Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY The widespread misuse of prescription opioids, opioid addiction, and overdose has underscored the urgent need to develop effective, non-addicting medications to treat chronic pain, a leading cause of insomnia. Agonists at the nociceptin/orphanin FQ (N/OFQ) receptor (NOPR) have shown promise as modulators of the antinociceptive and rewarding effects of opioids. We have found that two different NOPR agonists potently induced sleep and increased EEG delta power in rats, mice, and non-human primates, suggesting that the N/OFQ-NOPR system may have a previously unrecognized role in sleep/wake regulation. Since our studies used synthetic compounds, the hypothesis to be tested in this proposal is that the N/OFQ-NOPR system is a component of the endogenous sleep/wake regulatory system. First, we will evaluate whether disruption of endogenous NOPR tone affects the regulation of activity, sleep/wake and/or body temperature (Tb) using a novel, inducible NOPR (iNOPR) KO mouse strain in which NOPR can be deleted throughout the brain by systemic administration of tamoxifen. We will expand on our initial results which indicate that, not only do iNOPR KO mice fail to respond to NOPR agonism by increasing NREM sleep, they exhibit a partial insomnia under baseline conditions with longer wake bouts during the major sleep period. We will then begin to establish the neuroanatomical foundation for the phenotypes identified in the global deletion study and for subsequent circuit-based studies by determining the chemotypes of neurons activated by NOPR agonism. First, we will determine NOPR expression in neuronal populations known to be involved in sleep/wake control. Global assessment of NOP agonist-induced c-Fos expression showed that two of 316 brain areas stood out as having increased Fos expression: the lateral habenula (LHb) and the anterodorsal preoptic and adjacent parastrial (ADP/PS) nuclei. We will follow up by obtaining a global view on NOP agonist-induced Fos expression in Oprl1 KI-eGFP and Pnoc-IRES-Cre (Prepronociceptin-IRES-Cre) mice and use other genetic markers to further characterize and quantify the Fos+ neurons. Next, we will determine whether local NOPR deletion affects activity, sleep/wake and/or Tb by injecting a Cre-dependent virus into candidate brain regions in NOPRlox/lox mice, particularly focusing on the LHb and ADP/PS nuclei. We will then chemogenetically activate glutamatergic and NOPR+ neurons in the LHb to determine whether these cells affect activity, sleep/wake and/or Tb and use the Fos-TRAP method to chemogenetically reactivate LHb and ADP/PS neurons labelled after NOPR agonist treatment. The information obtained will further our understanding of the role of the N/OFQ – NOP system in sleep/wake control and enable us to develop a circuit-based model to understand the effects on NOPR agonism on sleep/wake physiology.
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