title: Nociceptin induces hypophagia in the perifornical and lateral hypothalamic area.
abstract: Nociceptin/orphanin FQ (N/OFQ) is known to induce food intake when administered into the lateral ventricle or certain brain areas. This is somewhat contradictory to its reward-suppressing role, as food is a strong rewarding stimulus. This discrepancy may be due to the functional diversity of N/OFQ's target brain areas. N/OFQ has been shown to inhibit orexin and melanin-concentrating hormone (MCH) neurons, both of which are appetite-inducing cells. As the expression of these neurons is largely confined to the lateral hypothalamus/perifornical area (LH/PFA), we hypothesized that N/OFQ inhibits food intake by acting in this area. To test this hypothesis, we examined the effect of local N/OFQ infusion within the LH/PFA on food intake in the rat and found that N/OFQ decreased sugar pellet as well as chow intake. This effect was not seen when the injection site was outside of the LH/PFA, suggesting a site-specific effect. Next, to determine a possible cellular mechanism of N/OFQ action on food intake, whole cell patch clamp recordings were performed on rat orexin neurons. As previously reported in mice, N/OFQ induced a strong and long lasting hyperpolarization. Pharmacological study indicated that N/OFQ directly inhibited orexin neurons by activating ATP-sensitive potassium (KATP) channels. This effect was partially but significantly attenuated by the inhibitors of PI3K, PKC and PKA, suggesting that the N/OFQ signaling is mediated by these protein kinases. In summary, our results demonstrate a KATP channel-dependent N/OFQ signaling and that N/OFQ is a site-specific anorexic peptide.
authors.affiliation: Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's, Newfoundland and Labrador, Canada.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Parsons
authors.forename: Julia
authors.initials: J
authors.lastname: Burt
authors.forename: Amanda
authors.initials: A
authors.lastname: Cranford
authors.forename: Christian
authors.initials: C
authors.lastname: Alberto
authors.forename: Katrin
authors.initials: K
authors.lastname: Zipperlen
authors.forename: Michiru
authors.initials: M
authors.lastname: Hirasawa
mesh_terms: D000818:Animals; D004435:Eating / Q000187:drug effects*; D004594:Electrophysiology; D007026:Hypothalamic Area, Lateral / Q000187:drug effects* / Q000378:metabolism; D007150:Immunohistochemistry; D054086:KATP Channels / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018847:Opioid Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000097629:Nociceptin
chemical_list: D054086:KATP Channels; D018847:Opioid Peptides; D000097629:Nociceptin