Naloxone Increases the Anorexic Effect of MTII in OLETF Rats

Background: Leptin, an adipocyte-derived hormone, inhibits obesity in lean subjects, but is not widely used because of leptin resistance. Thus, circumventing the arcuate nucleus of the hypothalamus, the site responsible for leptin resistance, has been evaluated for treatment of obesity. However, chronic treatment of melanotan II (MTII), a synthetic agonist of the melanocortin 3/4 receptor, induces tachyphylaxis. Here, we evaluated whether naloxone, a non-specific agouti-related peptide (AgRP) antagonist, increases the anorexic effect of MTII in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Methods: We measured food intake following intracerebroventricular (i.c.v.) infusion of MTII and/or naloxone in OLETF rats. Sprague-Dawley rats were used as a normal control group. Results: The anorexic effect of i.c.v. MTII infusion decreased with tim e in OLETF rats, indicating the development of tachyphylaxis. In normal control rats, naloxone alone decreased AgRP expression in the hypothalamus but failed to induce anorexia. Moreover, there was no additional anorexic effect with co-treatment of naloxone and MTII. In OLETF rats, naloxone alone did not show an anorexic effect despite increased POMC expression in the hypothalamus. However, naloxone sensitized the anorexic effect of MTII when treated together. Conclusion: These results suggest that naloxone augmented the anorexic effect of MTII when treated together in OLETF rats, but had no effect alone. These results suggest that a combination therapy of naloxone and a melanocortin receptor activator would be an effective modality for treatment of obesity. (J Kor Endocr Soc 23:18~26 2008)