DOCSLIB.ORG

Currents in Guinea Pig CA3 Pyramidal Cells

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Currents in Guinea Pig CA3 Pyramidal Cells The Journal of Neuroscience, September 1994. 14(g): 55806589 Kp Opioid Receptors Inhibit NMDA Receptor-mediated Synaptic Currents in Guinea Pig CA3 Pyramidal Cells Robert M. Caudle,’ Charles Chavkin,* and Ronald Dubner’ ‘Neurobiology and Anesthesiology Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892 and *Department of Pharmacology, University of Washington,‘Seattle, Washington 98195 The role of the endogenous opioid peptide dynorphin (l- 17) dynorphin’s concentration in the spinal cord increasesfollowing in regulating NMDA receptor-mediated synaptic currents was peripheral tissue and nerve injury (Iadarola et al., 1988; Nahin examined in guinea pig hippocampus. Schaffer collateral/ et al., 1989; Kajander et al., 1990), and spinal cord injury (Faden commissural fiber-evoked NMDA synaptic currents were re- et al., 1985), and that its concentration in the hippocampus corded using whole-cell patch-clamp techniques in CA3 py- increases(Lee et al., 1987) and decreases(McGinty et al., 1986) ramidal cells. Dynorphin was found to have dual effects on following seizures.These studies of endogenousdynorphin have NMDA synaptic currents, increasing currents at low concen- also provided little information concerning dynorphin’s role in trations and decreasing currents at high concentrations. Only the CNS. In our present course of investigation, we have nar- the inhibitory action of dynorphin was sensitive to naloxone, rowed our studiesto structures that have dynorphin-containing indicating that this effect was mediated by an opioid recep- afferents that were demonstrated to release dynorphin under tor. The inhibitory effect was mimicked by bremazocine, but physiological conditions. The logic behind this approach is that not by U69,593, U50,466, [D-Ala*, KMe-Phe4, Gly-oll-en- an effect of exogenous dynorphin should be demonstrable for kephalin, or [D-PerV]-enkephalin. Bremazocine’s effect was endogenousdynorphin. Thus, if exogenousand endogenousdy- blocked by naloxone, but not by nor-binaltorphimine, cypro- norphin produce similar effects it is likely that a physiological dime, or naltrindole. These findings suggest that bremazo- function for dynorphin was demonstrated. tine’s effect was mediated by the K2 subtype of opioid re- The hippocampus of rodents contains a substantial concen- ceptor. In addition, 1 AM naloxone and antisera to dynorphin tration of dynorphin. This dynorphin resides primarily in the (l-1 7) were found to increase NMDA-mediated synaptic cur- mossy fiber pathway that extends from the dentate granule cells rents. Nor-binaltorphimine, cyprodime, naltrindole, and an- to the CA3 pyramidal cells (Gall et al., 1981; McGinty et al., tisera to met-enkephalin did not increase the NMDA synaptic 1983; McLean et al., 1987). The mossy fibers serve as the major current. These findings suggest that endogenous dynorphin excitatory input to the CA3 region. Previous attempts to dem- was acting at K2 receptors to inhibit NMDA receptor-medi- onstrate effects of dynorphin and other K-S&&T opioids in the ated synaptic currents. Overall, these findings indicate that CA3 region of the rodent hippocampuswere either unsuccessful dynorphin is an endogenous agonist for K* receptors in the (Caudle and Chavkin, 1990) or ambiguous(Moises and Walker, CA3 region of the guinea pig hippocampus and that these 1985). On the other hand, we demonstrated that K agonists, receptors regulate NMDA receptor function. including dynorphin, inhibit excitatory transmitter releasefrom [Key words: opioids, dynorphin, kappa receptors, N-me- the perforant path onto dentate granule cells in guinea pig hip- thy/-D-aspartate receptors (NMDA), whole cell patch clamp, pocampus(Wagner et al., 1992,1993). Other groups have found hippocampus, guinea pig, CA31 that dynorphin, through