Relevant bibliographies by topics / Opioid Receptors Signaling

Academic literature on the topic 'Opioid Receptors Signaling'

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Published: 10 December 2022
Last updated: 28 January 2023

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Journal articles on the topic "Opioid Receptors Signaling"

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Gomes, Ivone, Salvador Sierra, Lindsay Lueptow, Achla Gupta, Shawn Gouty, Elyssa B. Margolis, Brian M. Cox, and Lakshmi A. Devi. "Biased signaling by endogenous opioid peptides." Proceedings of the National Academy of Sciences 117, no. 21 (May 11, 2020): 11820–28. http://dx.doi.org/10.1073/pnas.2000712117.

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Opioids, such as morphine and fentanyl, are widely used for the treatment of severe pain; however, prolonged treatment with these drugs leads to the development of tolerance and can lead to opioid use disorder. The “Opioid Epidemic” has generated a drive for a deeper understanding of the fundamental signaling mechanisms of opioid receptors. It is generally thought that the three types of opioid receptors (μ, δ, κ) are activated by endogenous peptides derived from three different precursors: Proopiomelanocortin, proenkephalin, and prodynorphin. Posttranslational processing of these precursors generates >20 peptides with opioid receptor activity, leading to a long-standing question of the significance of this repertoire of peptides. Here, we address some aspects of this question using a technical tour de force approach to systematically evaluate ligand binding and signaling properties ([35S]GTPγS binding and β-arrestin recruitment) of 22 peptides at each of the three opioid receptors. We show that nearly all tested peptides are able to activate the three opioid receptors, and many of them exhibit agonist-directed receptor signaling (functional selectivity). Our data also challenge the dogma that shorter forms of β-endorphin do not exhibit receptor activity; we show that they exhibit robust signaling in cultured cells and in an acute brain slice preparation. Collectively, this information lays the groundwork for improved understanding of the endogenous opioid system that will help in developing more effective treatments for pain and addiction.
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Al-Hasani, Ream, and Michael R. Bruchas. "Molecular Mechanisms of Opioid Receptor-dependent Signaling and Behavior." Anesthesiology 115, no. 6 (December 1, 2011): 1363–81. http://dx.doi.org/10.1097/aln.0b013e318238bba6.

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Opioid receptors have been targeted for the treatment of pain and related disorders for thousands of years and remain the most widely used analgesics in the clinic. Mu (μ), kappa (κ), and delta (δ) opioid receptors represent the originally classified receptor subtypes, with opioid receptor like-1 (ORL1) being the least characterized. All four receptors are G-protein coupled and activate inhibitory G proteins. These receptors form homo- and heterodimeric complexes and signal to kinase cascades and scaffold a variety of proteins.The authors discuss classic mechanisms and developments in understanding opioid tolerance and opioid receptor signaling and highlight advances in opioid molecular pharmacology, behavioral pharmacology, and human genetics. The authors put into context how opioid receptor signaling leads to the modulation of behavior with the potential for therapeutic intervention. Finally, the authors conclude there is a continued need for more translational work on opioid receptors in vivo.
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Scherer, Paul C., Nicholas W. Zaccor, Neil M. Neumann, Chirag Vasavda, Roxanne Barrow, Andrew J. Ewald, Feng Rao, Charlotte J. Sumner, and Solomon H. Snyder. "TRPV1 is a physiological regulator of μ-opioid receptors." Proceedings of the National Academy of Sciences 114, no. 51 (December 4, 2017): 13561–66. http://dx.doi.org/10.1073/pnas.1717005114.

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Opioids are powerful analgesics, but also carry significant side effects and abuse potential. Here we describe a modulator of the μ-opioid receptor (MOR1), the transient receptor potential channel subfamily vanilloid member 1 (TRPV1). We show that TRPV1 binds MOR1 and blocks opioid-dependent phosphorylation of MOR1 while leaving G protein signaling intact. Phosphorylation of MOR1 initiates recruitment and activation of the β-arrestin pathway, which is responsible for numerous opioid-induced adverse effects, including the development of tolerance and respiratory depression. Phosphorylation stands in contrast to G protein signaling, which is responsible for the analgesic effect of opioids. Calcium influx through TRPV1 causes a calcium/calmodulin-dependent translocation of G protein-coupled receptor kinase 5 (GRK5) away from the plasma membrane, thereby blocking its ability to phosphorylate MOR1. Using TRPV1 to block phosphorylation of MOR1 without affecting G protein signaling is a potential strategy to improve the therapeutic profile of opioids.
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Gutstein, Howard B., Elizabeth A. Rubie, Alfred Mansour, Huda Akil, and James R. Woodgett. "Opioid Effects on Mitogen-activated Protein Kinase Signaling Cascades." Anesthesiology 87, no. 5 (November 1, 1997): 1118–26. http://dx.doi.org/10.1097/00000542-199711000-00016.

