Abstract
BackgroundOrphanin FQ (aka nociceptin; N/OFQ) binds to its nociceptin opioid peptide (NOP) receptor expressed in proopiomelanocortin (POMC) neurons within the arcuate nucleus (ARC), a critical anorexigenic component of the hypothalamic energy balance circuitry. It inhibits POMC neurons by modifying neuronal excitability both pre- and postsynaptically. We tested the hypothesis that N/OFQ inhibits neurotransmission at synapses involving steroidogenic factor (SF)-1 neurons in the ventromedial nucleus (VMN) and ARC POMC neurons in a sex- and diet-dependent fashion.MethodsElectrophysiological recordings were done in intact male and in cycling and ovariectomized female NR5A1-Cre and eGFP-POMC mice. Energy homeostasis was assessed in wildtype animals following intra-ARC injections of N/OFQ or its saline vehicle.ResultsN/OFQ (1 μM) decreased light-evoked excitatory postsynaptic current (leEPSC) amplitude more so in males than in diestrus or proestrus females, which was further accentuated in high-fat diet (HFD)-fed males. N/OFQ elicited a more robust outward current and increase in conductance in males than in diestrus, proestrus, and estrus females. These pleiotropic actions of N/OFQ were abrogated by the NOP receptor antagonist BAN ORL-24 (10 μM). In ovariectomized female eGFP-POMC mice, 17β-estradiol (E2; 100 nM) attenuated the N/OFQ-induced postsynaptic response. SF-1 neurons from NR5A1-Cre mice also displayed a robust N/OFQ-induced outward current and increase in conductance that was sexually differentiated and suppressed by E2. Finally, intra-ARC injections of N/OFQ increased energy intake and decreased energy expenditure, which was further potentiated by exposure to HFD and diminished by estradiol benzoate (20 μg/kg; s.c.).ConclusionThese findings show that males are more responsive to the pleiotropic actions of N/OFQ at anorexigenic VMN SF-1/ARC POMC synapses, and this responsiveness can be further enhanced under conditions of diet-induced obesity/insulin resistance.
Highlights
Nociceptin/orphanin FQ (N/OFQ) is a hepadecapeptide that is similar in structure to the endogenous κ-opioid peptide dynorphin A, yet it does not bind to classical opioid receptors [1, 2]
In order to examine if N/OFQ can decrease glutamatergic input onto POMC neurons via nociceptin opioid peptide (NOP) activation, we evoked excitatory postsynaptic currents (EPSCs) generated by light stimulation of steroidogenic factor (SF)-1 neurons located in the dorsomedial ventromedial nucleus (VMN)
These results provide a clear indication that N/OFQ inhibits glutamatergic input emanating from SF-1 neurons in the dorsomedial VMN due to the activation of the NOP receptor
Summary
Nociceptin/orphanin FQ (N/OFQ) is a hepadecapeptide that is similar in structure to the endogenous κ-opioid peptide dynorphin A, yet it does not bind to classical opioid receptors [1, 2]. N/OFQ binds with high affinity to its cognate nociceptin opioid peptide (NOP) receptor, which is a G protein coupled receptor (GPCR) that is structured similar to that of classical opioid receptors like the μ-,δ-, and κ-opioid receptors [1]. NOP receptors trigger different intracellular events including a decrease in the activity of adenylyl cyclase [8] These receptors couple directly to G protein-gated, inwardly rectifying K+ (GIRK) channels in oocytes [2], as well as neurons in the dorsal raphe [9], locus coeruleus [10], periaqueductal gray [11], and the hypothalamic arcuate nucleus (ARC) [12]. We tested the hypothesis that N/OFQ inhibits neurotransmission at synapses involving steroidogenic factor (SF)-1 neurons in the ventromedial nucleus (VMN) and ARC POMC neurons in a sex- and diet-dependent fashion
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