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Pharmacopsychiatry 2004; 37: 189-197
DOI: 10.1055/s-2004-832677
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

Neuropharmacology of the Anxiolytic Drug Opripramol, a Sigma Site Ligand

W. E. Müller1 , B. Siebert1 , G. Holoubek1 , C. Gentsch2
  • 1Department of Pharmacology, Biocenter University Frankfurt, Frankfurt (Germany)
  • 2Novartis Institutes for Biomedical Research, Neuroscience Disease Area, Basel (Switzerland)
Further Information

Publication History

Publication Date:
17 November 2004 (online)

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Although opipramol is structurally related to imipramine, it does not represent a tricyclic antidepressant drug as it does not inhibit the neuronal uptake of norepinephrine and/or serotonin. Unlike imipramine it is a rather potent sigma ligand with modest subclass selectivity which is similar in vitro as well as ex vivo. Opipramol is active in several behavioural paradigms indicative of anxiolytic properties at doses (1 - 10 mg/kg), which are also needed to occupy sigma binding sites. Somewhat higher doses (10 - 20 mg/kg) are needed for ”antidepressant like” effects. The data allow the conclusion that interaction with sigma sites is involved in the anxiolytic and antidepressant effects of opipramol albeit a contribution of its weaker D2-antagonistic and 5-HT2-antagonistic properties cannot be totally be excluded.

