Orexigenic effects of endomorphin-2 (EM-2) related to decreased CRH gene expression and increased dopamine and norepinephrine activity in the hypothalamus

• Endomorphin-2 administration into the arcuate nucleus increased food intake.
• Endomorphin-2 decreased hypothalamic CRH gene expression.
• Endomorphin-2 increased hypothalamic dopamine and norepinephrine levels.
• All effects are blocked by μ-opioid antagonist β-funaltrexamine.

Endomorphin-1 (EM-1) and endomorphin-2 (EM-2) are opioid peptides which are selective partial agonists of μ-opioid receptor. We studied the effects of EM-2 injected into the arcuate nucleus (ARC) of the hypothalamus on feeding behavior and gene expression of orexigenic [agouti-related peptide (AgRP), neuropeptide Y (NPY) and orexin-A] and anorexigenic [cocaine and amphetamine-regulated transcript (CART), corticotrophin releasing hormone (CRH) and proopiomelanocortin (POMC)] peptides in male Wistar rats fed a standard laboratory diet. Furthermore, we evaluated the effects of EM-2 on dopamine (DA), norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) steady state concentrations, in the hypothalamus. 64 rats (16 for each group of treatment) were injected into the ARC, at 9.00 am, with either vehicle or EM-2 (0.50–0.75 μmol/kg) or EM-2 (0.50 μmol/kg) plus β-funaltrexamine (0.20 μmol/kg). Food intake was recorded through 24 h following injection, and hypothalamic DA, NE, 5-HT levels and neuropeptide gene expression were evaluated 24 h after EM-2 administration. Compared to vehicle, EM-2 significantly increased food intake, throughout 24 h post-injection. Furthermore, EM-2 treatment led to a significant increase of DA and NE concentrations and a decrease of CRH mRNA levels. On the other hand, β-funaltrexamine administration reverted both feeding stimulatory and neuromodulatory effects induced by EM-2. We can conclude that the orexigenic effect of μ-opioid receptor activation by EM-2 could be related to both inhibition of CRH and stimulation of dopamine and norepinephrine levels, in the hypothalamus.