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https://www.readbyqxmd.com/read/28821664/differential-desensitization-observed-at-multiple-effectors-of-somatic-mu-opioid-receptors-underlies-sustained-agonist-mediated-inhibition-of-proopiomelanocortin-neuron-activity
#1
Philip D Fox, Shane T Hentges
Activation of somatic mu opioid receptors (MORs) in hypothalamic proopiomelanocortin (POMC) neurons leads to the activation of G-protein-coupled inward rectifier potassium (GIRK) channels and hyperpolarization, but in response to continued signaling, MORs undergo acute desensitization resulting in robust reduction in the peak GIRK current after minutes of agonist exposure. We hypothesized that the attenuation of the GIRK current would lead to a recovery of neuronal excitability whereby desensitization of the receptor would lead to a new steady-state of POMC neuron activity reflecting the sustained GIRK current observed after the initial decline from peak with continued agonist exposure...
August 7, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28807672/pharmacological-characterization-of-novel-synthetic-opioids-nso-found-in-the-recreational-drug-marketplace
#2
REVIEW
Michael H Baumann, Susruta Majumdar, Valerie Le Rouzic, Amanda Hunkele, Rajendra Uprety, Xi Ping Huang, Jin Xu, Bryan L Roth, Ying-Xian Pan, Gavril W Pasternak
Novel synthetic opioids (NSO) are increasingly encountered in illicit heroin and counterfeit pain pills. Many NSO are resurrected from older biomedical literature or patent applications, so limited information is available about their biological effects. Here we examined the pharmacology of three structurally-distinct NSO found in the recreational drug market: N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenylbutyramide (butyrylfentanyl), 3,4-dichloro-N-[(1R,2R)-2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) and 1-cyclohexyl-4-(1,2-diphenylethyl)piperazine (MT-45)...
August 11, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28798303/understanding-the-molecular-basis-of-agonist-antagonist-mechanism-of-human-mu-opioid-receptor-through-gaussian-accelerated-molecular-dynamics-method
#3
Yeng-Tseng Wang, Yang-Hsiang Chan
The most powerful analgesic and addictive properties of opiate alkaloids are mediated by the μ opioid receptor (MOR). The MOR has been extensively investigated as a drug target in the twentieth century, with numerous compounds of varying efficacy being identified. We employed molecular dynamics and Gaussian accelerated molecular dynamics techniques to identify the binding mechanisms of MORs to BU72 (agonist) and β-funaltrexamine (antagonist). Our approach theoretically suggests that the 34 residues (Lys209-Phe221 and Ile301-Cys321) of the MORs were the key regions enabling the two compounds to bind to the active site of the MORs...
August 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28796483/placement-of-hydroxy-moiety-on-pendant-of-peptidomimetic-scaffold-modulates-mu-and-kappa-opioid-receptor-efficacy
#4
Aubrie A Harland, Irina D Pogozheva, Nicholas W Griggs, Tyler J Trask, John R Traynor, Henry I Mosberg
In an effort to expand the structure-activity relationship (SAR) studies of a series of mixed-efficacy opioid ligands, peptidomimetics that incorporate methoxy and hydroxy groups around a benzyl or 2-methylindanyl pendant on a tetrahydroquinoline (THQ) core of the peptidomimetics were evaluated. Compounds containing a methoxy or hydroxy moiety in the o- or m- positions increased binding affinity to the kappa opioid receptor (KOR), whereas compounds containing methoxy or hydroxy groups in the p- position decreased KOR affinity and reduced or eliminated efficacy at the mu opioid receptor (MOR)...
August 10, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28745394/opioids-for-chronic-non-cancer-pain-in-children-and-adolescents
#5
REVIEW
Tess E Cooper, Emma Fisher, Andrew L Gray, Elliot Krane, Navil Sethna, Miranda Al van Tilburg, Boris Zernikow, Philip J Wiffen
BACKGROUND: Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past, pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time, and relief of pain is now seen as importantWe designed a suite of seven reviews on chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol as priority areas) in order to review the evidence for children's pain utilising pharmacological interventions in children and adolescents...
