Associate editor: D. HoyerNociceptin/orphanin FQ receptor antagonists as innovative antidepressant drugs
Introduction
Depression is one of the most prevalent and costly psychiatric disorders leading to substantial cognitive and affective disturbances, which has a negative impact on the quality of life. It is estimated that about 15–20% of people in the Western world suffer from depressive episodes during their lifetime (Greenberg et al., 2003, Kessler et al., 2003). According to the American Psychiatric Association (1994), depression is a heterogeneous disorder often manifested with symptoms at psychological, behavioral and physiological levels, which comprises depressed mood, markedly diminished pleasure in most activities most of the day, fatigue, poor concentration, alterations in appetite, insomnia or excessive sleeping, feelings of worthlessness, excessive guilt, and thoughts of death or suicide. Current evidence indicates that the pathology of depression involves dysfunction of monoamine neurotransmitter circuits in the central nervous system, particularly serotonin (5-HT) and noradrenaline. It should be noted that classical antidepressant drugs act by i) blocking presynaptic monoamine transporter proteins, which remove released transmitters from the extracellular space; ii) inhibiting the enzyme monoamine oxidase, which degrades monoamine neurotransmitters or iii) interacting with pre- or postsynaptic receptors that regulate monoamine transmitter release and/or neuronal firing rate (Nemeroff & Owens, 2002).
The pharmacotherapy of depression is costly and widely prescribed by physicians. Nevertheless, less than half of treated patients attain complete remission after therapy with a single antidepressant drug. Other patients exhibit partial or no remission, some patients display intolerant responses to the treatment, emphasizing the need to identify novel classes of antidepressants (Berton & Nestler, 2006). Challenges for the design of new agents to treat depression are threefold: rapid onset of antidepressant response, broader efficacy, and fewer adverse effects (Berton & Nestler, 2006). Neuropeptidergic systems represent an important target for the development of innovative antidepressants (Holmes et al., 2003, Madaan and Wilson, 2009, Werner and Coveñas, 2010). Among these, nociceptin/orphanin FQ (N/OFQ) and its receptor (the N/OFQ peptide receptor, NOP) constitute a peptide-receptor system expressed in brain areas involved in emotional processing. Additionally, a growing body of evidence suggests a crucial role played by the N/OFQ system in modulating the effects of stress on limbic structures, mainly the hippocampus and hypothalamus–pituitary–adrenal (HPA) axis. In this review, we focus on a critical evaluation and discussion of the experimental evidence in support of the development of NOP receptor antagonists as innovative antidepressant drugs. It should however be emphasized that the available evidence is mainly based on preclinical findings and that the translational value of animal models of depression is limited. Thus, futher efforts are needed to assess and validate depressive-like symptoms in animals in order to facilitate the translation of experimental findings across basic science and clinical research (Dzirasa & Covington, 2012).
Section snippets
Nociceptin/orphanin FQ and its receptor system
N/OFQ is a heptadecapeptide (FGGFTGARKSARKLANQ) acting as the endogenous ligand for the NOP receptor. This peptide was independently isolated from animal brain extracts by two research groups in 1995 (Meunier et al., 1995, Reinscheid et al., 1995). N/OFQ is structurally related to opioid peptides; however, it does not bind to classical opioid receptors (Reinscheid et al., 1995) and endogenous opioid ligands have no affinity for the NOP receptor (Cox et al., 2000). At a cellular level, the NOP
Nociceptin/orphanin FQ peptide receptor antagonists
A detailed analysis of the available molecules acting as NOP receptor selective antagonists and of their pharmacological profile goes beyond the purpose of this article. In this section we summarize the basic pharmacological properties of the most commonly used compounds able to block the NOP receptor in order to allow the reader to better appreciate the data obtained with these molecules in vivo in animal models relevant for emotional states.
Antidepressant effects of nociceptin/orphanin FQ peptide receptor antagonists
Studies performed in rodents subjected to behavioral despair tests (i.e., forced swimming and tail suspension tests) support a crucial role of the N/OFQ-NOP receptor system in the modulation of mood-related behaviors. Relevant preclinical findings supporting a role for NOP receptor antagonists in experimental depression are summarized in Table 2. The first evidence came from a study demonstrating that two chemically different NOP receptor antagonists, i.e. the peptide [Nphe1]N/OFQ(1–13)-NH2 and
Nociceptin/orphanin FQ levels in patients with mood disorders
There are only two studies in humans that reported an association of depressive mood disorders and elevated plasma N/OFQ (Gu et al., 2003, Wang et al., 2009). In the first study plasma N/OFQ and 5-HT levels were measured: 21 patients with post-partum depression were compared with 25 healthy controls (Gu et al., 2003). Plasma N/OFQ levels were significantly elevated in the post-partum depression group. By contrast, 5-HT levels in the post-partum depression group were lower compared to controls.