K receptors, inhibits calcium currents and calcium action potentials in cultured dorsal root ganglion The opioid peptide dynorphin is thought to be the endogenous cells(Werz and MacDonald, 1985; MacDonald and Werz, 1986; ligand for K-opioid receptors (Chavkin et al., 1982). This peptide Gross and MacDonald, 1987). Therefore, we proposed that the has been examined in numerous models in order to determine inhibition of calcium currents was likely to be the mechanism its functional role in the CNS. The effects produced by exoge- for K receptor-mediated inhibition of excitatory amino acid re- nously applied dynorphin vary from neurotoxicity (Caudle and leasefrom the perforant path (Wagner et al., 1992, 1993). Isaac, 1987) to inhibition of calcium potentials (Werz and Mac- Using the K,-SekCtiVe ligand 3H-U69,593 for autoradiogra- Donald, 1985; MacDonald and Werz, 1986; Gross and Mac- phy, we found that virtually all of the specific binding was lo- Donald, 1987). These differing actions of exogenousdynorphin cated in the molecular layer of the guinea pig dentate gyrus have not provided a clear answerto dynorphin’s function in the (Wagner et al., 1991, 1992). This pattern of binding by 3H- CNS. Adding to the confusion are reports demonstrating that U69,593 explained the lack of effect of this compound in the CA3 region of the guinea pig hippocampus in our physiological studies(Caudle and Chavkin, 1990). However, Weisskopf et al. Received Sept. 13, 1993; revised Mar. 17, 1994; accepted Mar. 24, 1994. (1993) reported that U69,593 had inhibitory effectsin the guinea We thank Drs. Gene Williams and Ke Ren for their comments and advice in pig CA3. Given the lack of binding sites for U69,593 in this the preparation ofthis manuscript. C.C. is supported by U.S. Public Health Service region of the guinea pig hippocampus, Weisskopf et al.‘s findings Grant DA04 123. Correspondence should be addressed to R. M. Caudle, NAB, NIDR, NIH, are difficult to interpret. Building 49/Roam IA-1 1, 9000 Rockville Pike, Bethesda, MD 20892. Recently, evidence was presented indicating the existence of Copyright 0 1994 Society for Neuroscience 0270-6474/94/145580-10$05.00/O at least two subtypes of K-opioid receptors (Neck et al., 1988, The Journal of Neuroscience, September 1994, M(9) 5581 1990, 1993; Zukin et al., 1988; Rothman et al., 1992). U69,593 Stimulating Electrode selectively binds to one of these sites and this site has been labeled the K, receptor. Compounds like ethylketocyclazocine and bremazocine, in the presence of p- and &opioid receptor blockers, bind to the U69,593 binding site and to another site with approximately equal affinity. The U69,593-insensitive site has been labeled the K2 receptor (Zukin et al., 1988; Rothman et al., 1992) or the t receptor (Neck et al., 1990, 1993). Auto- radiographic studies of K-Opioid binding sites using either 3H- ethylketocyclazocine or 3H-bremazocine in guinea pig hippo- campus resulted in binding to both the molecular layer of the dentate gyrus and the stratum lucidum of the CA3 (McLean et al., 1986; Zukin et al., 1988). The binding in the CA3 contrasts with ‘H-U69,593 binding (Wagner et al., 199 1, 1992), and sug- gests that these sites are K2 or t receptors. The close proximity of the K2 binding sites in the guinea pig / CA3 to the terminals of the dynorphin-containing mossy fibers, Kappas Receptors as compared to the K, binding sites in the dentate gyrus, suggests that dynorphin may be an endogenous ligand for this receptor. Figure 1. Diagrammaticrepresentation of a guineapig hippocampal If endogenous dynorphin acts at K2 receptors, the question then slice.The cellthat the patchelectrode is connected to isa CA3 pyramidal cell. The stimulatingelectrode is placedin the Schaffercollateral/com- becomes what physiological function do K2 receptors perform missuralpathway. The gray shadedarea representsthe location of NMDA and how can we measure that