The biology of Nociceptin/Orphanin FQ (N/OFQ) related to obesity, stress, anxiety, mood, and drug dependence

Abstract

Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide that was deorphanized in 1995. The generation of specific agonists, antagonists and receptor deficient mice and rats has enabled progress in elucidating the biological functions of nociceptin. In addition, radio-imaging technologies have been advanced for investigation of this system in animals and humans. Together with traditional neurobehavioral techniques, these tools have been utilized to identify the biological significance of the N/OFQ system and its interacting partners. The present commentary focuses on the role of N/OFQ in the regulation of feeding and body weight homeostasis, stress and the stress-related psychiatric disorders of depression and anxiety, and in drug and alcohol dependence. Critical evaluation of the current scientific preclinical literature suggests that small molecule modulators of nociceptin opioid peptide receptors (NOP) might be useful in the treatment of diseases related to these biological functions. In particular, the literature data suggest that antagonism of NOP receptors will produce anti-obesity and antidepressant activities in humans. However, there are also contradictory data discussed. The current literature on the role of N/OFQ in anxiety and addiction, on the other hand points primarily to a role of agonist modulation being potentially therapeutic. Some drug-like molecules that function either as agonists or antagonists of NOP receptors have been optimized for human clinical study to test some of these hypotheses. The discovery of PET ligands for NOP receptors, combined with the pharmacological tools and burgeoning preclinical data set discussed here bodes well for a rapid advancement of clinical understanding and potential therapeutic benefit.

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

“…In a separate study it was demonstrated that Ro 64-6198 is also active in reducing ethanol self-administration and preventing relapse of ethanol drinking (Kuzmin et al, 2007). These results obtained with Ro 64-6198 are in line with a rather large number of findings obtained with N/OFQ, or other NOP ligands, suggesting that NOP agonists are worthy of further exploration as innovative treatments for drug abuse (Zaveri, 2011;Witkin et al, 2014). However, one should keep in mind the observation that NOP receptor agonists appear to be more efficacious for attenuation of CPP than self-administration, as discussed above, once again displaying the complicated nature of the NOP receptor system.…”

Genetic Deletion of the Nociceptin/Orphanin FQ Receptor in the Rat Confers Resilience to the Development of Drug Addiction

“…Consistent with this localization, evidence suggests that the N/OFQ system is involved in the regulation of several addiction-related phenomena, including drug intake, withdrawal, and relapse for a variety of psychotropic agents including opioids, psychostimulants, and ethanol (Ciccocioppo et al, 2000a;Kallupi et al, 2014;Witkin et al, 2014;Zaveri, 2011).…”

A Novel Nociceptin Receptor Antagonist LY2940094 Inhibits Excessive Feeding Behavior in Rodents: A Possible Mechanism for the Treatment of Binge Eating Disorder

“…The effects of N/OFQ on feeding are well documented (for review, see Witkin et al, 2014). Hyperphagia is consistently observed after intracerebroventricular administration of N/OFQ into either the lateral or third ventricle but not the fourth ventricle (Pomonis et al, 1996;Polidori et al, 2000).…”

“…Moreover, NOP is expressed in the peripheral nervous system as well as in the gastrointestinal tract, smooth muscles, and in cells of the immune system. Initially, N/OFQ was found to produce hyperalgesia, leading to the naming the peptide nociceptin (Meunier et al, 1995); however, in addition to pain, N/OFQ modulates other CNS behaviors, including stress and anxiety, depression, substance abuse, prolactin secretion, locomotor activity, body temperature, memory, and feeding (Mustazza and Bastanzio, 2011;Gavioli and Calo', 2013;Singh et al, 2013;Witkin et al, 2014).…”