Effects And Mechanisms Of Neuro-nostation In The Pain Modulation In Mice

Somatostatin plays an important role in the regulation of diverse neuroendocrine functions, and neuronostatin is encoded by pro-mRNA of somatostatin. Neuronostatin is involved in modulating a variety of biological actions, such as neuroendocrine system, cardiovascular system and metabolic system. Both experimental and clinical investigations have indicated that somatostatin contributes to modulation of nociception. However, to our knowledge, there have been no published papers about the nociceptive effect of neuronostatin.In the present study, we evaluated the nociceptive effect of neuronostatin in mice of acute pain models (the tail immersion assay) and investigated the nociceptive mechanisms induced by neuronostatin. In addition, we assessed whether C-terminal amidation modification of neuronostatin is essential to exert its analgesic activity. The results of this study indicate that i.c.v. administration of neuronostatin (0.3,3,6,12nmol/mouse) produced a dose- and time-related antinociceptive effect. The antinociceptive effect was evoked most effectively by 6nmol/mouse neuronostatin, and there was no further increase of antinociception by either higher or lower dose of neuronostatin, which could be interpreted by a bell-shaped dose-response curve. The antinociceptive effect of neuronostatin was significantly antagonized by naloxone, and was strongly inhibited by co-injection withβ-funaltrexamine or nor-binaltorphimine, but not by naltrindole. I.c.v. administration of neuronostatin (6nmol/mouse) potentiated the analgesic effect induced by morphine (i.c.v.,5μg/kg) and this potentiated effect can be also reversed by naloxone. These data indicated the involvement of bothμ-andκ-opioid receptors in the analgesic response induced by neuronostatin and an indirect functional interrelationship between neuronostatin and opioid systems in the modulation of nociceptive responses. Our results showed that non-amidated neuronostatin did not induce antinociceptive effect, suggesting that C-terminal amidation modification of neuronostatin is essential to exert its antinociceptive effect. Moreover, the associated alterations in c-Fos expression suggest that the antinociceptive effect of neuronostatin is associated with an increase in neuronal activity at the level of the PAG and NRM, and that these alterations in neuronal activity enhanced the activity of endogenous pain inhibitor system, and finally exerted the antinociceptive effect. Taken together, this study is the first to reveal that neuronostatin produces antinociceptive effect via opioid receptors, which is associated with an increase in neuronal activity the PAG and NRM.