July 26, 2017: Cochrane Database of Systematic Reviews
https://www.readbyqxmd.com/read/28743488/mu-opioid-receptor-biased-ligands-a-safer-and-painless-discovery-of-analgesics
#6
REVIEW
Abraham Madariaga-Mazón, Andrés F Marmolejo-Valencia, Yangmei Li, Lawrence Toll, Richard A Houghten, Karina Martinez-Mayorga
Biased activation of G-protein-coupled receptors (GPCRs) is shifting drug discovery efforts and appears promising for the development of safer drugs. The most effective analgesics to treat acute pain are agonists of the μ opioid receptor (μ-OR), a member of the GPCR superfamily. However, the analgesic use of opioid drugs, such as morphine, is hindered by adverse effects. Only a few μ-OR agonists have been reported to selectively activate the Gi over β-arrestin signaling pathway, resulting in lower gastrointestinal dysfunction and respiratory suppression...
July 22, 2017: Drug Discovery Today
https://www.readbyqxmd.com/read/28727837/differing-roles-for-short-chain-fatty-acids-and-gpr43-agonism-in-the-regulation-of-intestinal-barrier-function-and-immune-responses
#7
Warren N D'Souza, Jason Douangpanya, Sharon Mu, Peter Jaeckel, Ming Zhang, Joseph R Maxwell, James B Rottman, Katja Labitzke, Angela Willee, Holger Beckmann, Yingcai Wang, Yang Li, Ralf Schwandner, James A Johnston, Jennifer E Towne, Hailing Hsu
Inflammatory bowel disease (IBD) is associated with a loss of intestinal barrier function and dysregulated immune responses. It has been shown that short chain fatty acids (SCFAs) are protective in IBD and that GPR43 mediates the protective effects of SCFAs. In this study, we investigated the effects of SCFAs in comparison to highly specific GPR43 agonists on human intestinal epithelial and immune cells. Our results confirm that SCFAs are enhancers of barrier function in intestinal epithelial cells. Additionally, SCFAs also displayed potent immunoregulatory properties based upon the ability to inhibit LPS-induced cytokine production in PBMC, and human T cell proliferation and cytokine production...
2017: PloS One
https://www.readbyqxmd.com/read/28699350/analgesic-properties-of-opioid-nk1-multitarget-ligands-with-distinct-in-vitro-profiles-in-naive-and-chronic-constriction-injury-mice
#8
Joanna Starnowska, Roberto Costante, Karel Guillemyn, Katarzyna Popiolek-Barczyk, Nga N Chung, Carole Lemieux, Attila Keresztes, Joost Van Duppen, Adriano Mollica, John Streicher, Jozef Vanden Broeck, Peter W Schiller, Dirk Tourwé, Joanna Mika, Steven Ballet, Barbara Przewlocka
The lower efficacy of opioids in neuropathic pain may be due to the increased activity of pronociceptive systems such as substance P. We present evidence to support this hypothesis in this work from the spinal cord in a neuropathic pain model in mice. Biochemical analysis confirmed the elevated mRNA and protein level of pronociceptive substance P, the major endogenous ligand of the neurokinin-1 (NK1) receptor, in the lumbar spinal cord of chronic constriction injury (CCI)-mice. To improve opioid efficacy in neuropathic pain, novel compounds containing opioid agonist and neurokinin 1 (NK1) receptor antagonist pharmacophores were designed...
July 26, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28674470/eluxadoline-viberzi-a-mu-opioid-receptor-agonist-for-the-treatment-of-irritable-bowel-syndrome-with-diarrhea
#9
Fraidy Maltz, Brooke Fidler
Eluxadoline (Viberzi) for the treatment of irritable bowel syndrome with diarrhea.
July 2017: P & T: a Peer-reviewed Journal for Formulary Management
https://www.readbyqxmd.com/read/28673713/alterations-in-opioid-inhibition-cause-widespread-nociception-but-do-not-affect-anxiety-like-behavior-in-oral-cancer-mice
#10
Yi Ye, Daniel G Bernabé, Elizabeth Salvo, Chi T Viet, Kentaro Ono, John C Dolan, Malvin Janal, Brad E Aouizerat, Christine Miaskowski, Brian L Schmidt
Widespread pain and anxiety are commonly reported in cancer patients. We hypothesize that cancer is accompanied by attenuation of endogenous opioid-mediated inhibition, which subsequently causes widespread pain and anxiety. To test this hypothesis we used a mouse model of oral squamous cell carcinoma (SCC) in the tongue. We found that mice with tongue SCC exhibited widespread nociceptive behaviors in addition to behaviors associated with local nociception that we reported previously. Tongue SCC mice exhibited a pattern of reduced opioid receptor expression in the spinal cord; intrathecal administration of respective mu (MOR), delta (DOR), and kappa (KOR) opioid receptor agonists reduced widespread nociception in mice, except for the fail flick assay following administration of the MOR agonist...
