Neuropeptide FF attenuates the acquisition and the expression of conditioned place aversion to endomorphin-2 in mice

It has been demonstrated that the endogenous mu opioid (MOP) agonist endomorphin-2 (EM-2) produces conditioned place aversion (CPA) and in contrast, morphine exerts opposite action. Neuropeptide FF (NPFF) was reported to act as a functional antagonist of mu opioid receptor and to exert opioid-modulating activities. The present study examined the influence of NPFF on the rewarding action of EM-2, using the unbiased conditioned place preference (CPP) paradigm. For testing the effect of NPFF on the acquisition of EM-2-induced CPA, NPFF and EM-2 were co-injected on the conditioning days without drug treatment on the followed test day. To explore the effect of NPFF on the expression of EM-2-induced CPA, EM-2 was administered alone on the conditioning days, and NPFF was given 5 min before placement in the CPP apparatus on the test day. The results showed that NPFF (2.5, 5 and 10 nmol, i.c.v.) alone caused little place preference change. However, NPFF dose-dependently reversed the acquisition of CPA induced by 30 nmol EM-2 (i.c.v.). Similarly, the expression of EM-2-induced CPA was also reduced by NPFF. Moreover, the effects of NPFF on the acquisition and the expression of EM-2-induced CPA were completely blocked by the NPFF receptors antagonist RF9 (10 nmol, i.c.v.). However, 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.