function? Several studies have receptorsin the CA3 regionof the guineapig hippocampus.The hatched suggested that dynorphin may play a role in the regulation of urea representsthe locationof U69,593-insensitivebremazocine bind- NMDA receptors (Caudle and Isaac, 1988a,b; Bakshi and Fa- ing sites(K2 receptors)in the guineapig hippocampus. den, 1990a,b; Faden et al., 1990; Isaac et al., 1990; Shukla et al., 1992; Skilling et al., 1992). In these studies, selective an- ceptor physiology and dynorphin’s effects on K2 receptors, it was tagonists to the NMDA receptor complex blocked the effects of necessaryto dissectK, , K2, and nonopioid effectsfrom eachother. exogenously applied dynorphin. The results of these experi- To avoid the influence of K, receptors, the CA3 region of the ments suggest that dynorphin may potentiate NMDA receptor guinea pig hippocampus was chosen for study. As previously function. However, several other studies have demonstrated mentioned, this region of the guinea pig hippocampuslacks 3H- that dynorphin has inhibitory actions in the CNS. In addition U69,593,binding sites (Wagner et al., 1992) and is innervated to the K, inhibitory effects, several investigators have found neu- by a dynorphinergic fiber bundle (Gall et al., 198 1; McGinty et roprotective (Baskin et al., 1984; Garant et al., 1985), inhibitory al., 1983; McLean et al., 1987). Using whole-cell voltage-clamp (Stevens et al., 1987; Stewart and Isaac, 199 l), and both excit- techniques, we demonstrate that K2 receptors inhibit NMDA- atory and inhibitory effects of dynorphin (Moises and Walker, mediated synaptic currents in the CA3 region of the guinea pig 1985; Knox and Dickenson, 1987; Hylden et al., 199 1) that may hippocampus, and evidence is presented that endogenousdy- or may not be mediated by
Load more

Recommended publications
  • Augmentation of Morphine-Induced Sensitization but Reduction in Morphine Tolerance and Reward in Delta-Opioid Receptor Knockout Mice
    Neuropsychopharmacology (2009) 34, 887–898 & 2009 Nature Publishing Group All rights reserved 0893-133X/09 $32.00 www.neuropsychopharmacology.org Augmentation of Morphine-Induced Sensitization but Reduction in Morphine Tolerance and Reward in Delta-Opioid Receptor Knockout Mice ,1 1 VI Chefer* and TS Shippenberg 1Integrative Neuroscience Section, Behavioral Neuroscience Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA Studies in experimental animals have shown that individuals exhibiting enhanced sensitivity to the locomotor-activating and rewarding properties of drugs of abuse are at increased risk for the development of compulsive drug-seeking behavior. The purpose of the present study was to assess the effect of constitutive deletion of delta-opioid receptors (DOPr) on the rewarding properties of morphine as well as on the development of sensitization and tolerance to the locomotor-activating effects of morphine. Locomotor activity testing revealed that mice lacking DOPr exhibit an augmentation of context-dependent sensitization following repeated, alternate injections of morphine (20 mg/kg; s.c.; 5 days). In contrast, the development of tolerance to the locomotor-activating effects of morphine following chronic morphine administration (morphine pellet: 25 mg: 3 days) is reduced relative to WT mice. The conditioned rewarding effects of morphine were reduced significantly in DOPrKO mice as compared to WT controls. Similar findings were obtained in response to pharmacological inactivation of DOPr in WT mice, indicating that observed effects are not due to developmental adaptations that occur as a consequence of constitutive deletion of DOPr. Together, these findings indicate that the endogenous DOPr system is recruited in response to both repeated and chronic morphine administration and that this recruitment serves an essential function in the development of tolerance, behavioral sensitization, and the conditioning of opiate reward.