June 30, 2017: Neuroscience
https://www.readbyqxmd.com/read/28669034/cannabinoid-reward-and-aversion-effects-in-the-posterior-ventral-tegmental-area-are-mediated-through-dissociable-opiate-receptor-subtypes-and-separate-amygdalar-and-accumbal-dopamine-receptor-substrates
#11
Tasha Ahmad, Steven R Laviolette
RATIONALE: The ventral tegmental area (VTA) and its projections to the basolateral amygdala (BLA) and nucleus accumbens (NAc) are critical for cannabinoid-related motivational effects. Cannabinoid CB1 receptor (CB1R) transmission modulates VTA dopamine (DA) neuron activity and previous reports demonstrate anatomically segregated effects of CB1R transmission in the VTA. However, the underlying pharmacological and anatomical regions responsible for these effects are currently unknown. OBJECTIVES: The objective of the study is to characterize the motivational effects of localized anterior vs...
August 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28667175/the-relevance-of-agrp-neuron-derived-gaba-inputs-to-pomc-neurons-differs-for-spontaneous-and-evoked-release
#12
Andrew R Rau, Shane T Hentges
Hypothalamic agouti-related peptide (AgRP) neurons potently stimulate food intake, whereas proopiomelanocortin (POMC) neurons inhibit feeding. Whether AgRP neurons exert their orexigenic actions, at least in part, by inhibiting anorexigenic POMC neurons remains unclear. Here, the connectivity between GABA-releasing AgRP neurons and POMC neurons was examined in brain slices from male and female mice. GABA-mediated spontaneous IPSCs (sIPSCs) in POMC neurons were unaffected by disturbing GABA release from AgRP neurons either by cell type-specific deletion of the vesicular GABA transporter or by expression of botulinum toxin in AgRP neurons to prevent vesicle-associated membrane protein 2-dependent vesicle fusion...
August 2, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28653080/alterations-of-expression-of-inflammation-immune-related-genes-in-the-dorsal-and-ventral-striatum-of-adult-c57bl-6j-mice-following-chronic-oxycodone-self-administration-a-rna-sequencing-study
#13
Yong Zhang, Yupu Liang, Orna Levran, Matthew Randesi, Vadim Yuferov, Connie Zhao, Mary Jeanne Kreek
INTRODUCTION: Non-medical use of prescription opioids such as the mu opioid receptor (MOP-r) agonist oxycodone is a growing problem in the USA and elsewhere. There is limited information about oxycodone's impact on diverse gene systems in the brain. OBJECTIVES: The current study was designed to examine how chronic oxycodone self-administration (SA) affects gene expression in the terminal areas of the nigrostriatal and mesolimbic dopaminergic pathways in mice. METHOD: Adult male C57BL/6J mice underwent a 14-day oxycodone self-administration procedure (4 h/day, 0...
August 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28650467/genome-wide-loss-of-function-genetic-screening-identifies-opioid-receptor-%C3%AE-1-as-a-key-regulator-of-l-asparaginase-resistance-in-pediatric-acute-lymphoblastic-leukemia
#14
S M Kang, J L Rosales, V Meier-Stephenson, S Kim, K Y Lee, A Narendran
L-asparaginase is a critical chemotherapeutic agent for acute lymphoblastic leukemia (ALL). It hydrolyzes plasma asparagine into aspartate and NH3, causing asparagine deficit and inhibition of protein synthesis and eventually, leukemic cell death. However, patient relapse often occurs due to development of resistance. The molecular mechanism by which ALL cells acquire resistance to L-asparaginase is unknown. Therefore, we sought to identify genes that are involved in L-asparaginase resistance in primary leukemic cells...
June 26, 2017: Oncogene
https://www.readbyqxmd.com/read/28645621/two-delta-opioid-receptor-subtypes-are-functional-in-single-ventral-tegmental-area-neurons-and-can-interact-with-the-mu-opioid-receptor
#15
Elyssa B Margolis, Wakako Fujita, Lakshmi A Devi, Howard L Fields
The mu and delta opioid receptors (MOR and DOR) are highly homologous members of the opioid family of GPCRs. There is evidence that MOR and DOR interact, however the extent to which these interactions occur in vivo and affect synaptic function is unknown. There are two stable DOR subtypes: DPDPE sensitive (DOR1) and deltorphin II sensitive (DOR2); both agonists are blocked by DOR selective antagonists. Robust motivational effects are produced by local actions of both MOR and DOR ligands in the ventral tegmental area (VTA)...
