Reversal of stress- and CRF-induced anorexia in rats by the synthetic nociceptin/orphanin FQ receptor agonist, Ro 64-6198.
BACKGROUND
(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 [Nphe(1)]NC(1-13)NH(2)(two injections of 33 or 66 microg/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.
Ciccocioppo
Roberto
R
Department of Pharmacological Sciences and Experimental Medicine, University of Camerino, Via Scalzino 3, 62032 Camerino, Italy. roberto.ciccocioppo@unicam.it
Biondini
Michela
M
Antonelli
Lorena
L
Wichmann
Juergen
J
Jenck
François
F
Massi
Maurizio
M
D000818:Animals; D000855:Anorexia / Q000139:chemically induced* / Q000188:drug therapy*; D014151:Anti-Anxiety Agents / Q000627:therapeutic use*; D003346:Corticotropin-Releasing Hormone / Q000009:adverse effects*; D007093:Imidazoles / Q000627:therapeutic use*; D008297:Male; D018847:Opioid Peptides / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000819:agonists*; D013141:Spiro Compounds / Q000627:therapeutic use*; D013312:Stress, Physiological / Q000188:drug therapy*; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D014151:Anti-Anxiety Agents; D003346:Corticotropin-Releasing Hormone; D007093:Imidazoles; D018847:Opioid Peptides; D011957:Receptors, Opioid; D013141:Spiro Compounds; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C408068:Ro 64-6198; C000722285:Oprl1 protein, rat