Activation of the nociceptin/orphanin-FQ receptor promotes NREM sleep and EEG slow wave activity

Abstract

Sleep/wake control involves several neurotransmitter and neuromodulatory systems yet the coordination of the behavioral and physiological processes underlying sleep is incompletely understood. Previous studies have suggested that activation of the Nociceptin/orphanin FQ (N/OFQ) receptor (NOPR) reduces locomotor activity and produces a sedation-like effect in rodents. In the present study, we systematically evaluated the efficacy of two NOPR agonists, Ro64-6198 and SR16835, on sleep/wake in rats, mice, and Cynomolgus macaques. We found a profound, dose-related increase in non-Rapid Eye Movement (NREM) sleep and electroencephalogram (EEG) slow wave activity (SWA) and suppression of Rapid Eye Movement sleep (REM) sleep in all three species. At the highest dose tested in rats, the increase in NREM sleep and EEG SWA was accompanied by a prolonged inhibition of REM sleep, hypothermia, and reduced locomotor activity. However, even at the highest dose tested, rats were immediately arousable upon sensory stimulation, suggesting sleep rather than an anesthetic state. NOPR agonism also resulted in increased expression of c-Fos in the anterodorsal preoptic and parastrial nuclei, two GABAergic nuclei that are highly interconnected with brain regions involved in physiological regulation. These results suggest that the N/OFQ–NOPR system may have a previously unrecognized role in sleep/wake control and potential promise as a therapeutic target for the treatment of insomnia.

Development of a genetically encoded sensor for probing endogenous nociceptin opioid peptide release

“…N/OFQ and its receptor NOPR have been implicated in neuromodulation of a wide variety of essential behavioral processes including stress, aversion, motivation, reward seeking, and feeding. 22,23,27,51,52,53,54,55,56 We have previously identified a role for VTA N/OFQ signaling in reward-related and aversive behavior, and using GCaMP found that pnVTA PNOC neurons activity is suppressed during sucrose consumption. 22 There-fore, we injected WT mice with AAV-DJ-hSyn-NOPLight in the VTA, implanted optical fibres above the injection site, and secured stainless steel rings to allow for head-fixed fibre photometry recording of NOP-Light during sucrose consumption ( Fig.…”

“…These data also provide the ability to align neuronal activity measured either by calcium dynamics or electrophysiology with neuropeptide release during freely-moving behaviorial epochs. Given the recent discoveries that PNOC and NOPR are important for motivation, feeding, and sleep induction 22,23,[50][51][52][53] , understanding the dynamic properties of this opioid peptide system is now of even greater importance as this receptor is now considered a major target for insomnia, addiction, and depression 49,61,62 .…”

“…We next examined NOPLight's ability to report transient, endogenous N/OFQ release evoked by different naturalistic behavioral states. N/OFQ and its receptor NOPR have been implicated in neuromodulation of a wide variety of essential behavioral processes including stress, aversion, motivation, reward seeking, and feeding 22,23,27,[50][51][52][53][54][55] . We previously identified a role for VTA N/OFQ signaling in reward-related and aversive behavior, and extensively characterized the calcium activity of pnVTA PNOC neurons during operant responding for reward.…”

Development of a genetically encoded sensor for probing endogenous nociceptin opioid peptide release

“…These data also provide the ability to align neuronal activity measured either by calcium dynamics or electrophysiology with neuropeptide release during freely moving behavioral epochs. Given the recent discoveries that PNOC and NOPR are important for motivation, feeding, and sleep induction 22 , 23 , 50 – 53 , understanding the dynamic properties of this opioid peptide system is now of even greater importance as this receptor is now considered a major target for insomnia, addiction, and depression 49 , 60 , 61 .…”