Role of Nociceptin/Orphanin FQ-NOP Receptor System in the Regulation of Stress-Related Disorders

Abstract

Nociceptin/orphanin FQ (N/OFQ) is a 17-residue neuropeptide that binds the nociceptin opioid-like receptor (NOP). N/OFQ exhibits nucleotidic and aminoacidics sequence homology with the precursors of other opioid neuropeptides but it does not activate either MOP, KOP or DOP receptors. Furthermore, opioid neuropeptides do not activate the NOP receptor. Generally, activation of N/OFQ system exerts anti-opioids effects, for instance toward opioid-induced reward and analgesia. The NOP receptor is widely expressed throughout the brain, whereas N/OFQ localization is confined to brain nuclei that are involved in stress response such as amygdala, BNST and hypothalamus. Decades of studies have delineated the biological role of this system demonstrating its involvement in significant physiological processes such as pain, learning and memory, anxiety, depression, feeding, drug and alcohol dependence. This review discusses the role of this peptidergic system in the modulation of stress and stress-associated psychiatric disorders in particular drug addiction, mood, anxiety and food-related associated-disorders. Emerging preclinical evidence suggests that both NOP agonists and antagonists may represent a effective therapeutic approaches for substances use disorder. Moreover, the current literature suggests that NOP antagonists can be useful to treat depression and feeding-related diseases, such as obesity and binge eating behavior, whereas the activation of NOP receptor by agonists could be a promising tool for anxiety.

The NOP antagonist BTRX-246040 increases stress resilience in mice without affecting adult neurogenesis in the hippocampus

“…Similar results were already obtained with the NOP antagonist SB-612111 and with the genetic blockage of the NOP receptor in NOP knockout mice (Holanda et al, 2020(Holanda et al, , 2019. As recently reviewed (Gavioli et al, 2021;Ubaldi et al, 2021), a growing body of evidence suggests that the activation of the N/OFQ -NOP system during stress exposure contributes to the development of depressive-like behaviors (Der-Avakian et al, 2017;Holanda et al, 2019). Under this view, the blockage of the NOP receptor can be proposed as an innovative strategy to increase stress resilience and to prevent depression episodes and stresstriggered diseases in vulnerable subjects.…”

Long-read nanopore sequencing reveals novel common genetic structural variants in Prader-Willi syndrome and associated psychosis

“…The protein encoded by OPRL1 functions as a receptor for the endogenous, opioid-related neuropeptide, nociceptin/orphanin FQ. This peptide is involved in the modulation of stress, addiction, mood, anxiety, obesity, and binge-eating behavior 33 .…”

Interactions between the Nociceptin and Toll-like Receptor Systems

“…In addition, PMA significantly upregulated nociceptin at mRNA and protein levels in human monocytic MM6 cells as well as in peripheral blood leukocytes [ 18 , 19 ]. Moreover, solid evidence from preclinical and clinical studies confirms that compounds targeting the nociceptin system are effective therapeutic approaches for substance abuse and potential candidates for pain management [ 27 , 28 , 29 , 30 , 31 ]. Previous studies mainly focused on the role of nociceptin and NOP in neural tissues; much less is known about their functions in blood immune cells.…”

“…Interestingly, in a rat model of neuropathic pain, TLR2 and TLR4 antagonists produced analgesia and improved the analgesic effects of buprenorphine [ 33 ]. In addition to the well-known dual interaction with mu and kappa opioid receptors [ 38 , 39 ], buprenorphine also seems to be a partial agonist for the nociceptin receptor and antagonist for the delta opioid receptor [ 4 , 29 , 40 , 41 , 42 ]. This suggests that TLRs may indeed play a role in the regulation of endogenous nociceptin during immune response in vivo.…”