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Reversal of stress- and CRF-induced anorexia in rats by the synthetic nociceptin/orphanin FQ receptor agonist, Ro 64-6198 - Psychopharmacology

  • ️Massi, Maurizio
  • ️Wed May 01 2002

Abstract.

Rationale: (1S,3aS)-8-(2,3,3,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro 64-6198), a non-peptidic agonist for the opioid receptor-like1 (ORL1) receptor, exhibits anxiolytic properties in stressful conditions. Objective: The present study was aimed at evaluating whether activation of ORL1 receptors by Ro 64-6198 may reverse the anorectic effect of restraint stress or intracerebroventricular (ICV) CRF injection. Methods: In body restraint experiments, 20-h food deprived rats were treated with intraperitoneal (IP) injection of Ro 64-6198 or vehicle. Ten minutes later, they were confined in cylindrical Plexiglas tubes for 60 min and then returned to their cage with food. In CRF experiments, 20-h food deprived rats were IP injected with Ro 64-6198 or vehicle. Ten minutes later, they received ICV CRF, 200 ng/rat or vehicle; food was offered after 20 min. Results: Intraperitoneal (IP) pretreatment with Ro 64-6198 reversed the hypophagic effect induced by both restraint or CRF; the effect was statistically significant at the three doses tested (0.3, 1.0 or 2.5 mg/kg). ICV administration of the selective ORL1 receptor antagonist [Nphe1]NC(1–13)NH2 (two injections of 33 or 66 µg/rat) abolished the effect of Ro 64-6198 on CRF-induced anorexia. In freely feeding rats, Ro 64-6198 significantly increased feeding at 2.5, but not at 0.3 or 1.0 mg/kg; in food deprived rats, Ro 64-6198 (0.3 or 1.0 mg/kg) did not modify food intake. Thus, reversal of stress- and CRF-induced anorexia by Ro 64-6198 can be evoked at doses lower than those that are hyperphagic. Ro 64-6198 (1 or 2.5 mg/kg) did not modify the anorectic effect of E. coli lipopolysaccharide, suggesting that its effect is selective for stress- or CRF-induced anorexia. Lastly, the benzodiazepine diazepam was unable to reduce the anorectic effect of CRF at the anxiolytic dose of 0.3 mg/kg, and partially reduced it at the hyperphagic dose of 1 mg/kg. Conclusions: The results of this study show that the non-peptidic ORL1 receptor agonist Ro 64-6198 markedly and selectively inhibits the anorectic effect of stress and CRF, and provide evidence that this effect is mediated by ORL1 receptors. Thus, Ro 64-6198 may represent an interesting tool for treatment of stress-induced anorexia.

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Authors and Affiliations

  1. Department of Pharmacological Sciences and Experimental Medicine, University of Camerino, Via Scalzino 3, 62032 Camerino, Italy, , , , ,

    Roberto Ciccocioppo, Michela Biondini, Lorena Antonelli & Maurizio Massi

  2. Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland, , , , ,

    Juergen Wichmann & François Jenck

Authors

  1. Roberto Ciccocioppo

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  2. Michela Biondini

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  3. Lorena Antonelli

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  4. Juergen Wichmann

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  5. François Jenck

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  6. Maurizio Massi

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Ciccocioppo, R., Biondini, M., Antonelli, L. et al. Reversal of stress- and CRF-induced anorexia in rats by the synthetic nociceptin/orphanin FQ receptor agonist, Ro 64-6198. Psychopharmacology 161, 113–119 (2002). https://doi.org/10.1007/s00213-002-1020-7

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  • Received: 22 April 2001

  • Accepted: 13 January 2002

  • Issue Date: May 2002

  • DOI: https://doi.org/10.1007/s00213-002-1020-7