    [Show full text]
  • In Vivoactivation of a Mutantμ-Opioid Receptor by Naltrexone Produces A
    The Journal of Neuroscience, March 23, 2005 • 25(12):3229–3233 • 3229 Brief Communication In Vivo Activation of a Mutant ␮-Opioid Receptor by Naltrexone Produces a Potent Analgesic Effect But No Tolerance: Role of ␮-Receptor Activation and ␦-Receptor Blockade in Morphine Tolerance Sabita Roy, Xiaohong Guo, Jennifer Kelschenbach, Yuxiu Liu, and Horace H. Loh Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455 Opioid analgesics are the standard therapeutic agents for the treatment of pain, but their prolonged use is limited because of the development of tolerance and dependence. Recently, we reported the development of a ␮-opioid receptor knock-in (KI) mouse in which the ␮-opioid receptor was replaced by a mutant receptor (S196A) using a homologous recombination gene-targeting strategy. In these animals, the opioid antagonist naltrexone elicited antinociceptive effects similar to those of partial agonists acting in wild-type (WT) mice; however, development of tolerance and physical dependence were greatly reduced. In this study, we test the hypothesis that the failure of naltrexone to produce tolerance in these KI mice is attributable to its simultaneous inhibition of ␦-opioid receptors and activation of ␮-opioid receptors. Simultaneous implantation of a morphine pellet and continuous infusion of the ␦-opioid receptor antagonist naltrindole prevented tolerance development to morphine in both WT and KI animals. Moreover, administration of SNC-80 [(ϩ)-4-[(␣R)-␣-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide], a ␦ agonist, in the naltrexone- pelleted KI animals resulted in a dose-dependent induction in tolerance development to both morphine- and naltrexone-induced anal- gesia. We conclude that although simultaneous activation of both ␮- and ␦-opioid receptors results in tolerance development, ␮-opioid receptor activation in conjunction with ␦-opioid receptor blockade significantly attenuates the development of tolerance.
    [Show full text]
  • Opioid Receptorsreceptors
    OPIOIDOPIOID RECEPTORSRECEPTORS defined or “classical” types of opioid receptor µ,dk and . Alistair Corbett, Sandy McKnight and Graeme Genes encoding for these receptors have been cloned.5, Henderson 6,7,8 More recently, cDNA encoding an “orphan” receptor Dr Alistair Corbett is Lecturer in the School of was identified which has a high degree of homology to Biological and Biomedical Sciences, Glasgow the “classical” opioid receptors; on structural grounds Caledonian University, Cowcaddens Road, this receptor is an opioid receptor and has been named Glasgow G4 0BA, UK. ORL (opioid receptor-like).9 As would be predicted from 1 Dr Sandy McKnight is Associate Director, Parke- their known abilities to couple through pertussis toxin- Davis Neuroscience Research Centre, sensitive G-proteins, all of the cloned opioid receptors Cambridge University Forvie Site, Robinson possess the same general structure of an extracellular Way, Cambridge CB2 2QB, UK. N-terminal region, seven transmembrane domains and Professor Graeme Henderson is Professor of intracellular C-terminal tail structure. There is Pharmacology and Head of Department, pharmacological evidence for subtypes of each Department of Pharmacology, School of Medical receptor and other types of novel, less well- Sciences, University of Bristol, University Walk, characterised opioid receptors,eliz , , , , have also been Bristol BS8 1TD, UK. postulated. Thes -receptor, however, is no longer regarded as an opioid receptor. Introduction Receptor Subtypes Preparations of the opium poppy papaver somniferum m-Receptor subtypes have been used for many hundreds of years to relieve The MOR-1 gene, encoding for one form of them - pain. In 1803, Sertürner isolated a crystalline sample of receptor, shows approximately 50-70% homology to the main constituent alkaloid, morphine, which was later shown to be almost entirely responsible for the the genes encoding for thedk -(DOR-1), -(KOR-1) and orphan (ORL ) receptors.
