Nociceptin/orphanin FQ neurons in the Arcuate Nucleus and Ventral Tegmental Area Act via Nociceptin Opioid Peptide Receptor Signaling to Inhibit Proopiomelanocortin and A10 Dopamine Neurons and Thereby Modulate Ingestion of Palatable Food

Adaptive Changes in the Central Control of Energy Homeostasis Occur in Response to Variations in Energy Status

“…Moreover, diet-induced obesity renders VMN SF-1/ARC POMC synapses more susceptible to the inhibitory effects of exogenous N/OFQ in males and hypoestrogenic OVX females [ 5 ]. This greatly curtails anorexigenic signaling at these synapses; causing exaggerated N/OFQ-induced increases in energy intake and decreases in energy expenditure, and is entirely in keeping with our recent demonstration that N/OFQ administered directly into the ARC significantly enhances binge-feeding behavior caused by short-term intermittent exposure to a HFD [ 179 ].…”

“…In addition, we have found that the rebound hyperphagia seen upon refeeding in fasted NOP receptor null mice is significantly blunted compared to their wildtype littermate controls [ 176 ]. The appetite-stimulating properties of N/OFQ can be attributed, at least in part, to the NOP receptor-mediated inhibition of POMC neurons via activation of GIRK channels, as seen with either exogenous bath application of the neuropeptide or high-frequency optogenetic stimulation of ARC N/OFQ neurons [ 5 , 176 , 177 , 178 , 179 ]. The observed effects of N/OFQ are not limited to anorexigenic pathways, however, and have been observed to also influence orexigenic circuitry.…”

“…In homeostatic energy balance, males are significantly more sensitive to the inhibitory effects of exogenous N/OFQ on excitatory neurotransmission at VMN SF-1/ARC POMC synapses than are females during E 2 -dominated phases of the estrous cycle in two ways: (1) the direct hyperpolarization/cessation of firing of both VMN SF-1 and ARC POMC neurons, as well as the underlying outward current, due to the activation of GIRK channels is greater in males than in females and (2) the presynaptic inhibition of glutamate released of VMN SF-1 neurons at these synapses is more substantive in males than in females [ 5 , 189 , 190 ]. Additionally, E 2 exerts powerful activational effects by diminishing the inhibitory effects of exogenous N/OFQ at VMN SF-1/ARC POMC synapses, as well as the decreased excitability of POMC neurons caused by optogenetic stimulation of ARC N/OFQ neurons, and protecting against the aberrant hyperphagia and reduction in energy expenditure caused by exogenous N/OFQ administered directly into the ARC of obese OVX females [ 5 , 178 , 179 , 191 ]. E 2 also attenuates the pleiotropic actions of N/OFQ on POMC neurons by binding to either ERα or the G q -mER, which leads to a signaling cascade that includes phospholipase C (PLC), PI3K, PKC, PKA and nNOS [ 191 ].…”

“…In addition, the exact mechanisms through which sex and diet interact to modulate NOP receptor-mediated inhibition of reward encoding A 10 dopamine neurons and hedonic feeding remained a mystery until very recently. We have discovered that the endogenous release of N/OFQ caused by high-frequency optogenetic stimulation of VTA neurons in mesencephalic slices from N/OFQ-cre mice powerfully inhibits neighboring VTA neurons; an effect that is faithfully recapitulated by exogenous bath application of N/OFQ during recordings of A 10 dopamine neurons in slices from TH-cre mice [ 179 ]. The membrane hyperpolarizations and underlying outward currents were attenuated by E 2 in females, and accentuated by diet-induced obesity in males [ 179 ].…”

“…We have discovered that the endogenous release of N/OFQ caused by high-frequency optogenetic stimulation of VTA neurons in mesencephalic slices from N/OFQ-cre mice powerfully inhibits neighboring VTA neurons; an effect that is faithfully recapitulated by exogenous bath application of N/OFQ during recordings of A 10 dopamine neurons in slices from TH-cre mice [ 179 ]. The membrane hyperpolarizations and underlying outward currents were attenuated by E 2 in females, and accentuated by diet-induced obesity in males [ 179 ]. These N/OFQ-induced inhibitory effects on A 10 dopamine neurons functionally translated into sex- and diet-dependent changes in binge-eating behavior, as N/OFQ delivered into the VTA decreased the rampant consumption seen during the binge episodes in obese but not lean males, and in both lean and obese females [ 179 ].…”