Reversal of cancer anorexia by blockade of central melanocortin receptors in rats

Anorexia is a debilitating manifestation of many malignancies. The etiology of cancer anorexia is poorly understood, and effective treatment options a re limited. To investigate the role of central melanocortin receptor signal ing in the pathogenesis of cancer anorexia, we assessed the effects on food intake of the melanocortin receptor antagonist SHU9119 administered into t he third cerebral ventricle of Lobund-Wistar rats that were anorexic from p rostate cancer. In anorexic tumor-bearing rats, daily treatment with SHU911 9 (0.35 nmol, intracerebroventricularly) increased food intake from 71 +/- 3% to 110 +/- 6% of preanorectic baseline and caused significant weight gai n (13 +/- 5 vs. 5 +/- 1 g/3 d, SHU9119 vs. baseline in tumor-bearing rats). In control rats pair-fed to the intake of tumor-bearing animals, SHU9119 w as ineffective at increasing food intake. The specificity of the SHU9119 fe eding response was assessed using two other orexigenic peptides, NPY and th e novel hormone ghrelin. Treatment of tumor-bearing rats with intracerebrov entricular ghrelin (10 mug) increased food intake, but the effect was blunt ed relative to that in controls. Intracerebroventricular injections of NPY (1 mug) also failed to reverse anorexia in tumor-bearing rats. Because SHU9 119 completely reverses cancer anorexia in this model, whereas ghrelin and NPY do not, increased central nervous system melanocortin signaling is impl icated in the pathogenesis of this disorder. This suggests that new targets for the treatment of cancer anorexia may be found in the melanocortin path ways.