    [Show full text]
  • 4 Supplementary File
    Supplemental Material for High-throughput screening discovers anti-fibrotic properties of Haloperidol by hindering myofibroblast activation Michael Rehman1, Simone Vodret1, Luca Braga2, Corrado Guarnaccia3, Fulvio Celsi4, Giulia Rossetti5, Valentina Martinelli2, Tiziana Battini1, Carlin Long2, Kristina Vukusic1, Tea Kocijan1, Chiara Collesi2,6, Nadja Ring1, Natasa Skoko3, Mauro Giacca2,6, Giannino Del Sal7,8, Marco Confalonieri6, Marcello Raspa9, Alessandro Marcello10, Michael P. Myers11, Sergio Crovella3, Paolo Carloni5, Serena Zacchigna1,6 1Cardiovascular Biology, 2Molecular Medicine, 3Biotechnology Development, 10Molecular Virology, and 11Protein Networks Laboratories, International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano, 34149, Trieste, Italy 4Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy 5Computational Biomedicine Section, Institute of Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, 52425, Jülich, Germany 6Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy 7National Laboratory CIB, Area Science Park Padriciano, Trieste, 34149, Italy 8Department of Life Sciences, University of Trieste, Trieste, 34127, Italy 9Consiglio Nazionale delle Ricerche (IBCN), CNR-Campus International Development (EMMA- INFRAFRONTIER-IMPC), Rome, Italy This PDF file includes: Supplementary Methods Supplementary References Supplementary Figures with legends 1 – 18 Supplementary Tables with legends 1 – 5 Supplementary Movie legends 1, 2 Supplementary Methods Cell culture Primary murine fibroblasts were isolated from skin, lung, kidney and hearts of adult CD1, C57BL/6 or aSMA-RFP/COLL-EGFP mice (1) by mechanical and enzymatic tissue digestion. Briefly, tissue was chopped in small chunks that were digested using a mixture of enzymes (Miltenyi Biotec, 130- 098-305) for 1 hour at 37°C with mechanical dissociation followed by filtration through a 70 µm cell strainer and centrifugation.
    [Show full text]
  • Constitutive Activity of the Δ-Opioid Receptor Expressed in C6 Glioma Cells
    British Journal of Pharmacology (1999) 128, 556 ± 562 ã 1999 Stockton Press All rights reserved 0007 ± 1188/99 $15.00 http://www.stockton-press.co.uk/bjp Constitutive activity of the d-opioid receptor expressed in C6 glioma cells: identi®cation of non-peptide d-inverse agonists 1Claire L. Neilan, 3Huda Akil, 1,2James H. Woods & *,1John R. Traynor 1Department of Pharmacology, University of Michigan Medical School, 1301 MSRB III, Ann Arbor, Michigan, MI 48109-0632, USA; 2Department of Psychology, University of Michigan Medical School, 1301 MSRB III, Ann Arbor, Michigan, MI 48109-0632, USA and 3Mental Health Research Institute, University of Michigan Medical School, Ann Arbor, Michigan, MI 48109-0720, USA 1 G-protein coupled receptors can exhibit constitutive activity resulting in the formation of active ternary complexes in the absence of an agonist. In this study we have investigated constitutive activity in C6 glioma cells expressing either the cloned d-(OP1) receptor (C6d), or the cloned m-(OP3) opioid receptor (C6m). 2 Constitutive activity was measured in the absence of Na+ ions to provide an increased signal. The degree of constitutive activity was de®ned as the level of [35S]-GTPgS binding that could be inhibited by pre-treatment with pertussis toxin (PTX). In C6d cells the level of basal [35S]-GTPgS binding was reduced by 51.9+6.1 fmols mg71 protein, whereas in C6m and C6 wild-type cells treatment with PTX reduced basal [35S]-GTPgS binding by only 10.0+3.5 and 8.6+3.1 fmols mg71 protein respectively. 3 The d-antagonists N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI 174,864), 7-benzylidenenaltrexone (BNTX) and naltriben (NTB), in addition to clocinnamox (C-CAM), acted as d-opioid receptor inverse agonists.
