Nociceptin/orphanin FQ Neurons in the Arcuate Nucleus and Ventral Tegmental Area Act Via Nociceptin Opioid Peptide Receptor Signaling to Inhibit Proopiomelanocortin and A Dopamine Neurons and Thereby Modulate Ingestion of Palatable Food

The neuropeptide nociceptin/orphanin FQ (N/OFQ) inhibits neuronal activity via its cognate nociceptin opioid peptide (NOP) receptor throughout the peripheral and central nervous systems, including those areas involved in the homeostatic and hedonic regulation of energy homeostasis. We thus tested the hypothesis that N/OFQ neurons in the hypothalamic arcuate nucleus (ARC) and ventral tegmental area (VTA) act via NOP receptor signaling to inhibit nearby anorexigenic proopiomelanocortin (POMC) and A dopamine neuronal excitability, respectively, and thereby modulate ingestion of palatable food. Electrophysiologic recordings were performed in slices prepared from transgenic male and ovariectomized (OVX) female N/OFQ-cre/enhanced green fluorescent protein-POMC, N/OFQ-cre and tyrosine hydroxylase-cre animals to see if optogenetically-stimulated peptide release from N/OFQ neurons could directly inhibit these neuronal populations. Binge-feeding behavioral experiments were also conducted where animals were exposed to a high-fat-diet (HFD) for one hour each day for five days and monitored for energy intake. Photostimulation of ARC and VTA N/OFQ neurons produces an outward current in POMC and A dopamine neurons receiving input from these cells. This is associated with a hyperpolarization and decreased firing. These features are also sex hormone- and diet-dependent; with estradiol-treated slices from OVX females being less sensitive, and obese males being more sensitive, to N/OFQ. Limited access to HFD causes a dramatic escalation in consumption, such that animals eat 25-45% of their daily intake during that one-hour exposure. Moreover, the NOP receptor-mediated regulation of these energy balance circuits are engaged, as N/OFQ injected directly into the VTA or ARC respectively diminishes or potentiates this binge-like increase in a manner heightened by diet-induced obesity or dampened by estradiol in females. Collectively, these findings provide key support for the idea that N/OFQ regulates appetitive behavior in sex-, site- and diet-specific ways, along with important insights into aberrant patterns of feeding behavior pertinent to the pathogenesis of food addiction.