Pharmacology of Neuropeptide S Receptor

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 26849

Special Issue Editors

Department of Biomedical and Specialty Surgical Sciences, Section of Pharmacology, University of Ferrara, Ferrara, Italy
Interests: neuropeptides; G protein coupled receptors; neuropeptide s; N/OFQ; opioids; in vitro pharmacology; in vivo pharmacology
Institute of Pharmacology and Toxicology, University Hospital Jena, Friedrich-Schiller-Universität, Jena, Germany
Interests: neuropeptides; GPCRs; signal transduction; behavior; NPS; N/OFQ; opioids; genetics

Special Issue Information

Dear Colleagues,

Neuropeptide S (NPS) is one of the youngest members in the growing list of neurotransmitters and physiological modulators. Identified in 2002 and first described in 2004 as the endogenous ligand of a previously orphan receptor, now termed Neuropeptide S receptor (NPSR1), tremendous progress has been made in understanding the pharmacology and the neurobiology of this system, as well as emerging clinical implications of NPSR1 genetic variants.

Much research regarding the NPS/NPSR-system has occurred in the area of neuro- and psychobiology. Strong genetic evidence also points to a role of the NPS-system in allergic and inflammatory diseases. Although drugs acting on NPSR1 are still lacking in clinical practice, this receptor continues to be a target of high interest for the understanding and treatment of several conditions, including anxiety and panic disorders, sleep disorders, drug addiction, food intake disorders, pain, cognitive deficit, and Parkinson’s disease, as well as allergies and chronic intestinal inflammatory conditions.

Authors involved in research on NPS / NPSR1 are invited to submit original and review articles on preclinical as well as clinical studies concerning functional and pathophysiological aspects of the NPS system. Also, studies involving medicinal chemistry and in vitro models are welcome.

Dr. Chiara Ruzza
Dr. Rainer K. Reinscheid
Guest Editors

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Keywords

  • Neuropeptide S (NPS)
  • Neuropeptide S receptor (NPSR1)

Published Papers (10 papers)