Proposed mechanisms of the antidepressant actions of nociceptin/orphanin FQ peptide receptor antagonists
As far as the mechanisms underlying the antidepressant-like actions of NOP receptor antagonists are concerned, several studies have described inhibitory effects elicited by N/OFQ on monoaminergic systems (see Table 3 and Fig. 1). The majority of antidepressants currently available to patients have, as a common mechanism of action, an increase in monoamine levels in the synaptic cleft (Nutt, 2002). This same final mechanism may also explain the effects of NOP receptor antagonists. Information in
Nociceptin/orphanin FQ peptide receptor, stress, anxiety and depression
Stress is one of the leading predisposing factors in the development of anxiety and depression. Responses to stress involve activation of the HPA axis and the autonomic nervous system. Activation of the HPA axis creates a neuroendocrine cascade that results in glucocorticoid enhancement, which contributes to important adaptative functions during the stress exposure (Herman & Cullinan, 1997). However, while initially these responses are adaptative, the prolonged and excessive activation of
Nociceptin/orphanin FQ peptide receptor antagonists: possible indications and contraindications
In view of the considerable number of comorbidities associated with depression and the large range of adverse effects of available antidepressants, there is a need for innovative drugs with a wide spectrum of therapeutic actions, that could treat concomitant diseases, with fewer side effects. In this regard, blockade of NOP receptor signaling could be an interesting approach to the treatment of depression in patients with Parkinson disease and possibly with inflammatory bowel disease. The
Concluding remarks
In conclusion, preclinical data support the notion that blockade of NOP receptor signaling could represent a promising strategy for the development of innovative antidepressants. This proposal is corroborated by the limited evidence available from clinical and human genetic studies.
A modulatory effect of NOP receptor signaling on monoaminergic (mainly 5-HTergic) neurotransmission in the brain is the most probable mechanism by which NOP receptor antagonists could evoke antidepressant actions. A
Acknowledgments
Research in the field of N/OFQ has been supported in ECG laboratory by Brazilian Agencies (CNPq and CAPES grants), and in GC laboratory by the University of Ferrara (FAR grants) and the Italian Ministry of University (PRIN and FIRB grants). We would like to acknowledge Stefano Molinari for preparing Table 1, Niall Murphy for helpful discussion, and David G. Lambert for suggestions and proofreading the manuscript. ECG held a Marie Curie incoming International fellowship (509520 - MOODNOP).
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2022, Neuroscience and Biobehavioral ReviewsNociceptin/orphanin FQ receptor system blockade as an innovative strategy for increasing resilience to stress
2021, PeptidesCitation Excerpt :It will be interesting in the future to test if these differences are related to a different expression of the NOP – N/OFQ system in male and female msP rats. It is worthy of mention that the antidepressant and stress-protective effects of NOP antagonists are probably not only due to their effect on HPA axis modulation but also to the control exerted by the N/OFQ – NOP receptor system on monoaminergic transmission (for a review see: Gavioli and Calo’, [66]). In this context, it has been reported that a single injection of a NOP agonist seems to facilitate depressive-like behaviors by reducing monoamine availability in critical brain areas crucial for the effects of conventional antidepressants [83].
Effects of non-peptide nociceptin/orphanin FQ receptor ligands on methylphenidate-induced hyperactivity in mice: Implications for bipolar disorders
2020, NeuropeptidesCitation Excerpt :Taken account present and literature findings, the genetic blockade of NOP receptor did not change the hyperlocomotor effects of psychostimulant drugs. It is important to note that NOP antagonists are potential antidepressant drugs (Gavioli, and Calo', G.’, 2013; Post et al., 2016). Additionally, NOP receptor knockout mice and rats display an antidepressant-like phenotype (Gavioli et al., 2003; Gavioli et al., 2004; Holanda et al., 2019; Medeiros et al., 2015; Rizzi et al., 2011).