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In 2004, Neuropeptide S (NPS) was identified to be the cognate ligand of the previously discovered orphan receptor GPCR 154, now termed as NPS receptor (NPSR). Since, then a wealth of data has elucidated the unique behavioral profile of this peptidergic system in numerous physiological function such as being pro-arousal and anxiolytic at the same time. Besides, its robust anxiolytic profile, this peptide system has been found to activate HPA axis and concomitant release of ACTH and corticosterone. Additionally, the involvement of NPS in reinstatement of drug seeking behavior has also been reported. In recent years, accumulating data from various labs have demonstrated an A/T single-nucleotide polymorphism (SNP) resulting in (Asn107Ile) switch in the human NPSR gene as the risk factor for various psychiatric disorders such as panic disorder, post traumatic syndrome, alcohol use disorders and enhanced anxiety sensitivity, although, this is in stark contrast to the findings made in animal models which have consistently projected the anxiolytic nature of this peptide system. Therefore, in context of robust involvement of NPS system in various psychiatric disorders this review article considers the importance of NPS from translational point of view and appraises the need of therapies to be tailored around NPSR. In this respect, pharmacology of important NPSR ligands which have been recently developed has been discussed together with their possible side effects profile. Additionally, this review article encompasses all recent developments in the field of NPS system highlighting the role of this neuropeptide in all those biological functions which are modulated by this system. The role of this peptide has been discussed in detail in the perspective of sleep regulation, anxiety, fear expression and most importantly in drug addiction. Additionally, neuroimaging and genetic linkage studies addressing the functional impact of NPSR1 variants in the aforementioned psychiatric disorders have also been discussed.

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Neuropeptide S (NPS) is a naturally occurring appetite stimulant, associated with anxiety, stress, and excitement regulation. Neuropeptide S serves as a hypothalamic energy regulator that enhances food intake with a reduced level of satiety. NPS activates fat angiogenesis and the proliferation of new adipocytes in obesity. NPS has an established role in energy regulation by many pre-clinical investigations; however we have limited data available to support this notion in humans. We found significant association of Neuropeptide S receptor (NPSR1) Asn107Ile (rs324981, A>T) polymorphism with obese male participants. The current investigation carried out genotype screening of NPSR1 allele to assess the spectrum of the Asn107Ile polymorphism in obese and healthy Pakistani individuals. We revealed a significant (p = 0.04) difference between AA vs TT + AT genotype distribution of NPSR1 (SNP rs324981,) between obese and healthy individuals (p = 0.04). In this genotype analysis of (SNP rs324981) of the NPSR1 gene, T allele was marked as risk allele with higher frequency in the obese (38%) compared to its frequency in the controls (25%). Single Nucleotide Polymorphism (SNP, rs324981) Asn107Ile of NPSR1gene, that switches an amino acid from Asn to Ile, has been found associated with increased susceptibility to obesity in Pakistani individuals. Furthermore, molecular simulation studies predicted a lower binding affinity of NPSR1 Asn107Ile variant to NPS than the wild-type consistent with the genotype studies. These molecular simulation studies predict a possible molecular mechanism of this interaction by defining the key amino acid residues. However, a significantly (p<0.0001) lower concentration of NPS was recorded independent of genotype frequencies in obese subjects compared to healthy controls. We believe that large scale polymorphism data of population for important gene players including NPSR1 will be more useful to understand obesity and its associated risk factors.