    [Show full text]
  • Modulation of MDMA-Induced Behavioral and Transcriptional
    Modulation of MDMA-induced behavioral and transcriptional effects by the delta opioid antagonist naltrindole in mice Emilie Belkaï , Jean-Michel Scherrmann , Florence Noble * , Cynthia Marie-Claire NAVVEC, Neuropsychopharmacologie des addictions. Vulnérabilité et variabilité expérimentale et clinique CNRS : UMR7157 , INSERM : U705 , IFR71 , Université Paris Descartes , Université Paris-Diderot - Paris VII , FR * Correspondence should be adressed to: Florence Noble <[email protected] > Abstract The delta opioid system is involved in the behavioral effects of various drugs of abuse. However, only few studies have focused on the possible interactions between the opioid system and the effects of MDMA. In order to examine the possible role of the delta opioid system in MDMA-induced behaviors in mice, locomotor activity and conditioned place preference were investigated in the presence of naltrindole, a selective delta opioid antagonist. Moreover, the consequences of acute and chronic MDMA administration on Penk (pro-enkephalin) and Pomc (pro-opioimelanocortin) gene expression were assessed by quantitative real-time PCR. The results showed that, after acute MDMA administration (9mg/kg; i.p.), naltrindole (5mg/kg, s.c.) was able to totally block MDMA-induced hyperlocomotion. Penk expression gene was not modulated by acute MDMA but a decrease of Pomc gene expression was observed that was not antagonized by naltrindole. Administration of the antagonist prevented the acquisition of MDMA-induced conditioned place preference, suggesting an implication of the delta opioid receptors in this behavior. Following chronic MDMA treatment only the level of Pomc was modulated. The observed increase was totally blocked by naltrindole pretreatment. All these results confirm the interactions between the delta opioid system (receptors and peptides) and the effects of MDMA.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2015/0202317 A1 Rau Et Al
    US 20150202317A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0202317 A1 Rau et al. (43) Pub. Date: Jul. 23, 2015 (54) DIPEPTDE-BASED PRODRUG LINKERS Publication Classification FOR ALPHATIC AMNE-CONTAINING DRUGS (51) Int. Cl. A647/48 (2006.01) (71) Applicant: Ascendis Pharma A/S, Hellerup (DK) A638/26 (2006.01) A6M5/9 (2006.01) (72) Inventors: Harald Rau, Heidelberg (DE); Torben A 6LX3/553 (2006.01) Le?mann, Neustadt an der Weinstrasse (52) U.S. Cl. (DE) CPC ......... A61K 47/48338 (2013.01); A61 K3I/553 (2013.01); A61 K38/26 (2013.01); A61 K (21) Appl. No.: 14/674,928 47/48215 (2013.01); A61M 5/19 (2013.01) (22) Filed: Mar. 31, 2015 (57) ABSTRACT The present invention relates to a prodrug or a pharmaceuti Related U.S. Application Data cally acceptable salt thereof, comprising a drug linker conju (63) Continuation of application No. 13/574,092, filed on gate D-L, wherein D being a biologically active moiety con Oct. 15, 2012, filed as application No. PCT/EP2011/ taining an aliphatic amine group is conjugated to one or more 050821 on Jan. 21, 2011. polymeric carriers via dipeptide-containing linkers L. Such carrier-linked prodrugs achieve drug releases with therapeu (30) Foreign Application Priority Data tically useful half-lives. The invention also relates to pharma ceutical compositions comprising said prodrugs and their use Jan. 22, 2010 (EP) ................................ 10 151564.1 as medicaments. US 2015/0202317 A1 Jul. 23, 2015 DIPEPTDE-BASED PRODRUG LINKERS 0007 Alternatively, the drugs may be conjugated to a car FOR ALPHATIC AMNE-CONTAINING rier through permanent covalent bonds.
    [Show full text]
  • 9-Tetrahydrocannabinol Dysphoric Effects in Dynorphin-Deficient Mice
    The Journal of Neuroscience, December 1, 2001, 21(23):9499–9505 Absence of ⌬-9-Tetrahydrocannabinol Dysphoric Effects in Dynorphin-Deficient Mice Andreas Zimmer,1,2 Emmanuel Valjent,3 Monika Ko¨ nig,1 Anne M. Zimmer,1,2 Patricia Robledo,3 Heidi Hahn,1 Olga Valverde,3 and Rafael Maldonado3 1Laboratory of Genetics, National Institute of Mental Health, Bethesda, Maryland 20892, 2Psychiatric Clinic, University of Bonn, 53105 Bonn, Germany, and 3Laboratori de Neurofarmacologia, Facultat de Cie` ncies de la Salut i de la Vida, Universitat Pompeu Fabra, 08003 Barcelona, Spain The involvement of dynorphin on ⌬-9-tetrahydrocannabinol aversion. In contrast, acute and chronic opioid effects were (THC) and morphine responses has been investigated by using normal. The lack of negative motivational effects of THC in the mice with a targeted inactivation of the prodynorphin (Pdyn) absence of dynorphin demonstrates that this endogenous opi- gene. Dynorphin-deficient mice show specific changes in the oid peptide mediates the dysphoric effects of marijuana. behavioral effects of THC, including a reduction of spinal THC Key words: cannabinoid; opioid; mice; mutation; withdrawal; analgesia and the absence of THC-induced conditioned place addiction; place aversion Pharmacological and genetic evidence suggest important func- suggested that both receptor types may interact at the level of tional interactions between the endogenous brain cannabinoid signal transduction (Manzanares et al., 1999). and opioid systems (Hine et al., 1975; Vela et al., 1995; Pugh et al., Of particular interest is the potential role of cannabis as a 1997; Tanda et al., 1997; Ledent et al., 1999; Manzanares et al., gateway drug, which has been investigated primarily with epide- 1999; Valverde et al., 2000, 2001).