References

  • 1 Abel E L. Alarm substance emitted by rats in the forced-swim test is a low volatile pherome. Physiol.  & Behav.. 1991;  50 723-727
    PubMedGoogle Scholar
  • 2 Akunne H C, Zoski K T, Whetzel S Z, Cordon J J, Brandon R M, Roman F, Pugslex T A. Neuropharmacological profile of a selective sigma ligand, igmesine: a potential antidepressant.  Neuropharmacology. 2001;  41 138-149
    CrossrefPubMedGoogle Scholar
  • 3 Arfwidsson L, Arn L, Breskow J. Ottoson JO, Persson G. A comparison between diazpam, dixyrazine, opipramol and placebo in anxiety states.  Acta Psychiatr Scand. 1971;  (Suppl) 19-32 (1971)
    PubMedGoogle Scholar
  • 4 Borsini F, Meli A. Is the forced swimming test a suitable model for prevealing antidepressant activity?.  Psychopharmacology. 1988;  94 147-160
    PubMedGoogle Scholar
  • 5 Bowen W D. Sigma receptor: recent advances and new clinical potentials.  Pharmaceut Acta Helvetiae. 2000;  74 211-218
    PubMedGoogle Scholar
  • 6 Chaki S, Nakazato A, Kennis L, Nakamura M, Mackie C, Sugiura M, Vinken P, Ashton D, Langlois X, Steckler T. Anxiolytic- and antidepressant-like profile of a new CRF1 receptor antagonist, R278995/CRA0450.  Eur J Pharmacol. 2004;  485 45-158
    PubMedGoogle Scholar
  • 7 Codony X, Fisas A, Ruiz M T, Guiart X, Farre A J. Anxiolytic-like effect of E-5842, a selective σ1 ligand with antipsychotic profile.  Behav Pharmacology. 2000;  11 334-335
    PubMedGoogle Scholar
  • 8 Cole J C, Rodgers R J. Ethological comparison of the effects of diazepam and acute/chronic imipramine on the behaviour of mice in the elevated plus-maze.  Pharmacol Biochem Behav. 1995;  52 73-478
    CrossrefPubMedGoogle Scholar
  • 9 Ferris C D, Hirsch D J, Brooks B P, Snowman A M, Snyder S H. [3H]Opipramol labels a novel binding site and sigma receptors in rat brain membranes.  Mol Pharmacol. 1991;  39 199-204
    PubMedGoogle Scholar
  • 10 Gentsch C. Opipramol in verhaltenspharmakologischen Angst- und Depressionsmodellen.  Fortsch Neurol Psychiatr. 1998;  66 (supplement 1) S17-20
    PubMedGoogle Scholar
  • 11 Gentsch C, Vassout A, Dixon K. Opipramol, Sigmaligand und Stimmungsaufhellendes Anxiolytikum. In: WE Müller, HJ Möller eds Therapieforum Biozentrum. Lingua-Med Verlags-GmbH 2001: p. 53-65
    Google Scholar
  • 12 Grosser H H, Ryan E. Drug treatment of anxiety: a controlled study of opipramol and chlordiazepoxide.  Br J Psychiatry. 1965;  111 134-141
    PubMedGoogle Scholar
  • 13 Guitart X, Codony X, Ballarin M, Dordal A, Farré A J. E-5842: A New potent and preferential sigma ligand. Preclinical Pharmacological Profile.  CNS Drug Rev. 1998;  4 201-224
    PubMedGoogle Scholar
  • 14 Hertel P, Nomikos G G, Iurlo M. Svensson TH. Risperidone: regional effects in vivo on release and metabolism of dopamine and serotonin in the rat-brain.  Psychopharmacology. 1996;  124 74-86
    CrossrefPubMedGoogle Scholar
  • 15 Holoubek G, Müller W E. Specific modulation of sigma binding sites by the anxiolytic drug opipramol.  J Neural Transm. 2003;  110 1169-1179
    CrossrefPubMedGoogle Scholar
  • 16 Kamei H, Kameyama T, Nabeshima T. (+)SKF-10,047 and dextromethorphan ameliorate conditioned fear stress via dopaminergic systems linked to phenytoin-regulated sigma 1 sites.  Eur J Pharmacol. 1996;  309 149-158
    CrossrefPubMedGoogle Scholar
  • 17 Käsermann H P. Stretched attend posture, a non-social form of ambivalence, is sensitive to a conflict-reducing drug action.  Psychopharmacology. 1986;  89 31-37
    PubMedGoogle Scholar
  • 18 Kinsora J J, Corbin A E, Snyder B J, Wiley J N, Meltzer L T, Heffner T G. Effects of igmesine in preclinical anti-depressant test.  Abstr.-Soc Neurosci. 1998;  24 291.3
    PubMedGoogle Scholar
  • 19 Langa F, Codony X, Tovar V, Lavado A, Gimenez E, Cozar P, Cantero M, Dordal A, Hernandez E, Perez R, Monroy X, T`Zamanillo D, Guitart X, Montoliu L. Generation and phenotypic analysis of sigma receptor type I (σ1) knockout mice.  Eur J Neuroscience. 2003;  18 2188-2196
    CrossrefPubMedGoogle Scholar
  • 20 Leadbetter R, Pande A, Slomkowski M, Smith F. Igmesine: a novel antidepressant.  Biol Psychiatry. 1999;  45 76S
    CrossrefPubMedGoogle Scholar
