Nociceptin or Orphanin FQ (N/OFQ) and its receptor NOP₁ are expressed in hypothalamic nuclei involved in energy homeostasis. N/OFQ administered by intracerebroventricular (ICV) or arcuate nucleus (ARC) injection increases food intake in satiated rats. The mechanisms by which N/OFQ increases food intake are unknown. We hypothesized that N/OFQ may regulate hypothalamic neurons containing peptides involved in the control of food intake such as cocaine and amphetamine regulated transcript (CART), -melanocyte stimulating hormone (-MSH), neuropeptide-Y (NPY) and agouti related protein (AgRP).

We investigated the ability of N/OFQ to alter the release of CART, -MSH, NPY and AgRP using ex vivo medial basal hypothalamic explants. Incubation of hypothalamic explants with N/OFQ (1, 10, 100 nM) resulted in significant changes in CART and AgRP release. One hundred nanomolar N/OFQ caused a 33% decrease in release of CART (55-102)-immunoreactivity (-IR) and increased release of AgRP-IR to 163%, but produced no change in either -MSH-IR or NPY-IR. Double immunocytochemistry (ICC) / in situ hybridization (ISH) demonstrated that CART-IR and NOP₁ mRNA are co-localized throughout the hypothalamus in particular in the paraventricular nucleus, lateral hypothalamus, zona incerta and ARC, providing an anatomical basis for N/OFQ action on CART release. Dual ISH demonstrated that AgRP neurons in the ARC also express the NOP₁ receptor. Our data suggests that nociceptin via the NOP₁ receptor, may increase food intake by decreasing the release of the anorectic peptide CART and increasing the release of the orexigenic peptide AgRP.