September 1, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28626987/prolactinomas-diagnosed-in-the-postmenopausal-period-clinical-phenotype-and-outcomes
#16
Sandhya Santharam, Metaxia Tampourlou, Wiebke Arlt, John Ayuk, Neil Gittoes, Andrew Toogood, Rachel Webster, Niki Karavitaki
OBJECTIVE: Most prolactinomas in females are diagnosed during the reproductive age and the majority are microadenomas. Prolactinomas detected in the postmenopausal period are less common with limited published data on their presentation and prognosis. Our objective was to assess the presenting clinical, biochemical and imaging findings, as well as the outcomes of women diagnosed with a prolactinoma in the postmenopausal period. DESIGN AND METHODS: We undertook a retrospective cohort study of women diagnosed with prolactinoma after menopause and followed-up in a large UK pituitary center...
June 19, 2017: Clinical Endocrinology
https://www.readbyqxmd.com/read/28594147/casein-kinase-1-epsilon-deletion-increases-mu-opioid-receptor-dependent-behaviors-and-binge-eating1
#17
L R Goldberg, S L Kirkpatrick, N Yazdani, K P Luttik, O A Lacki, R Keith Babbs, D F Jenkins, W Evan Johnson, C D Bryant
Genetic and pharmacological studies indicate that casein kinase 1 epsilon (Csnk1e) contributes to psychostimulant, opioid, and ethanol motivated behaviors. We previously used pharmacological inhibition to demonstrate that Csnk1e negatively regulates the locomotor stimulant properties of opioids and psychostimulants. Here, we tested the hypothesis that Csnk1e negatively regulates opioid and psychostimulant reward using genetic inhibition and the conditioned place preference assay in Csnk1e knockout mice. Similar to pharmacological inhibition, Csnk1e knockout mice showed enhanced opioid-induced locomotor activity with the mu opioid receptor agonist fentanyl (0...
June 8, 2017: Genes, Brain, and Behavior
https://www.readbyqxmd.com/read/28590714/reaching-out-for-sensitive-evaluation-of-the-mu-opioid-receptor-in-vivo-positron-emission-tomography-imaging-of-the-agonist-11c-ah7921
#18
Waqas Rafique, Shivashankar Khanapur, Mona Milde Spilhaug, Patrick J Riss
Imaging of the mu-opioid receptor availability with PET is a pertinent challenge in Neuroscience. Both, regulation of receptor expression and occupancy by endogeneous opioids play into cognitive and behavioural phenotypes of healthy function and disease. Receptor expression in the active and inactive states can be measured using high affinity radioagonist and radioanatonist PET tracers, respectively. Occupancy assessment requires radioligands showing competitive and reversible binding with moderate affinity to the MOR, which may lead to physical extinction of the receptor specific signal in vivo...
June 7, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28574864/methadone-management-of-withdrawal-associated-with-loperamide-related-opioid-use-disorder
#19
Raphael J Leo, Muhammad A Ghazi, Kelly S Jaziri
: Loperamide hydrochloride is an over-the-counter anti-diarrheal agent, acting via mu-opioid receptor agonist effects in the intestinal myenteric plexus. Although preclinical investigations suggested that abuse liability associated with loperamide use is low, there are increasing numbers of cases reported to the US Food and Drug Administration, of abuse, dependence, and withdrawal associated with loperamide use. A case of a patient with opioid use disorder, that is, in the form of protracted loperamide excess use, requiring management of withdrawal with methadone is presented...
June 1, 2017: Journal of Addiction Medicine
https://www.readbyqxmd.com/read/28567699/effects-of-nalfurafine-on-the-reinforcing-thermal-antinociceptive-and-respiratory-depressant-effects-of-oxycodone-modeling-an-abuse-deterrent-opioid-analgesic-in-rats
#20
E Andrew Townsend, Jennifer E Naylor, S Stevens Negus, Shelley R Edwards, Hina N Qureshi, Hunter W McLendon, Christopher R McCurdy, Coco N Kapanda, Jussara M do Carmo, Fernanda S da Silva, John E Hall, Kenneth J Sufka, Kevin B Freeman
RATIONALE: Strategies to reduce the misuse of mu opioid agonists are critically needed. Previous work has shown that kappa opioid agonists can diminish the abuse-related effects and augment the antinociceptive effects of mu agonists. However, use of traditional kappa agonists is limited by their dysphoric side effects. OBJECTIVES: The current study examined the effects of nalfurafine, a clinically available atypical kappa agonist, on the reinforcing, thermal antinociceptive, and respiratory-depressant effects of oxycodone in male rats...
May 31, 2017: Psychopharmacology
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