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Background The molecular mechanisms underlying both beneficial and undesirable opioid actions are poorly understood. Recently, the three currently known mammalian mitogen-activated protein kinase (MAPK) signaling cascades (extracellular signal-related kinase [ERK], stress-activated protein kinase, and p38 kinase) were shown to play important roles in transducing receptor-mediated signaling processes. Methods To determine whether any of these kinase cascades were activated by opioids, mu, delta, or kappa opioid receptors were transiently introduced into COS-7 cells together with MAPKs tagged to allow recognition by specific antibodies, and then exposed to opioids. Mitogen-activated protein kinase activation was determined by an in vitro MAPK activation assay. In addition, C6 glioma cells with either mu, delta, or kappa receptors stably introduced were exposed to opioids and MAPK activation determined by in vitro activation assay or antibody detection of activated forms. Results Transient experiments in COS cells revealed potent stimulation of ERK by mu and delta receptor activation, weak stimulation of stress-activated protein kinase by all receptor types, and no activation of p38. In stably transfected C6 glioma cells, only ERK activation was observed. Extracellular signal-related kinase induction was rapid, peaking 5 min after stimulation, and its activation was receptor-type specific. Mu and delta receptor stimulation activated ERK, but kappa stimulation did not. Conclusions These results show that acute opioid signaling is not only inhibitory, but can strongly activate an important signaling cascade. Extracellular signal-related kinase activation may contribute to desirable responses to opioids, such as analgesia and sedation, and also to undesirable adaptive responses, such as tolerance, physical dependence, and possibly addiction. Further study of this system could provide greater insight into the molecular mechanisms underlying these clinical problems.
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Williams, John T., MacDonald J. Christie, and Olivier Manzoni. "Cellular and Synaptic Adaptations Mediating Opioid Dependence." Physiological Reviews 81, no. 1 (January 1, 2001): 299–343. http://dx.doi.org/10.1152/physrev.2001.81.1.299.

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Although opioids are highly effective for the treatment of pain, they are also known to be intensely addictive. There has been a massive research investment in the development of opioid analgesics, resulting in a plethora of compounds with varying affinity and efficacy at all the known opioid receptor subtypes. Although compounds of extremely high potency have been produced, the problem of tolerance to and dependence on these agonists persists. This review centers on the adaptive changes in cellular and synaptic function induced by chronic morphine treatment. The initial steps of opioid action are mediated through the activation of G protein-linked receptors. As is true for all G protein-linked receptors, opioid receptors activate and regulate multiple second messenger pathways associated with effector coupling, receptor trafficking, and nuclear signaling. These events are critical for understanding the early events leading to nonassociative tolerance and dependence. Equally important are associative and network changes that affect neurons that do not have opioid receptors but that are indirectly altered by opioid-sensitive cells. Finally, opioids and other drugs of abuse have some common cellular and anatomical pathways. The characterization of common pathways affected by different drugs, particularly after repeated treatment, is important in the understanding of drug abuse.
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Lešnik, Samo, Éva Bertalan, Urban Bren, and Ana-Nicoleta Bondar. "Opioid Receptors and Protonation-Coupled Binding of Opioid Drugs." International Journal of Molecular Sciences 22, no. 24 (December 12, 2021): 13353. http://dx.doi.org/10.3390/ijms222413353.

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Opioid receptors are G-protein-coupled receptors (GPCRs) part of cell signaling paths of direct interest to treat pain. Pain may associate with inflamed tissue characterized by acidic pH. The potentially low pH at tissue targeted by opioid drugs in pain management could impact drug binding to the opioid receptor, because opioid drugs typically have a protonated amino group that contributes to receptor binding, and the functioning of GPCRs may involve protonation change. In this review, we discuss the relationship between structure, function, and dynamics of opioid receptors from the perspective of the usefulness of computational studies to evaluate protonation-coupled opioid-receptor interactions.
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Bolte, Craig, Gilbert Newman, and Jo El J. Schultz. "Hypertensive state, independent of hypertrophy, exhibits an attenuated decrease in systolic function on cardiac κ-opioid receptor stimulation." American Journal of Physiology-Heart and Circulatory Physiology 296, no. 4 (April 2009): H967—H975. http://dx.doi.org/10.1152/ajpheart.00909.2008.