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Research

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29 pages, 3451 KiB  
Article
Identification of a Novel Neuropeptide S Receptor Antagonist Scaffold Based on the SHA-68 Core
by Allison Zarkin, Rajwana Jahan, Rajendra Uprety, Yanan Zhang, Charles McElhinny, Rodney Snyder, Elaine Gay, Gabriel Jewula, Heather Bool, Stewart D Clark and Scott Runyon
Pharmaceuticals 2021, 14(10), 1024; https://doi.org/10.3390/ph14101024 - 06 Oct 2021
Cited by 1 | Viewed by 1738
Abstract
Activation of the neuropeptide S receptor (NPSR) system has been shown to produce anxiolytic-like actions, arousal, and enhance memory consolidation, whereas blockade of the NPSR has been shown to reduce relapse to substances of abuse and duration of anesthetics. We report here the [...] Read more.
Activation of the neuropeptide S receptor (NPSR) system has been shown to produce anxiolytic-like actions, arousal, and enhance memory consolidation, whereas blockade of the NPSR has been shown to reduce relapse to substances of abuse and duration of anesthetics. We report here the discovery of a novel core scaffold (+) N-benzyl-3-(2-methylpropyl)-1-oxo-3-phenyl-1H,3H,4H,5H,6H,7H-furo[3,4-c]pyridine-5-carboxamide with potent NPSR antagonist activity in vitro. Pharmacokinetic parameters demonstrate that 14b reaches pharmacologically relevant levels in plasma and the brain following intraperitoneal (i.p.) administration, but is cleared rapidly from plasma. Compound 14b was able to block NPS (0.3 nmol)-stimulated locomotor activity in C57/Bl6 mice at 3 mg/kg (i.p.), indicating potent in vivo activity for the structural class. This suggests that 14b can serve as a useful tool for continued mapping of the pharmacological functions of the NPS receptor system. Full article
(This article belongs to the Special Issue Pharmacology of Neuropeptide S Receptor)
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21 pages, 3761 KiB  
Article
Effect of Neuropeptide S Administration on Ultrasonic Vocalizations and Behaviour in Rats with Low vs. High Exploratory Activity
by Kadri Kõiv, Denis Matrov, Trine Uusen and Jaanus Harro
Pharmaceuticals 2021, 14(6), 524; https://doi.org/10.3390/ph14060524 - 30 May 2021
Cited by 2 | Viewed by 2200
Abstract
Neuropeptide S (NPS) is a peptide neurotransmitter that in animal studies promotes wakefulness and arousal with simultaneous anxiety reduction, in some inconsistency with results in humans. We examined the effect of NPS on rat ultrasonic vocalizations (USV) as an index of affective state [...] Read more.
Neuropeptide S (NPS) is a peptide neurotransmitter that in animal studies promotes wakefulness and arousal with simultaneous anxiety reduction, in some inconsistency with results in humans. We examined the effect of NPS on rat ultrasonic vocalizations (USV) as an index of affective state and on behaviour in novel environments in rats with persistent inter-individual differences in exploratory activity. Adult male Wistar rats were categorised as of high (HE) or low (LE) exploratory activity and NPS was administered intracerebroventricularly (i.c.v.) at a dose of 1.0 nmol/5 µL, after which USVs were recorded in the home-cage and a novel standard housing cage, and behaviour evaluated in exploration/anxiety tests. NPS induced a massive production of long and short 22 kHz USVs in the home cage that continued later in the novel environment; no effect on 50 kHz USVs were found. In LE-rats, the long 22 kHz calls were emitted at lower frequencies and were louder. The effects of NPS on behaviour appeared novelty- and test-dependent. NPS had an anxiolytic-like effect in LE-rats only in the elevated zero-maze, whereas in HE-rats, locomotor activity in the zero-maze and in a novel standard cage was increased. Thus NPS appears as a psychostimulant peptide but with a complex effect on dimensions of affect. Full article
(This article belongs to the Special Issue Pharmacology of Neuropeptide S Receptor)
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17 pages, 5142 KiB  
Article
Neuropeptide S Receptor Stimulation Excites Principal Neurons in Murine Basolateral Amygdala through a Calcium-Dependent Decrease in Membrane Potassium Conductance
