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.
Highlights
The rewarding nature of food can induce caloric intake in excess of our energy requirements by engaging the brain’s reward circuitry in a manner not unlike drugs of abuse [1,2,3]
Effect of Intra lateral hypothalamus/perifornical area (LH/PFA) Nociceptin/orphanin FQ (N/OFQ) on Food Intake To determine a site-specific role of N/OFQ, we investigated how the intake of sugar pellets is affected by a local N/OFQ administration into the LH/PFA
When N/OFQ was injected at a dose (10 nmol) shown to increase feeding in the ventromedial nucleus or nucleus accumbens [13], this resulted in a significant reduction in the sugar intake during the first hour of feeding compared to vehicle injection (Fig. 1B, n = 10, p,0.05, paired ttest)
Summary
The rewarding nature of food can induce caloric intake in excess of our energy requirements by engaging the brain’s reward circuitry in a manner not unlike drugs of abuse [1,2,3]. Nociceptin/orphanin FQ (N/ OFQ) is an endogenous opioid known to bind the N/OFQ peptide (NOP) receptor [6] and to have anti-reward properties It functionally opposes the actions of other endogenous opioids on reward-related behavioural responding [7,8] and decreases drug-induced dopamine release in the nucleus accumbens [9,10]. Despite the rewarding nature of food, N/ OFQ has been shown to induce, rather than inhibit, food intake when injected into the lateral ventricle [11] or several brain nuclei [12,13] This paradox of N/OFQ’s anti-reward and pro-feeding actions remains unresolved. A possible explanation is the functional heterogeneity of brain areas and neuronal types that mediate the N/OFQ effects
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