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Opioids/opiates are commonly administered to alleviate pain, unload the heart, or decrease breathlessness in patients with advanced heart failure. As such, it is important to evaluate whether the myocardial opioidergic system is altered in cardiac disease. A hamster model of spontaneous hypertension was investigated before the development of hypertension (1 mo of age) and in the hypertensive state (10 mo of age) to evaluate the effect of prolonged hypertension on myocardial opioidergic activity. Plasma β-endorphin was decreased before the development of hypertension and in the hypertensive state ( P < 0.05). There was no change in cardiac β-endorphin content at either time point. No differences were detected in cardiac or plasma dynorphin A, Met-enkephalin, or Leu-enkephalin, or in cardiac peptide expression of κ- or δ-opioid receptors. μ-Opioid receptor was not detected in either model. To determine how hypertension affects myocardial opioid signaling, the ex vivo work-performing heart was used to assess the cardiac response to opioid administration in healthy hearts and those subjected to chronic hypertension. Agonists selective for the κ- and δ-opioid receptors, but not μ-opioid receptors, induced a concentration-dependent decrease in cardiac function. The decrease in left ventricular systolic pressure on administration of the κ-opioid receptor-selective agonist, U50488H, was attenuated in hearts from hamsters subjected to chronic, untreated hypertension ( P < 0.05) compared with control. These results show that peripheral and myocardial opioid expression and signaling are altered in hypertension.
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GALLAGHER, SHANNON K., JULIA N. ANGLEN, JUSTIN M. MOWER, and JOZSEF VIGH. "Dopaminergic amacrine cells express opioid receptors in the mouse retina." Visual Neuroscience 29, no. 3 (April 3, 2012): 203–9. http://dx.doi.org/10.1017/s0952523812000156.

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AbstractThe presence of opioid receptors has been confirmed by a variety of techniques in vertebrate retinas including those of mammals; however, in most reports, the location of these receptors has been limited to retinal regions rather than specific cell types. Concurrently, our knowledge of the physiological functions of opioid signaling in the retina is based on only a handful of studies. To date, the best-documented opioid effect is the modulation of retinal dopamine release, which has been shown in a variety of vertebrate species. Nonetheless, it is not known if opioids can affect dopaminergic amacrine cells (DACs) directly, via opioid receptors expressed by DACs. This study, using immunohistochemical methods, sought to determine whether (1) μ- and δ-opioid receptors (MORs and DORs, respectively) are present in the mouse retina, and if present, (2) are they expressed by DACs. We found that MOR and DOR immunolabeling were associated with multiple cell types in the inner retina, suggesting that opioids might influence visual information processing at multiple sites within the mammalian retinal circuitry. Specifically, colabeling studies with the DAC molecular marker anti-tyrosine hydroxylase antibody showed that both MOR and DOR immunolabeling localize to DACs. These findings predict that opioids can affect DACs in the mouse retina directly, via MOR and DOR signaling, and might modulate dopamine release as reported in other mammalian and nonmammalian retinas.
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Guda, Rahul S., Katherine E. Odegaard, Chengxi Tan, Victoria L. Schaal, Sowmya V. Yelamanchili, and Gurudutt Pendyala. "Integrated Systems Analysis of Mixed Neuroglial Cultures Proteome Post Oxycodone Exposure." International Journal of Molecular Sciences 22, no. 12 (June 15, 2021): 6421. http://dx.doi.org/10.3390/ijms22126421.

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Opioid abuse has become a major public health crisis that affects millions of individuals across the globe. This widespread abuse of prescription opioids and dramatic increase in the availability of illicit opioids have created what is known as the opioid epidemic. Pregnant women are a particularly vulnerable group since they are prescribed for opioids such as morphine, buprenorphine, and methadone, all of which have been shown to cross the placenta and potentially impact the developing fetus. Limited information exists regarding the effect of oxycodone (oxy) on synaptic alterations. To fill this knowledge gap, we employed an integrated system approach to identify proteomic signatures and pathways impacted on mixed neuroglial cultures treated with oxy for 24 h. Differentially expressed proteins were mapped onto global canonical pathways using ingenuity pathway analysis (IPA), identifying enriched pathways associated with ephrin signaling, semaphorin signaling, synaptic long-term depression, endocannabinoid signaling, and opioid signaling. Further analysis by ClueGO identified that the dominant category of differentially expressed protein functions was associated with GDP binding. Since opioid receptors are G-protein coupled receptors (GPCRs), these data indicate that oxy exposure perturbs key pathways associated with synaptic function.
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Rocchi, Giulio, Bruno Sterlini, Samuele Tardito, Matilde Inglese, Anna Corradi, Gilberto Filaci, Mario Amore, Paola Magioncalda, and Matteo Martino. "Opioidergic System and Functional Architecture of Intrinsic Brain Activity: Implications for Psychiatric Disorders." Neuroscientist 26, no. 4 (March 5, 2020): 343–58. http://dx.doi.org/10.1177/1073858420902360.

