Central administration of neuronostatin induces antinociception in mice

► I.c.v. administration of neuronostatin produced a dose- and time-related antinociceptive effect in the tail immersion assay in mice. ► Neuronostatin produces its full analgesic effect by activating μ-and κ-opioid receptors. ► The analgesic effects of neuronostatin are dependent upon the central melanocortin system ► C-terminal amidation modification of neuronostatin is essential to exert its antinociceptive effect. ► Neuronostatin (6nmol, i.c.v.) increased c-Fos protein expression in the periaqueductal gray (PAG) and the nucleus raphe magnus (NRM). Neuronostatin, a recently discovered endogenous bioactive peptide, was encoded by pro-mRNA of somatostatin that contributes to modulation of nociception. However, nociceptive effect of neuronostatin is still not fully known. The aim of this study was to evaluate effect of neuronostatin on nociception and elucidate its possible mechanism of action. Intracerebroventricular (i.c.v.) administration of neuronostatin (0.3, 3, 6, 12nmol/mouse) produced a dose- and time-related antinociceptive effect in the tail immersion assay in mice, an acute pain model. The antinociceptive effect of neuronostatin was significantly antagonized by naloxone, and was strongly inhibited by co-injection with β-funaltrexamine or nor-binaltorphimine, but not by naltrindole. Also, melanocortin 3/4 receptor antagonist, SHU9119, completely blocked the effect of neuronostatin. These data indicated the involvement of both μ- and κ-opioid receptors and central melanocortin system in the analgesic response induced by neuronostatin. In addition, neuronostatin (6nmol, i.c.v.) increased c-Fos protein expression in the periaqueductal gray (PAG) and the nucleus raphe magnus (NRM) that have a pivotal role in regulating descending pain pathways. Taken together, this study is the first to reveal that neuronostatin produces antinociceptive effect via opioid and central melanocortin systems, which is associated with an increase in neuronal activity the PAG and NRM.