Neuropeptide S pathway in PTSD and neuropsychiatric disorders: A review

Abstract

Post-traumatic stress disorder (PTSD) is a multidimensional illness that seldom occurs alone: roughly 80 % of patients also meet criteria for anxiety, depression, chronic pain, substance-use, eating or cognitive disorders. Converging genetic, neurochemical and behavioural findings implicate the neuropeptide S (NPS) system-acting through its G-protein-coupled NPS receptor (NPSR)-as a common regulator of these diverse phenotypes. This narrative review surveys studies published 2000-2024 in PubMed, Embase and Web of Science that examine NPS/NPSR involvement in core PTSD features and typical comorbidities. The functional rs324981 A/T polymorphism, which boosts NPSR surface expression and signalling, consistently associates with greater PTSD risk and symptom severity. In rodent models, exogenous NPS reduces anxiety- and fear-like behaviours, speeds fear-memory extinction, stabilises the hypothalamic-pituitary-adrenal axis, enhances dopaminergic tone and elevates hippocampal brain-derived neurotrophic factor (BDNF)-changes concordant with symptom relief. Additional work shows that NPS lessens pain affect, dampens alcohol and opioid intake, eases withdrawal-induced anxiety and lowers food consumption, hinting at a multimodal therapeutic profile. These effects converge on limbic and mid-brain circuits (amygdala, ventral tegmental area, locus coeruleus, paraventricular nucleus) and engage oxytocinergic, adenosinergic and endocannabinoid pathways. Translation remains limited by NPS's rapid degradation, poor blood-brain-barrier penetration and scarcity of brain-penetrant NPSR ligands, but advances in intranasal delivery, lipid-acylated analogues, biased NPSR agonists and "humanised" NPSR-variant models offer promising solutions. Collectively, current pre-clinical and genetic evidence positions the NPS-NPSR axis as a versatile therapeutic target for both core PTSD symptoms and their disabling comorbidities, warranting rigorous translational studies to refine mechanism, optimise drug-like properties and test clinical efficacy.

Figure 1.

Role of NPS–NPSR system in PTSD and related neuropsychiatric disorders. The orange and blue boxes describe the core symptoms of PTSD and related neuropsychiatric disorders, respectively. A variation in the NPSR gene (SNP rs324981) increases the incidence of PTSD in human. Animal models can mimic the core symptoms of PTSD and related neuropsychiatric disorders. Administration of NPS inhibits PTSD through mechanisms involving NE, DA, HPA, and BDNF. Abbreviations: NPS: Neuropeptide S; NPSR: Neuropeptide S receptor; PTSD: Post-traumatic stress disorder; NE: Norepinephrine; DA: Dopamine; HPA: Hypothalamic-pituitary-adrenal axis; BDNF: Brain-derived neurotrophic factor.

Figure 2.

Brain regions mediate the alleviating effects of NPS on the animal behaviors associated with PTSD and its related neuropsychiatric disorders. The various colored solid circles displayed in the different brain regions represent the various symptoms that can be relieved by NPS. The Generic Diagramming Platform (GDP), accessible at http://biogdp.com, was employed to create the schematic diagram. Abbreviations: ACC: Anterior cingulate cortex; PFC: Prefrontal cortex; BNST: Bed nucleus of the stria terminalis; BLA: Basolateral amygdala; PVN: Paraventricular nucleus of the hypothalamus; LH: Lateral hypothalamus; PeF: Perifornical area; MeA: Medial amygdala; VTA: Ventral tegmental area; DRN: Dorsal raphe nucleus; LDT: Laterodorsal tegmental nucleus.