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The opioidergic system and intrinsic brain activity, as organized in large-scale networks such as the salience network (SN), sensorimotor network (SMN), and default-mode network (DMN), play core roles in healthy behavior and psychiatric disorders. This work aimed to investigate how opioidergic signaling affects intrinsic brain activity in healthy individuals by reviewing relevant neuroanatomical, molecular, functional, and pharmacological magnetic resonance imaging studies in order to clarify their physiological links and changes in psychiatric disorders. The SN shows dense opioidergic innervations of subcortical structures and high expression levels of opioid receptors in subcortical-cortical areas, with enhanced or reduced activity with low or very high doses of opioids, respectively. The SMN shows high levels of opioid receptors in subcortical areas and functional disconnection caused by opioids. The DMN shows low levels of opioid receptors in cortical areas and inhibited or enhanced activity with low or high doses of opioids, respectively. Finally, we proposed a working model. Opioidergic signaling enhances SN and suppresses SMN (and DMN) activity, resulting in affective excitation with psychomotor inhibition; stronger increases in opioidergic signaling attenuate the SN and SMN while disinhibiting the DMN, dissociating affective and psychomotor functions from the internal states; the opposite occurs with a deficit of opioidergic signaling.
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Dissertations / Theses on the topic "Opioid Receptors Signaling"

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ZHANG, SHENGWEN. "THE OPIOID RECEPTOR-LIKE RECEPTOR ORL1: SIGNALING AND INTERACTION WITH OPIOID RECEPTORS." University of Cincinnati / OhioLINK, 2002. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1029419843.

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Zhang, Shengwen. "The opioid receptor-like receptor ORL1 signaling and interaction with opioid receptors /." Cincinnati, Ohio : University of Cincinnati, 2002. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=ucin1029419843.

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Basti, Vida. "Ligand biased signaling of opioid agonists forphosphorylation and regulation of μ -opioid receptors." Thesis, Uppsala universitet, Farmakologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-192584.

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Abstract Ligand biased signaling of opioid agonists for phosphorylation andregulation of μ -opioid receptors Student: Vida Basti. Supervisor: Prof Macdonald Christie. Departmement of Neuropharmacology, The University of Sydney. Examiner: Prof Ingrid Nylander. Departement of Phamacology, University of Uppsala. Opioid drugs are of great use in the medical practise. The drugs are commonly prescribed formany types of illnesses, mostly in cases of pain management. Although opioids come withmany benefits they are causing a lot of problems as well. The side effects are many andamongst these is tolerance development which may lead to abuse and addiction. Because ofthe fast tolerance development in patients, higher doses up to 10 times the therapeutic doseare being prescribed. This is a major issue in today’s society and must be addressed.Scientists are trying to figure out the mechanism behind tolerance by comparing differenttypes opioid drugs. Some opioids causes tolerance in a much faster rate than others but it isstill uncertain why and what is causing this. Two of the most commonly prescribed opioidsare oxycodone and morphine and so in this rapport these opioids are compared with respectto their capability to cause internalization in neurons. In the experiments a positive control,DAMGO, is being used as well as a negative control. The method being used is an indirectmethod of immunohistochemistry on AtT20 transfected cell culture. The results show thatOxycodone seems to cause no internalization at all in comparison to the control.
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Xiang, Guoqing. "Signaling Through Homomeric and Heteromeric Cannabinoid CB1 receptors." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5683.

