWR mice displaying among the most robust preferences. Dopamine D1 and opioid receptor antagonism differentially reduces the acquisition (learning) and expression (maintenance) of fat-conditioned flavor preferences in these two strains. Because noncompetitive NMDA receptor antagonism with MK-801 differentially altered sugar-conditioned flavor preferences in these strains, and because NMDA receptors are involved in fat intake, the present study examined whether MK-801 differentially altered expression and acquisition of fat (Intralipid)-conditioned flavor preferences in BALB/c and SWR mice...
March 15, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28119127/antagonizing-the-different-stages-of-kappa-opioid-receptor-activation-selectively-and-independently-attenuates-acquisition-and-consolidation-of-associative-memories
#17
Ryan Loh, Lily Chau, Ali Aijaz, Kevin Wu, Roberto Galvez
Previous work from our laboratory has shown that nonspecific kappa opioid receptor (KOR) antagonism in primary somatosensory cortex (S1) can inhibit acquisition for the forebrain-dependent associative task, Whisker-Trace Eyeblink conditioning (WTEB). Although studies have demonstrated that KOR activation can alter stimuli salience, our studies controlled for these factors, demonstrating that KOR also plays a role in facilitating learning. KOR has two distinct phases of activation followed by internalization/downregulation, that each independently activate kinases and transcription factors known to mediate task acquisition and memory consolidation respectively...
April 14, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28114964/antinociceptive-effect-of-methanol-extract-of-dalbergia-sissoo-leaves-in-mice
#18
Md Abdul Mannan, Ambia Khatun, Md Farhad Hossen Khan
BACKGROUND: Dalbergia sissoo DC. (Family: Fabaceae) is a medium to large deciduous tree, is locally called "shishu" in Bangladesh. It is used to treat sore throats, dysentery, syphilis, bronchitis, inflammations, infections, hernia, skin diseases, and gonorrhea. This study evaluated the antinociceptive effect of the methanol extract of D. sissoo leaves (MEDS) in mice. METHODS: The extract was assessed for antinociceptive activity using chemical and heat induced pain models such as hot plate, tail immersion, acetic acid-induced writhing, formalin, glutamate, and cinnamaldehyde test models in mice at the doses of 100, 200, and 400 mg/kg (p...
January 23, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/28093646/mechanisms-of-inhibitory-action-of-trk-130-naltalimide-a-%C3%AE-opioid-receptor-partial-agonist-on-the-micturition-reflex
#19
Morihiro Fujimura, Naoki Izumimoto, Sayoko Kanie, Ryosuke Kobayashi, Satoru Yoshikawa, Shinobu Momen, Mikito Hirakata, Toshikazu Komagata, Satoshi Okanishi, Masashi Iwata, Tadatoshi Hashimoto, Takayuki Doi, Naoki Yoshimura, Koji Kawai
PURPOSE: To clarify the mechanism of inhibitory action of TRK-130 (Naltalimide), a unique µ-opioid receptor partial agonist, on the micturition reflex. METHODS: The effect of TRK-130 on isovolumetric rhythmic bladder contractions (RBCs) was examined in guinea pigs, the effect of which was clarified by co-treatment with naloxone or in spinal cord transection. The effect of TRK-130 on urodynamic parameters was also observed in guinea pigs. In addition, the effect of TRK-130 on bladder contraction induced by peripheral stimulation of the pelvic nerve was investigated in rats...
April 2017: International Urology and Nephrology
https://www.readbyqxmd.com/read/28035588/clinical-pharmacokinetics-and-pharmacodynamics-of-naloxegol-a-peripherally-acting-%C3%A2%C2%B5-opioid-receptor-antagonist
#20
REVIEW
Khanh Bui, Diansong Zhou, Hongmei Xu, Eike Floettmann, Nidal Al-Huniti
Naloxegol is a peripherally acting µ-opioid receptor antagonist approved for use as an orally administered tablet (therapeutic doses of 12.5 and 25 mg) for the treatment of opioid-induced constipation. Over a wide dose range (i.e. single supratherapeutic doses up to 1000 mg in healthy volunteers), the pharmacokinetic properties of naloxegol appear to be time- and dose-independent. Naloxegol is rapidly absorbed, with mean time to maximum plasma concentration of <2 h. Following once-daily administration, steady state is achieved within 2-3 days and minimal accumulation is observed...
June 2017: Clinical Pharmacokinetics
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