by Sion Park, Pia Flüthmann, Carla Wolany, Lena Goedecke, Hannah Maleen Spenner, Thomas Budde, Hans-Christian Pape and Kay Jüngling
Pharmaceuticals 2021, 14(6), 519; https://doi.org/10.3390/ph14060519 - 27 May 2021
Cited by 2 | Viewed by 2829
Abstract
Background: The neuropeptide S system, consisting of the 20 amino acid neuropeptide NPS and its G-protein-coupled receptor (GPCR) neuropeptide S receptor 1 (NPSR1), has been studied intensively in rodents. Although there is a lot of data retrieved from behavioral studies using pharmacology or [...] Read more.
Background: The neuropeptide S system, consisting of the 20 amino acid neuropeptide NPS and its G-protein-coupled receptor (GPCR) neuropeptide S receptor 1 (NPSR1), has been studied intensively in rodents. Although there is a lot of data retrieved from behavioral studies using pharmacology or genetic interventions, little is known about intracellular signaling cascades in neurons endogenously expressing the NPSR1. Methods: To elucidate possible G-protein-dependent signaling and effector systems, we performed whole-cell patch-clamp recordings on principal neurons of the anterior basolateral amygdala of mice. We used pharmacological interventions to characterize the NPSR1-mediated current induced by NPS application. Results: Application of NPS reliably evokes inward-directed currents in amygdalar neurons recorded in brain slice preparations of male and female mice. The NPSR1-mediated current had a reversal potential near the potassium reversal potential (EK) and was accompanied by an increase in membrane input resistance. GDP-β-S and BAPTA, but neither adenylyl cyclase inhibition nor 8-Br-cAMP, abolished the current. Intracellular tetraethylammonium or 4-aminopyridine reduced the NPS-evoked current. Conclusion: NPSR1 activation in amygdalar neurons inhibits voltage-gated potassium (K+) channels, most likely members of the delayed rectifier family. Intracellularly, Gαq signaling and calcium ions seem to be mandatory for the observed current and increased neuronal excitability. Full article
(This article belongs to the Special Issue Pharmacology of Neuropeptide S Receptor)
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21 pages, 9308 KiB  
Article
Neuropeptide S-Mediated Modulation of Prepulse Inhibition Depends on Age, Gender, Stimulus-Timing, and Attention
by Wei Si, Xiaobin Liu, Hans-Christian Pape and Rainer K. Reinscheid
Pharmaceuticals 2021, 14(5), 489; https://doi.org/10.3390/ph14050489 - 20 May 2021
Cited by 2 | Viewed by 2218
Abstract
Conflicting reports about the role of neuropeptide S (NPS) in animal models of psychotic-like behavior and inconsistent results from human genetic studies seeking potential associations with schizophrenia prompted us to reevaluate the effects of NPS in the prepulse inhibition (PPI) paradigm in mice. [...] Read more.
Conflicting reports about the role of neuropeptide S (NPS) in animal models of psychotic-like behavior and inconsistent results from human genetic studies seeking potential associations with schizophrenia prompted us to reevaluate the effects of NPS in the prepulse inhibition (PPI) paradigm in mice. Careful examination of NPS receptor (NPSR1) knockout mice at different ages revealed that PPI deficits are only expressed in young male knockout animals (<12 weeks of age), that can be replicated in NPS precursor knockout mice and appear strain-independent, but are absent in female mice. PPI deficits can be aggravated by MK-801 and alleviated by clozapine. Importantly, treatment of wildtype mice with a centrally-active NPSR1 antagonist was able to mimic PPI deficits. PPI impairment in young male NPSR1 and NPS knockout mice may be caused by attentional deficits that are enhanced by increasing interstimulus intervals. Our data reveal a substantial NPS-dependent developmental influence on PPI performance and confirm a significant role of attentional processes for sensory-motor gating. Through its influence on attention and arousal, NPS appears to positively modulate PPI in young animals, whereas compensatory mechanisms may alleviate NPS-dependent deficits in older mice. Full article
(This article belongs to the Special Issue Pharmacology of Neuropeptide S Receptor)
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Review