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Cannabis (Marijuana) has multiple effects on the human body, such as analgesia, euphoria and memory impairment. Delta-9 tetrahydrocannabinol (D9-THC), the active ingredient in cannabis, binds to cannabinoid receptors, seven-transmembrane G protein-coupled receptors (GPCRs) that mediate a variety of physiological functions. GPCRs were believed to function only in homomeric forms, however, recent findings show that different GPCRs can also form heteromeric complexes that may expand their signaling properties. In this study, we focused on Cannabinoid CB1 receptor (CB1R) heteromers with the mu-opioid receptor (MOR) and the Dopamine type 2 receptor (D2R), respectively. We utilized a variety of techniques, such as the calcium mobilization assay, a luciferase complementation assay and an electrophysiology assay to study the pharmacology of the CB1R-MOR and CB1R-D2R heteromers. Our data demonstrate that co-expression of CB1R enhances the Gi signaling through MOR and inhibits the beta-arrestin recruitment to MOR. We also show that co-application of CB1R ligands can further accentuate the MOR signaling modulation. Co-expression of a CB1R transmembrane domain 5 (TM5), but not a TM1, mini-gene abrogated the signaling change suggesting that it is likely due to heteromerization of MOR and CB1R. Utilizing this herteromeric signaling could provide a novel therapeutic approach that may yield potent analgesic effects with reduced side effects. We have also found that CB1R switched its signaling specificity from Gi to Gs upon its heteromerizaiton with D2R. In conclusion, our data show that CB1R expands its signaling repertory and modulates the partner receptor signaling upon heteromerization.
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Harrison, Charlotte. "Activation of multiple signaling pathways in cells expressing recombinant opioid receptors." Thesis, University of Leicester, 2000. http://hdl.handle.net/2381/29356.

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Although opioids have been used for centuries in the management of pain, the opioid receptor family has only recently been cloned, thus allowing detailed studies on opioid receptor mediated signal transduction pathways to be performed. In addition, two novel opioid peptides, endomorphin-1 and -2, were identified in 1997, and it is believed that these represent new endogenous u-opioid receptor ligands. This thesis represents a study into opioid receptor mediated increases in Ca2+ j and provides an investigation into the cellular signaling pathways of endomorphin-1 and -2. Activation of the recombinant 6-opioid receptor expressed in CHO cells (CH05) by D- Pen2'5 -enkephalin produced a concentration dependent, pertussis toxin and thapsigargin sensitive increase in Ca2+ i in whole cell suspensions. Truncation of this receptor by the 37 C-terminal amino acids produced a rightward shift in the concentration response curve for Ca j release. In single adherent CHOu, CHOk (CHO cells expressing recombinant u- or K-opioid receptors respectively) or CH05 cells, application of fentanyl, spiradoline or D-Pen2' -enkephalin respectively produced an increase in Ca i in some cells. The putative u.-opioid receptor endogenous ligands endomorphin- 1 and endomorphin-2 bound with high affinity and selectivity to u-opioid receptors from CHOu, and SH-SY5Y cells. Endomorphin-1 and -2 concentration-dependently inhibited forskolin stimulated cAMP formation in CHOp. and SH-SY5Y cells and endomorphin-1 and -2 produced an increase in Ca2+ j in CHOji cells. Prolonged endomorphin-1 pretreatment desensitized the -opioid receptor in CHO cells, characterized by a reduction in maximal endomorphin-1 mediated cAMP inhibition, an up-regulation of cAMP formation and was due to receptor - G protein uncoupling. Endomorphin-1 pre-treatment produced a rapid loss of cell surface receptors from CHOp. cells, which was possibly accompanied by receptor degradation. Collectively these data add to our understanding of opioid receptor-mediated signal transduction pathways.
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Yu, Xiaochun, and 喻曉春. "Negative modulation of B-adrenoceptor by K-opioid receptor in the heart: signaling mechanisms and clinicalsignificance." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1999. http://hub.hku.hk/bib/B31241323.

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Velazquez-Marrero, Cristina M. "Modulation of Neuropeptide Release via Voltage-Dependent and -Independent Signaling in Isolated Neurohypophysial Terminals: a Dissertation." eScholarship@UMMS, 2008. https://escholarship.umassmed.edu/gsbs_diss/367.

