Modulatory Effects Of Neuropeptide FF System On The Biological Activities Of Endomorphin-2

Neuropeptide FF (NPFF) was reported to act as an opioid-modulating peptide. So far, it has been indicated that NPFF plays important roles in nociceptive modulation, reward and other biological activities induced by opioids, especially morphine. Endomorphin-1and-2are the selective agonists of opioid receptor. However, the mechanism of endomorphin-2(EM-2) in rewards and pain regulation is different from morphine and endomorphin-1(EM-1). In order to further reveal the interaction between the endogenous opioid regulatory peptides and the opioid system, the present study was conducted to further investigate the modulating role of supraspinal NPFF system in biological effects of EM-2.The present study examined the influence of NPFF on the rewarding action of EM-2, using the unbiased conditioned place preference (CPP) paradigm. The results indicated that i.c.v. administration of EM-2at doses of7.5-30nmol (i.c.v.) produced a dose-dependent conditioned place aversion (CPA). NPFF alone caused little place preference change. NPFF dose-dependently reversed the acquisition and expression of CPA induced by30nmol EM-2. Moreover, the effects of NPFF on the acquisition and the expression of EM-2induced CPA were completely blocked by the NPFF receptors antagonist RF9. Central injection of NPFF neither changed the locomotor activity nor modified the locomotor action of EM-2. These data provide the first evidence for a functional interaction of the endogenous ligands for NPFF and MOP receptors, and further support an anti-opioid character of NPFF system.In tail flick experiments, NPFF dose-dependently enhanced the analgesia of EM-2. As is well known, EM-2stimulates a subtype of μ opioid receptor that is different from other μ opioid agonists activated, and subsequently activates κ receptor indirectly. As expected, we found that NPFF dose-dependently enhanced the central analgesia effect of U69593, a selective κ opioid receptor agonist. This data suggested that NPFF enhanced the analgesic effects of EM-2in central may be caused by activation of κ receptor. In order to explore more about NPFF system how to modulate the EM-2biological activity, we further conducted NPVF and dNPA which are high selective agonists of NPFF1and NPFF2receptors respectively, on the regulation of central analgesia effects of EM-2. NPVF and dNPA both enhanced the analgesic of EM-2, and the antagonist RF9completely blocked those enhancement effects. Those data indicated that NPFF system modulates the analgesic effects of EM-2which is mainly κ opioid receptor mediated via activating NPFF, and NPFF2receptors.In formalin test, NPFF enhanced the analgesic of EM-2in phase I, μ and κ opioid receptor antagonists can both weak the analgesic effects of EM-2in phase I. Likewise, this enhancement presents itself in phase Ⅱ, but only the μ receptor antagonist can weak the analgesic effect of EM-2. Interestingly, NPFF decreased the analgesic of U69593in either phase I or phase II. Therefore, we presume that μ and κ opioid receptors both participate in phase I, and only μ opioid receptors are involved in phase Ⅱ, but not statistically significant. And in pathological conditions, the regulation effect of NPFF system on EM-2in formalin test is different from μ receptor system which is specially activated by EM-2.In a word, NPFF reversed the acquisition and expression of CPA induced by EM-2, while enhanced the analgesia of EM-2in the physical and chemical stimuli pain, because its μ opioid system which is different form other receptor agonist.