Neuropeptide S Attenuates the Alarm Pheromone-Evoked Defensive and Risk Assessment Behaviors Through Activation of Cognate Receptor-Expressing Neurons in the Posterior Medial Amygdala

Neuropeptide S (NPS) acts by activating its cognate receptor (NPSR). High level expression of NPSR in the posterior medial amygdala suggests that NPS-NPSR system should be involved in regulation of social behaviors induced by social pheromones. The present study was undertaken to investigate the effects of central administration of NPS or with NPSR antagonist on the alarm pheromone (AP)-evoked defensive and risk assessment behaviors in mice. Furthermore, H129-H8, a novel high-brightness anterograde multiple trans-synaptic virus, c-Fos and NPSR immunostaining were employed to reveal the involved neurocircuits and targets of NPS action. The mice exposed to AP displayed an enhancement in defensive and risk assessment behaviors. NPS (0.1–1 nmol) intracerebroventricular (i.c.v.) injection significantly attenuated the AP-evoked defensive and risk assessment behaviors. NPSR antagonist [D-Val5]NPS at the dose of 40 nmol completely blocked the effect of 0.5 nmol of NPS which showed the best effective among dose range. The H129-H8-labeled neurons were observed in the bilateral posterodorsal medial amygdala (MePD) and posteroventral medial amygdala (MePV) 72 h after the virus injection into the unilateral olfactory bulb (OB), suggesting that the MePD and MePV receive olfactory information inputs from the OB. The percentage of H129-H8-labeled neurons that also express NPSR were 90.27 ± 3.56% and 91.67 ± 2.46% in the MePD and MePV, respectively. NPS (0.5 nmol, i.c.v.) remarkably increased the number of Fos immunoreactive (-ir) neurons in the MePD and MePV, and the majority of NPS-induced Fos-ir neurons also expressed NPSR. The behavior characteristic of NPS or with [D-Val5]NPS can be better replicated in MePD/MePV local injection within lower dose. The present findings demonstrated that NPS, via selective activation of the neurons bearing NPSR in the posterior medial amygdala, attenuates the AP-evoked defensive and risk assessment behaviors in mice.

Identification of a Novel Neuropeptide S Receptor Antagonist Scaffold Based on the SHA-68 Core

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.

Neuropeptide S receptor in GtoPdb v.2021.3

The neuropeptide S receptor (NPS, provisional nomenclature [23]) responds to the 20 amino-acid peptide neuropeptide S derived from a precursor (NPS, P0C0P6).

Neuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis

Endometriosis is a common chronic inflammatory condition causing pelvic pain and infertility in women, with limited treatment options and 50% heritability. We leveraged genetic analyses in two species with spontaneous endometriosis, humans and the rhesus macaque, to uncover treatment targets. We sequenced DNA from 32 human families contributing to a genetic linkage signal on chromosome 7p13-15 and observed significant overrepresentation of predicted deleterious low-frequency coding variants in NPSR1, the gene encoding neuropeptide S receptor 1, in cases (predominantly stage III/IV) versus controls (P = 7.8 × 10−4). Significant linkage to the region orthologous to human 7p13-15 was replicated in a pedigree of 849 rhesus macaques (P = 0.0095). Targeted association analyses in 3194 surgically confirmed, unrelated cases and 7060 controls revealed that a common insertion/deletion variant, rs142885915, was significantly associated with stage III/IV endometriosis (P = 5.2 × 10−5; odds ratio, 1.23; 95% CI, 1.09 to 1.39). Immunohistochemistry, qRT-PCR, and flow cytometry experiments demonstrated that NPSR1 was expressed in glandular epithelium from eutopic and ectopic endometrium, and on monocytes in peritoneal fluid. The NPSR1 inhibitor SHA 68R blocked NPSR1-mediated signaling, proinflammatory TNF-α release, and monocyte chemotaxis in vitro (P < 0.01), and led to a significant reduction of inflammatory cell infiltrate and abdominal pain (P < 0.05) in a mouse model of peritoneal inflammation as well as in a mouse model of endometriosis. We conclude that the NPSR1/NPS system is a genetically validated, nonhormonal target for the treatment of endometriosis with likely increased relevance to stage III/IV disease.