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This thesis details my examination of several mechanisms for modulation of neuropeptide release via voltage-dependent and voltage-independent intraterminal signaling in isolated neurohypophysial terminals. The first part of this work characterizes depolarization-induced neuropeptide release in the absence of extracellular calcium. The goal of this project was to examine the relationship between depolarization-induced release of intracellular calcium stores and depolarization-secretion coupling of neuropeptides. We demonstrate that depolarization in the absence of extracellular calcium induced by either High K+ or electrical stimulation induces a rise in [Ca2+]i and subsequent neuropeptide release from Hypothalamic Neurohypophysial System (HNS) terminals. A portion of extracellular calcium-independent neuropeptide release is due to intraterminal calcium, but the remaining depolarization-induced release may be due to calcium-independent voltage-dependent (CIVD) release (Zhang and Zhou, 2002; Zhang et al., 2004; Yang et al., 2005). Nevertheless, our results clearly show that extracellular calcium is notnecessary for depolarization-induced neuropeptide secretion from these CNS terminals. In addition, I investigated the role of internal calcium stores in mediating μ-opioid inhibition of voltage-gated calcium channels (VGCCs). Inhibition of VGCCs via μ-opioid agonists has been shown to reduce neuropeptide release in response to High K+ stimulation of isolated terminals (Bicknell et al., 1985b; Russell et al., 1993; van Wimersma Greidanus and van de Heijning, 1993; Munro et al., 1994; Ortiz-Miranda et al., 2003; Russell et al., 2003; Ortiz-Miranda et al., 2005). My findings show μ-opioid inhibition, of VGCC and High K+-mediated rise in [Ca2+]i, are via a voltage-independent diffusible second-messenger targeting release of calcium from ryanodine-sensitive stores, possibly mediated via the cyclic ADP ribose signaling pathway. Furthermore, I detail a different intracellular messenger pathway mediating the κ-opioid inhibition of VGCC and High K+-mediated rise in [Ca2+]ii. In contrast to the μ-opioid inhibition, κ-receptor activation is coupled to a voltage-dependent membrane-delimited pathway. Inhibition of neuropeptide release via both endogenous and exogenous κ-opioid agonists has been extensively studied (Bicknell et al., 1985a; Nordmann et al., 1986a; Wammack and Racke, 1988; Munro et al., 1994; Ingram et al., 1996; Rusin et al., 1997a). My investigation shows that the κ-inhibition of VGCC is voltage-dependent and is furthermore, relieved within the context of a physiological burst of action potentials (APs). This physiologically-evoked, activity-dependent modulation of VGCC and subsequent release, represents an important mechanism for short-term synaptic plasticity at the level of the terminals. Given the ubiquitous nature of voltage-dependent G-protein signaling in the CNS, our results may prove important in understanding modulatory effects of specific bursting patterns throughout the CNS. In the last 30 years the neurohypophysial system has proven to be an excellent system to study the complexities of depolarization-secretion coupling (DSC). There have been many advances in our understanding of the underlying mechanisms involved and their physiological implications. The current work focuses on two important features of DSC; voltage and calcium. Although in many ways these two are intrinsically linked through VGCC activation, we have found that in isolated HNS terminals that is not always the case. We have further found that when voltage and calcium influx are linked during DSC, modulation by opioids may or may not be linked to activity-dependent relief depending on the opioid receptor activated. This finding has important implications in neuropeptide release during patterned stimulation in vivo. As I will discuss further, many factors play into the complexities of the regulatory mechanisms involving release. As investigations into this remarkable field continue, I hope to have contributed a valuable piece to the puzzle.
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Tumati, Suneeta. "Functional regulation of opioid receptor signaling." Diss., The University of Arizona, 2009. http://hdl.handle.net/10150/194989.

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Studies have shown that long-term opioid agonist (such as morphine) treatment produces antinociceptive tolerance and increased pain sensitivity (hyperalgesia and/or allodynia), limiting the clinical efficacy of morphine. Prolonged opiate administration also upregulates spinal pain neurotransmitter (such as calcitonin gene-related peptide (CGRP)) levels and enhances evoked CGRP release in the dorsal horn of rats. It was suggested that augmented spinal pain neurotransmission may contribute to paradoxical pain sensitization and antinociceptive tolerance. The cellular signal transduction pathways involved in sustained opioid mediated augmentation of spinal pain neurotransmitter are not fully clarified.Sustained morphine treatment was shown to augment the concentrations of inflammatory mediators, such as PGE2 in the spinal cord. Studies have shown that PGE2 stimulates cAMP formation and CGRP release by activation of Gs protein-coupled prostaglandin receptor types in primary sensory neurons. Interestingly, it was found earlier that sustained opioid agonist treatment leads to a Raf-1-dependent sensitization of adenylyl cyclase(s) (AC superactivation), augmenting forskolin-stimulated cAMP formation upon opioid withdrawal (cAMP overshoot). It is well demonstrated that cAMP activates cAMP-dependent protein kinase (PKA), which plays an important role in the modulation of presynaptic neurotransmitter release. Therefore, in this study, we investigate the physiological role of Raf-1 mediated AC superactivation and subsequent PKA activation in A. sustained morphine-mediated augmentation of basal or evoked pain neurotransmitter release in vitro, in cultured primary sensory neurons, and B. in vivo, in sustained morphine mediated paradoxical pain sensitization and antinociceptive tolerance in rats.Our data demonstrates that A. sustained morphine treatment augments both basal and capsaicin-evoked CGRP release from isolated primary sensory neurons in a PKA- and Raf-1- dependent manner. B. sustained morphine treatment- augments of PGE2-evoked CGRP release from these cells. C. selective knockdown of spinal PKA or Raf-1 protein levels by intrathecal PKA- or Raf-1-specific siRNA pretreatment completely attenuates sustained morphine-mediated thermal hyperalgesia, tactile allodynia and greatly reduces antinociceptive tolerance in rats.In conclusion, we suggest that Raf-1-mediated AC superactivation may have a crucial trigger role in sustained morphine-mediated compensatory adaptations in the nervous system. Thus, we expect that pharmacological attenuation of Raf-1-mediated AC superactivation may improve the clinical treatment of chronic and neuropathic pain.
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Olson, Keith Mathew, and Keith Mathew Olson. "Atypical Opioid Interactions – Development of Selective Mu-Delta Heterodimer Antagonists, Clinical Opioids at Non-Mu Pain Targets and Endogenous Biased Signaling." Diss., The University of Arizona, 2017. http://hdl.handle.net/10150/626669.