    [Show full text]
  • Agonists and Antagonists Bind to Different Domains of the Cloned C Opioid Receptor HAEYOUNG KONG*, KAREN RAYNOR*, HIDEKI Yanot, JUN Takedat, GRAEME I
    Proc. Nadl. Acad. Sci. USA Vol. 91, pp. 8042-8046, August 1994 Neurobiology Agonists and antagonists bind to different domains of the cloned c opioid receptor HAEYOUNG KONG*, KAREN RAYNOR*, HIDEKI YANOt, JUN TAKEDAt, GRAEME I. BELLt, AND TERRY REISINE*t *Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and tHoward Hughes Medical Institute and Departments of Biochemistry and Molecular Biology and Medicine, University of Chicago, Chicago, IL 60637 Communicated by L. B. Flexner, May 6, 1994 ABSTRACT Opium and its derivatives are potent analge- intracellular COOH termini are divergent. It seems reason- sics that can also induce severe side effects, including respira- able to assume that these divergent extracellular regions may tory depression and addiction. Opioids exert their diverse be responsible for the distinct ligand-binding profiles ofthe 8, physiological effects through specific membrane-bound recep- K, and 1i receptors. To test this hypothesis, we have ex- tors. Three major types of opioid receptors have been de- changed the extracellular NH2 termini of the mouse 8 and K scribed, termed 8, c, and ,t. The recent molecular cloning of receptors (3, 4) and examined the abilities of these chimeric these receptor types opens up the possibility to identify the receptors to bind 8- and K-selective agonists and antagonists, ligand-binding domains of these receptors. To identify the as well as to mediate inhibition of adenylyl cyclase activity. ligand-binding domains of the K and 8 receptors, we have expressed in COS-7 cells the cloned mouse 8 and K receptors METHODS and chimeric 8/K and K!8 receptors in which the NH2 termini have been exchanged.
    [Show full text]
  • Modulation of Opioid Transport at the Blood-Brain Barrier by Altered ATP-Binding Cassette (ABC) Transporter Expression and Activity
    pharmaceutics Review Modulation of Opioid Transport at the Blood-Brain Barrier by Altered ATP-Binding Cassette (ABC) Transporter Expression and Activity Junzhi Yang 1, Bianca G. Reilly 2, Thomas P. Davis 1,2 and Patrick T. Ronaldson 1,2,* 1 Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1295 N. Martin St., P.O. Box 210207, Tucson, AZ 85721, USA; [email protected] (J.Y.); [email protected] (T.P.D.) 2 Department of Pharmacology, College of Medicine, University of Arizona, 1501 N. Campbell Ave, P.O. Box 245050, Tucson, AZ 85724-5050, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-520-626-2173 Received: 19 September 2018; Accepted: 16 October 2018; Published: 18 October 2018 Abstract: Opioids are highly effective analgesics that have a serious potential for adverse drug reactions and for development of addiction and tolerance. Since the use of opioids has escalated in recent years, it is increasingly important to understand biological mechanisms that can increase the probability of opioid-associated adverse events occurring in patient populations. This is emphasized by the current opioid epidemic in the United States where opioid analgesics are frequently abused and misused. It has been established that the effectiveness of opioids is maximized when these drugs readily access opioid receptors in the central nervous system (CNS). Indeed, opioid delivery to the brain is significantly influenced by the blood-brain barrier (BBB). In particular, ATP-binding cassette (ABC) transporters that are endogenously expressed at the BBB are critical determinants of CNS opioid penetration. In this review, we will discuss current knowledge on the transport of opioid analgesic drugs by ABC transporters at the BBB.
