Vol. 303, Issue 3, 1317-1324, December 2002

Developmental Changes in Opioid Peptides and Their Receptors in Cpe^fat/Cpe^fat Mice Lacking Peptide Processing Enzyme Carboxypeptidase E

Mikhail Boudarine, Oleg Yegorov¹, Anna Sterling-Dubrovsky, Lakshmi A. Devi² and Yemiliya Berman

Department of Pharmacology, New York University School of Medicine, New York, New York

Carboxypeptidase E (CPE) is involved in the biosynthesis of a number of neuropeptides including opioid peptides. A point mutation in this gene results in a loss of enzyme activity, decrease in mature neuroendocrine peptides, and development of late onset obesity as seen in Cpe^fat/Cpe^fat mice. In this study, we examined the processing of peptides derived from prodynorphin and proenkephalin in various brain regions of these mice during development. At 6 to 8 weeks, an age prior to the onset of obesity, levels of dynorphin peptides are decreased in all brain regions, whereas levels of ir-Met-enkephalin are differentially altered. There is an accumulation of C-terminally extended forms of all three opioid peptides in Cpe^fat/Cpe^fat mice, consistent with a lack of CPE activity. Thus, it appears that there is no direct correlation between the level of mature opioid peptides and the development of obesity in these mice. Since altered levels of peptides can influence the opioid receptor system, we examined the functional activity of µ and  opioid receptors using [³⁵S]guanosine-5'-O-(-thio)-triphosphate binding assays. We find no differences in  receptor activity in Cpe^fat/Cpe^fat compared with control littermate mice. In contrast, the µ receptor activity is differentially altered in select regions of Cpe^fat/Cpe^fat mice in response to a µ-specific ligand. Taken together, these results suggest that the lack of CPE activity leads to alterations in the level of opioid peptides during development and that changes in peptide levels differentially affect opioid receptor activity in vivo.