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Most clinical opioids produce analgesia through the Mu Opioid Receptor (MOR) providing the only effective treatment for chronic pain patients. These studies explore three pre-clinical strategies to improve MOR analgesia and minimize side effects: 1) compounds that target G-protein Coupled Receptors (GPCRs) heterodimers, such as heterodimerization between the Delta Opioid Receptor (DOR) and MOR (MDOR); 2) multi-functional compounds that target multiple receptor systems for synergistic effects, such as a MOR agonist and a the serotonin reuptake transporter (SERT) inhibitor; or 3) biased agonists that preferentially activate one signaling pathway associated with analgesia over another associated with side effects at the same receptor. First, several indirect lines of evidence indicate the MOR-DOR heterodimer (MDOR) can regulate MOR opioid tolerance and withdrawal. However, studying MDOR remains difficult because no selective MDOR antagonists are available. To address this need, we created a novel series of bivalent MDOR antagonists by connecting a low affinity MOR antagonist (H-Tyr-Pro-Phe-D1Nal-NH2) to a moderate affinity DOR (H- Tyr-Tic-OH) antagonist with variable length polyamide spacers (15-41 atoms). In vitro radioligand binding and [35S]-GTPγS coupling assays in MOR, DOR, and MDOR expressing cell lines show bivalent ligands produce a clear length dependence in MDOR but not MOR or DOR cell lines. The lead compound – D24M with a 24-atom spacer – displayed high potency (IC50MDOR = 0.84 nM) with 91-fold selectivity for MDOR:DOR and 1,000-fold MDOR:MOR selectivity. Second, clinicians have long appreciated subtle but distinct differences in analgesia and side effects of MOR opioids. A variety of non-MOR targets including DOR, Kappa Opioid Receptor (KOR), the Cannabinoid Receptor-1 (CB1), the Sigma-1 Receptor (σ1R), the Dopamine- (DAT), Serotonin- (SERT) and Norepinephrine- Reuptake Transporters (NET) induce analgesia and/or modulate MOR mediated side effects. To determine if different opioid profiles arise from non-MOR interactions, we evaluated the binding and function of nine clinical analgesics at the nine aforementioned targets revealing several clinical opioids contain previously unidentified affinity’s or activity’s. Hydrocodone displayed low affinity at the MOR (KI = 1800 nM) and only ~2 fold less affinity at the σ1R (KI = 4000 nM). Second buprenorphine promoted monoamine influx at DAT, SERT and NET with EC50 > 1,000 nM. These novel interactions suggest the nuanced differences of clinical opioids may arise from previously unappreciated off-target effects. Future studies will assess whether these in vitro results predict hydrocodone and buprenorphine activity in vivo. Finally, the unique function of the numerous endogenous opioid peptides at a given receptor remains unclear. How endogenous ligands interact with ORs produces obvious drug design consequences. These studies show two endogenous Dynorphin analogues – Dynorphin A and Dynorphin B – differentially regulate two ubiquitous signaling modules – βarrestin2 and Gαi/o– at the DOR. Dynorphin A and Dynorphin B swap potency rank orders for β-arrestin2 recruitment and [35S]-GTPγS signaling, indicating two distinct signaling platforms are formed. Dynorphin A but not Dynorphin B treatment simulated AC super activation, while Dynoprhin B internalized DOR better than Dynorphin A. These in vitro assays suggest endogenous Dynorphin analogues differentially regulate signals at the DOR in vitro. Future work includes further characterizing signaling differences in vitro and testing these changes in vivo.
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Yu, Y. Joy. "Regulation of mu opioid receptor trafficking, signaling, and recycling in neurons." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3378518.

