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The vital role of arcuate nociceptin/orphanin FQ neurones in mounting an oestradiol‐dependent adaptive response to negative energy balance via inhibition of nearby proopiomelanocortin neurones

We tested the hypothesis that N/OFQ neurones in the arcuate nucleus (N/OFQARC) inhibit proopiomelanocortin (POMCARC) neurones in a diet‐ and hormone‐dependent manner to promote a more extensive rebound hyperphagia upon re‐feeding following an 18 h fast. We utilized intact male or ovariectomized (OVX) female mice subjected to ad libitum‐feeding or fasting conditions. N/OFQARC neurones under negative energy balance conditions displayed heightened sensitivity as evidenced by a decreased rheobase threshold, increased firing frequency, and increased burst duration and frequency compared to ad libitum‐feeding conditions. Stimulation of N/OFQARC neurones more robustly inhibited POMCARC neurones under fasting conditions compared to ad libitum‐feeding conditions. N/OFQARC inhibition of POMCARC neurones is hormone dependent as chemostimulation of N/OFQARC neurones from fasted males and OVX females produced a sizable outward current in POMCARC neurones. Oestradiol (E2) markedly attenuated the N/OFQ‐induced POMCARC outward current. Additionally, N/OFQ tonically inhibits POMCARC neurones to a greater degree under fasting conditions than in ad libitum‐feeding conditions as evidenced by the abrogation of N/OFQ–nociceptin opioid peptide (NOP) receptor signalling and inhibition of N/OFQ release via chemoinhibition of N/OFQARC neurones. Intra‐arcuate nucleus application of N/OFQ further elevated the hyperphagic response and increased meal size during the 6 h re‐feed period, and these effects were mimicked by chemostimulation of N/OFQARC neurones in vivo. E2 attenuated the robust N/OFQ‐induced rebound hyperphagia seen in vehicle‐treated OVX females. These data demonstrate that N/OFQARC neurones play a vital role in mitigating the impact of negative energy balance by inhibiting the excitability of anorexigenic neural substrates, an effect that is diminished by E2 in females.