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20 pages, 915 KiB  
Review
A Role for Neuropeptide S in Alcohol and Cocaine Seeking
by Nazzareno Cannella, Anna Maria Borruto, Michele Petrella, Maria Vittoria Micioni Di Bonaventura, Laura Soverchia, Carlo Cifani, Sara De Carlo, Esi Domi and Massimo Ubaldi
Pharmaceuticals 2022, 15(7), 800; https://doi.org/10.3390/ph15070800 - 27 Jun 2022
Cited by 3 | Viewed by 1764
Abstract
The neuropeptide S (NPS) is the endogenous ligand of the NPS receptor (NPSR). The NPSR is widely expressed in brain regions that process emotional and affective behavior. NPS possesses a unique physio-pharmacological profile, being anxiolytic and promoting arousal at the same time. Intracerebroventricular [...] Read more.
The neuropeptide S (NPS) is the endogenous ligand of the NPS receptor (NPSR). The NPSR is widely expressed in brain regions that process emotional and affective behavior. NPS possesses a unique physio-pharmacological profile, being anxiolytic and promoting arousal at the same time. Intracerebroventricular NPS decreased alcohol consumption in alcohol-preferring rats with no effect in non-preferring control animals. This outcome is most probably linked to the anxiolytic properties of NPS, since alcohol preference is often associated with high levels of basal anxiety and intense stress-reactivity. In addition, NPSR mRNA was overexpressed during ethanol withdrawal and the anxiolytic-like effects of NPS were increased in rodents with a history of alcohol dependence. In line with these preclinical findings, a polymorphism of the NPSR gene was associated with anxiety traits contributing to alcohol use disorders in humans. NPS also potentiated the reinstatement of cocaine and ethanol seeking induced by drug-paired environmental stimuli and the blockade of NPSR reduced reinstatement of cocaine-seeking. Altogether, the work conducted so far indicates the NPS/NPSR system as a potential target to develop new treatments for alcohol and cocaine abuse. An NPSR agonist would be indicated to help individuals to quit alcohol consumption and to alleviate withdrawal syndrome, while NPSR antagonists would be indicated to prevent relapse to alcohol- and cocaine-seeking behavior. Full article
(This article belongs to the Special Issue Pharmacology of Neuropeptide S Receptor)
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22 pages, 883 KiB  
Review
Role of the Neuropeptide S System in Emotionality, Stress Responsiveness and Addiction-Like Behaviours in Rodents: Relevance to Stress-Related Disorders
by Ann-Marie Tobinski and Virginie Rappeneau
Pharmaceuticals 2021, 14(8), 780; https://doi.org/10.3390/ph14080780 - 08 Aug 2021
Cited by 9 | Viewed by 2871
Abstract
The neuropeptide S (NPS) and its receptor (NPSR1) have been extensively studied over the last two decades for their roles in locomotion, arousal/wakefulness and anxiety-related and fear-related behaviours in rodents. However, the possible implications of the NPS/NPSR1 system, especially those of the single [...] Read more.
The neuropeptide S (NPS) and its receptor (NPSR1) have been extensively studied over the last two decades for their roles in locomotion, arousal/wakefulness and anxiety-related and fear-related behaviours in rodents. However, the possible implications of the NPS/NPSR1 system, especially those of the single nucleotide polymorphism (SNP) rs324981, in stress-related disorders and substance abuse in humans remain unclear. This is possibly due to the fact that preclinical and clinical research studies have remained separated, and a comprehensive description of the role of the NPS/NPSR1 system in stress-relevant and reward-relevant endpoints in humans and rodents is lacking. In this review, we describe the role of the NPS/NPSR1 system in emotionality, stress responsiveness and addiction-like behaviour in rodents. We also summarize the alterations in the NPS/NPSR1 system in individuals with stress-related disorders, as well as the impact of the SNP rs324981 on emotion, stress responses and neural activation in healthy individuals. Moreover, we discuss the therapeutic potential and possible caveats of targeting the NPS/NPSR1 system for the treatment of stress-related disorders. The primary goal of this review is to highlight the importance of studying some rodent behavioural readouts modulated by the NPS/NPSR1 system and relevant to stress-related disorders. Full article
(This article belongs to the Special Issue Pharmacology of Neuropeptide S Receptor)
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12 pages, 704 KiB  
Review
Neuropeptide S Receptor as an Innovative Therapeutic Target for Parkinson Disease
by Victor A. D. Holanda, Julia J. Didonet, Manara B. B. Costa, Adriano H. do Nascimento Rangel, Edilson D. da Silva, Jr. and Elaine C. Gavioli
Pharmaceuticals 2021, 14(8), 775; https://doi.org/10.3390/ph14080775 - 06 Aug 2021
Cited by 4 | Viewed by 2860
Abstract
Parkinson disease (PD) is a neurodegenerative disease mainly characterized by the loss of nigral dopaminergic neurons in the substantia nigra pars compacta. Patients suffering from PD develop severe motor dysfunctions and a myriad of non-motor symptoms. The treatment mainly consists of increasing central [...] Read more.
Parkinson disease (PD) is a neurodegenerative disease mainly characterized by the loss of nigral dopaminergic neurons in the substantia nigra pars compacta. Patients suffering from PD develop severe motor dysfunctions and a myriad of non-motor symptoms. The treatment mainly consists of increasing central dopaminergic neurotransmission and alleviating motor symptoms, thus promoting severe side effects without modifying the disease’s progress. A growing body of evidence suggests a close relationship between neuropeptide S (NPS) and its receptor (NPSR) system in PD: (i) double immunofluorescence labeling studies showed that NPSR is expressed in the nigral tyrosine hydroxylase (TH)-positive neurons; (ii) central administration of NPS increases spontaneous locomotion in naïve rodents; (iii) central administration of NPS ameliorates motor and nonmotor dysfunctions in animal models of PD; (iv) microdialysis studies showed that NPS stimulates dopamine release in naïve and parkinsonian rodents; (v) central injection of NPS decreases oxidative damage to proteins and lipids in the rodent brain; and, (vi) 7 days of central administration of NPS protects from the progressive loss of nigral TH-positive cells in parkinsonian rats. Taken together, the NPS/NPSR system seems to be an emerging therapeutic strategy for alleviating motor and non-motor dysfunctions of PD and, possibly, for slowing disease progress. Full article