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Books on the topic "Opioid Receptors Signaling"

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Dickenson, Tony. Endogenous opioids in the CNS. Edited by Paul Farquhar-Smith, Pierre Beaulieu, and Sian Jagger. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198834359.003.0019.

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This short and concise paper was the first to unequivocally reveal that there were endogenous opioids in the central nervous system (CNS), identify their peptide nature and sequence, and show that they exerted physiological inhibitory effects. The idea that there were natural opioids fitted with concurrent reports of opiate-binding sites, and this led to the description of multiple receptors with their own families of peptide transmitters. No truly novel opioid drugs have emerged since, and attempts to protect and manipulate the enkephalins for pain control have yet to be successful. This does not detract from this key study, which made us think about pain modulation in a different way, and subsequent work has clearly shown how endogenous opioid signalling is critical in CNS function, perhaps most importantly in endogenous pain control, such as that harnessed by placebo analgesia.
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Book chapters on the topic "Opioid Receptors Signaling"

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Stowers, Lisa, Sandeepa Dey, Vladana Vukojević, Yu Ming, and Lars Terenius. "Opioid Receptors: Cellular and Molecular Mechanisms Underlying Opioid Receptor Function." In Encyclopedia of Signaling Molecules, 1304–12. New York, NY: Springer New York, 2012. http://dx.doi.org/10.1007/978-1-4419-0461-4_596.

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Moorman, Jonathan, Zhi Qiang Yao, Edward J. Bilsky, and Deling Yin. "Opioid Receptor Antagonist-Mediated Signaling in the Immune System." In Opiate Receptors and Antagonists, 67–80. Totowa, NJ: Humana Press, 2009. http://dx.doi.org/10.1007/978-1-59745-197-0_4.

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Pamenter, Matthew E. "Neuroprotective Interactions Between Delta-Opioid Receptors and Glutamatergic Signaling Mediate Hypoxia-Tolerance in Brain." In Neural Functions of the Delta-Opioid Receptor, 363–88. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/978-3-319-25495-1_8.

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Vukojević, Vladana, Yu Ming, Tijana Jovanović-Talisman, and Lars Terenius. "Opioid Receptor." In Encyclopedia of Signaling Molecules, 3656–65. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-67199-4_596.

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Vukojević, Vladana, Yu Ming, Tijana Jovanović-Talisman, and Lars Terenius. "Opioid Receptor." In Encyclopedia of Signaling Molecules, 1–10. New York, NY: Springer New York, 2017. http://dx.doi.org/10.1007/978-1-4614-6438-9_596-1.

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Doly, Stéphane, Silvina Laura Diaz, Arnauld Belmer, Anne Roumier, Luc Maroteaux, Carine Becamel, Philippe Marin, and Joël Bockaert. "δ-Opioid Receptor." In Encyclopedia of Signaling Molecules, 20. New York, NY: Springer New York, 2012. http://dx.doi.org/10.1007/978-1-4419-0461-4_100004.

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Doly, Stéphane, Silvina Laura Diaz, Arnauld Belmer, Anne Roumier, Luc Maroteaux, Carine Becamel, Philippe Marin, and Joël Bockaert. "κ-Opioid Receptor." In Encyclopedia of Signaling Molecules, 20. New York, NY: Springer New York, 2012. http://dx.doi.org/10.1007/978-1-4419-0461-4_100006.

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Doly, Stéphane, Silvina Laura Diaz, Arnauld Belmer, Anne Roumier, Luc Maroteaux, Carine Becamel, Philippe Marin, and Joël Bockaert. "μ-Opioid Receptor." In Encyclopedia of Signaling Molecules, 20. New York, NY: Springer New York, 2012. http://dx.doi.org/10.1007/978-1-4419-0461-4_100007.

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Horstkorte, Rüdiger, Bettina Büttner, Kaya Bork, Navdeep Sahota, Sarah Sabir, Laura O’Regan, Joelle Blot, et al. "Nociceptin Opioid Receptor." In Encyclopedia of Signaling Molecules, 1254. New York, NY: Springer New York, 2012. http://dx.doi.org/10.1007/978-1-4419-0461-4_100932.

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Law, P‐Y, and H. H. Loh. "Opioid Receptor Signaling and Regulation." In Handbook of Neurochemistry and Molecular Neurobiology, 357–89. Boston, MA: Springer US, 2006. http://dx.doi.org/10.1007/978-0-387-30381-9_18.

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