  • 21 Leonard B E. The potential contribution of sigma receptors to antidepressant actions. In: Skolnick P (ed) A, Antidepressants - new pharmacological strategies. Humana Press Totowa; 1997: pp 159-172
    Google Scholar
  • 22 Maj J, Rogoz Z, Skusa G. Some behavioral effects of 1,3-DI-O-tolylguanidine, opipramol and sertraline, the sigma site ligands.  Pol J Pharmacol. 1996;  48 379-395
    PubMedGoogle Scholar
  • 23 Matsuno K, Kobayashi T, Tanaka M K, Mita S. σ1 receptor subtype is involved in the relief of behavioral despair in the mouse forced swim test.  Eur J Pharmacol. 1996;  312 267-271
    CrossrefPubMedGoogle Scholar
  • 24 Möller H J, Volz H P, Reimann I R, Stoll K D. Opipramol for the treatment of generalized anxiety disorder. A placebo-controlled trial including an alprazolam treated group.  J Clin Psychopharmacol. 2001;  21 59-65
    CrossrefPubMedGoogle Scholar
  • 25 Müller W E, Siebert B. Opipramol im Vergleich zu anderen Therapeutika - Neue pharmakologische Daten.  Fortschr Neuro Psychiat. 1998;  66 9-12
    PubMedGoogle Scholar
  • 26 Porsolt R D, Anon G, Blavet N, Jalfre M. Behavioral despair in rats: a new animal model sensitive to antidepressant treatments.  Eur J Pharmacol. 1978;  47 379-391
    CrossrefPubMedGoogle Scholar
  • 27 Rajotte P, Bordeleau J M, Tetreault L, Doucet P, Rajotte E. A double-blind comparative study of opipramol and amitriptyline in neurotic and endogenous depressions.  Can Psychiatr Assoc. 1966;  11 68
    PubMedGoogle Scholar
  • 28 Rao T S, Cler J A, Mich S J, Dilworth V M, Contreres P C, Iyengar S, Wood P L. Neurochemical characterization of dopaminergic effects of Opipramol, a potent sigma receptor ligand, in vivo.  Neuropharmacology. 1990;  29 1191-1197
    CrossrefPubMedGoogle Scholar
  • 29 Sanchez C, Arnt J, Costall B, Kelly M E, Meier E, Naylor R J, Perregaard J. The selective σ2-ligand LU 28 - 179 has potential anxiolytic-like effects in rodents.  J Pharmacol Exp Ther. 1997;  283 1323-1332
    PubMedGoogle Scholar
  • 30 Sanchez C, Papp M. The selective σ2-ligand Lu 28 - 179 has an antidepressant-like profile in the rat chronic mild stress model of depression.  Behav Pharmacol. 2000;  11 117-124
    PubMedGoogle Scholar
  • 31 Spooren W PJM, Schoeffter P, Gasparini F, Kuhn R, Gentsch C. Pharmacological and endocrinological characterisation of stress-induced hyperthermia in singly housed mice using classical and candidate anxiolytics (LY314582, MPEP and NKP608).  Eur J Pharmacol. 2002;  435 161-170
    CrossrefPubMedGoogle Scholar
  • 32 Theobald W, Büch O, Morpurgo C, Stenger E G, Kunz H A, Wilhelmi G. Vergleichende pharmakologische Untersuchungen mit Tofranil, Pertofran und Insidon.  Arch Int Pharmacodyn Ther. 1964;  148 560-596
    PubMedGoogle Scholar
  • 33 Ukai M, Meada H, Nanya Y, Kameyama T, Matsuno K. Beneficial effect of acute and repeated administrations of σ receptor agonists on behavioral despair in mice exposed to tail suspension.  Pharmacol Biochem Behav. 1998;  61 247-252
    CrossrefPubMedGoogle Scholar
  • 34 Urani A, Roman F J, Phan V -L, Su T -P, Maurice T. The antidepressant-like effect induced by σ1-receptor agonists and neuroactive steroids in mice submitted to the forced swimming test.  J Pharmacol Exp Ther. 2001;  298 1269-1279
    PubMedGoogle Scholar
  • 35 Urani A, Romieu P, Roman F J, Yamada K, Noda Y, Kamei H, Tran H M, Nagai T, Nabeshima T, Maurice T. Enhanced antidepressant efficacy if σ1 receptor agonists in rats after chronic intracerebroventricular infusion of β-amyloid (1 - 40) protein.  Eur J Pharmacol. 2004;  486 151-161
    CrossrefPubMedGoogle Scholar
  • 36 Van der Heyden J AM, Zethof T JJ, Olivier B. Stress-induced hyperthermia in singly housed mice.  Physiol Behav. 1997;  62 463-470
    CrossrefPubMedGoogle Scholar
  • 37 Volz H P, Möller H J, Reimann I, Stoll K D. Opipramol for the treatment of somatoform disorders, results from a placebo-controlled trial.  Eur Neuropsychopharmacol. 2000;  10 211-217
    PubMedGoogle Scholar

Prof. Dr. Walter E. Müller

Department of Pharmacology

Biocenter University Frankfurt

Marie-Curie-Str. 9

D-60439 Frankfurt

Phone: #49 69 798 29373

Fax: #49 69 798 29374

Email: pharmacolnat@em.uni-frankfurt.de

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