    [Show full text]
  • Salvinorin a Analogues PR37 and PR38 Attenuate Compound 48
    British Journal of DOI:10.1111/bph.13212 www.brjpharmacol.org BJP Pharmacology RESEARCH PAPER Correspondence Jakub Fichna, Department of Biochemistry, Faculty of Medicine, Medical University of Salvinorin A analogues Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland. E-mail: jakub.fi[email protected] PR-37 and PR-38 attenuate ---------------------------------------------------------------- Received 18 January 2015 compound 48/80-induced Revised 26 May 2015 Accepted itch responses in mice 1 June 2015 M Salaga1, P R Polepally2, M Zielinska1, M Marynowski1, A Fabisiak1, N Murawska1, K Sobczak1, M Sacharczuk3,JCDoRego4, B L Roth5, J K Zjawiony2 and J Fichna1 1Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland, 2Department of BioMolecular Sciences, Division of Pharmacognosy and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS, USA, 3Department of Molecular Cytogenetic, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Jastrzebiec, Poland, 4Platform of Behavioural Analysis (SCAC), Institute for Research and Innovation in Biomedicine (IRIB), Faculty of Medicine & Pharmacy, University of Rouen, Rouen Cedex, France, and 5Department of Pharmacology, Division of Chemical Biology and Medicinal Chemistry, Medical School, NIMH Psychoactive Drug Screening Program, University of North Carolina, Chapel Hill, NC, USA BACKGROUND AND PURPOSE The opioid system plays a crucial role in several physiological processes in the CNS and in the periphery. It has also been shown that selective opioid receptor agonists exert potent inhibitory action on pruritus and pain. In this study we examined whether two analogues of Salvinorin A, PR-37 and PR-38, exhibit antipruritic properties in mice. EXPERIMENTAL APPROACH To examine the antiscratch effect of PR-37 and PR-38 we used a mouse model of compound 48/80-induced pruritus.
    [Show full text]
  • Salvia Divinorum and Salvinorin A: an Update on Pharmacology And
    Oliver Grundmann Stephen M. Phipps Salvia divinorum and Salvinorin A: An Update on Immo Zadezensky Veronika Butterweck Pharmacology and Analytical Methodology Review Abstract derstand and elucidate the various medicinal properties of the plant itself and to provide the legislative authorities with enough Salvia divinorum (Lamiaceae) has been used for centuries by the information to cast judgement on S. divinorum. Mazatecan culture and has gained popularity as a recreational drug in recent years. Its potent hallucinogenic effects seen in Key words case reports has triggered research and led to the discovery of Salvia divinorum ´ Lamiaceae ´ depression ´ opioid antagonist ´ the first highly selective non-nitrogenous k opioid receptor ago- pharmacokinetics ´ pharmacology ´ toxicology ´ salvinorin A nist salvinorin A. This review critically evaluates the reported pharmacological and toxicological properties of S. divinorum Abbreviations and one of its major compounds salvinorin A, its pharmacokinet- CNS: central nervous system ic profile, and the analytical methods developed so far for its de- FST: forced swimming test tection and quantification. Recent research puts a strong empha- i.t.: intrathecal sis on salvinorin A, which has been shown to be a selective opioid KOR: kappa opioid receptor antagonist and is believed to have further beneficial properties, LSD: lysergic acid diethylamide rather than the leaf extract of S. divinorum. Currently animal norBNI: norbinaltorphimine studies show a rapid onset of action and short distribution and p.o.: per os 1039 elimination half-lives as well as a lack of evidence of short- or s.c.: subcutaneous long-term toxicity. Salvinorin A seems to be the most promising ssp.: subspecies approach to new treatment options for a variety of CNS illnesses.
    [Show full text]