Effects of central neuropeptide S in the mouse formalin test

Neuropeptide S (NPS), a recently discovered bioactive peptide, was reported to regulate arousal, anxiety, locomotion, feeding behaviors, memory, and drug addiction. NPS receptor (NPSR) mRNA was found in several brain regions related to descending control system of pain, including the periaqueductal gray (PAG). Our previous study had shown that NPS could produce antinociception in mice. The present study was designed to evaluate whether NPS may produce antinociceptive effect observed in the mouse formalin test, a model of inflammatory pain. NPS (0.1–100 pmol) administrated intracerebroventricularly (i.c.v.) dose-dependently attenuated both first-phase and second-phase nociceptive behaviors induced by paw formalin injection. NPS (10 pmol, i.c.v.)-elicited antinociceptive effect was counteracted by co-injection with 1000 and 10,000 pmol [D-Val5]NPS, which alone induced neither hyperalgesia nor antinociception. The antinociception induced by NPS (10 pmol, i.c.v.) was not affected by naloxone (i.p., 10 mg/kg) and naloxone alone had no effect in the formalin test. In addition, compared to the saline (i.c.v.) treated group, NPS (10 pmol, i.c.v.) treated group increased c-Fos protein expression in nearly all subdivisions of the PAG in the formalin-injected mice. The above results revealed that NPS could produce antinociception in the formalin test through NPSR, which may be involved in the activation of PAG, suggesting that NPS–NPSR system may be a potential target for developing new analgesic drugs.

Research highlights▶ Neuropeptide S (NPS) reduced both first-phase and second-phase nociceptive behaviors in the mouse formalin test, a model of inflammatory pain. ▶ NPS-induced antinociception was mediated via NPS receptor (NPSR), but not opioid receptors. ▶ NPS-elicited antinociceptive effect may be associated with the activation of the midbrain periaqueductal gray (PAG).