(This article belongs to the Special Issue Pharmacology of Neuropeptide S Receptor)
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13 pages, 528 KiB  
Review
Roles of Neuropeptide S in Anesthesia, Analgesia, and Sleep
by Tetsuya Kushikata, Kazuyoshi Hirota, Junichi Saito and Daiki Takekawa
Pharmaceuticals 2021, 14(5), 483; https://doi.org/10.3390/ph14050483 - 19 May 2021
Cited by 9 | Viewed by 2908
Abstract
Neuropeptide S (NPS) is an endogenous peptide that regulates various physiological functions, such as immune functions, anxiety-like behaviors, learning and memory, the sleep–wake rhythm, ingestion, energy balance, and drug addiction. These processes include the NPS receptor (NPSR1). The NPS–NPSR1 system is also significantly [...] Read more.
Neuropeptide S (NPS) is an endogenous peptide that regulates various physiological functions, such as immune functions, anxiety-like behaviors, learning and memory, the sleep–wake rhythm, ingestion, energy balance, and drug addiction. These processes include the NPS receptor (NPSR1). The NPS–NPSR1 system is also significantly associated with the onset of disease, as well as these physiologic functions. For example, NPS is involved in bronchial asthma, anxiety and awakening disorders, and rheumatoid arthritis. In this review, among the various functions, we focus on the role of NPS in anesthesia-induced loss of consciousness; analgesia, mainly by anesthesia; and sleep–wakefulness. Progress in the field regarding the functions of endogenous peptides in the brain, including NPS, suggests that these three domains share common mechanisms. Further NPS research will help to elucidate in detail how these three domains interact with each other in their functions, and may contribute to improving the quality of medical care. Full article
(This article belongs to the Special Issue Pharmacology of Neuropeptide S Receptor)
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11 pages, 658 KiB  
Review
Pharmacology, Physiology and Genetics of the Neuropeptide S System
by Rainer K. Reinscheid and Chiara Ruzza
Pharmaceuticals 2021, 14(5), 401; https://doi.org/10.3390/ph14050401 - 23 Apr 2021
Cited by 7 | Viewed by 3093
Abstract
The Neuropeptide S (NPS) system is a rather ‘young’ transmitter system that was discovered and functionally described less than 20 years ago. This review highlights the progress that has been made in elucidating its pharmacology, anatomical distribution, and functional involvement in a variety [...] Read more.
The Neuropeptide S (NPS) system is a rather ‘young’ transmitter system that was discovered and functionally described less than 20 years ago. This review highlights the progress that has been made in elucidating its pharmacology, anatomical distribution, and functional involvement in a variety of physiological effects, including behavior and immune functions. Early on, genetic variations of the human NPS receptor (NPSR1) have attracted attention and we summarize current hypotheses of genetic linkage with disease and human behaviors. Finally, we review the therapeutic potential of future drugs modulating NPS signaling. This review serves as an introduction to the broad collection of original research papers and reviews from experts in the field that are presented in this Special Issue. Full article
(This article belongs to the Special Issue Pharmacology of Neuropeptide S Receptor)
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19 pages, 1112 KiB  
Review
The Neural Network of Neuropeptide S (NPS): Implications in Food Intake and Gastrointestinal Functions
by Luca Botticelli, Emanuela Micioni Di Bonaventura, Massimo Ubaldi, Roberto Ciccocioppo, Carlo Cifani and Maria Vittoria Micioni Di Bonaventura
Pharmaceuticals 2021, 14(4), 293; https://doi.org/10.3390/ph14040293 - 26 Mar 2021
Cited by 9 | Viewed by 2728
Abstract
The Neuropeptide S (NPS), a 20 amino acids peptide, is recognized as the endogenous ligand of a previously orphan G protein-coupled receptor, now termed NPS receptor (NPSR). The limited distribution of the NPS-expressing neurons in few regions of the brainstem is in contrast [...] Read more.
The Neuropeptide S (NPS), a 20 amino acids peptide, is recognized as the endogenous ligand of a previously orphan G protein-coupled receptor, now termed NPS receptor (NPSR). The limited distribution of the NPS-expressing neurons in few regions of the brainstem is in contrast with the extensive expression of NPSR in the rodent central nervous system, suggesting the involvement of this receptor in several brain functions. In particular, NPS promotes locomotor activity, behavioral arousal, wakefulness, and unexpectedly, at the same time, it exerts anxiolytic-like properties. Intriguingly, the NPS system is implicated in the rewarding properties of drugs of abuse and in the regulation of food intake. Here, we focus on the anorexigenic effect of NPS, centrally injected in different brain areas, in both sated and fasted animals, fed with standard or palatable food, and, in addition, on its influence in the gastrointestinal tract. Further investigations, regarding the role of the NPS/NPSR system and its potential interaction with other neurotransmitters could be useful to understand the mechanisms underlying its action and to develop novel pharmacological tools for the treatment of aberrant feeding patterns and obesity. Full article
(This article belongs to the Special Issue Pharmacology of Neuropeptide S Receptor)
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