Distribution of neuropeptide FF (NPFF) receptors in correlation with morphine-induced reward in the rat brain

Neuropeptide FF (NPFF) exhibited anti-/pro-opioid effects when centrally injected. It was proved to bind to its own receptors, namely NPFF1 and NPFF2 receptors, but did not bind to opioid receptors. In our previous study, we found that i.c.v. injected NPFF suppressed morphine-induced conditioned place preference (CPP) in rats, which indicated that NPFF may play a role in the modulation of morphine-induced reward. In the present study, we further investigated the action site of NPFF to attenuate morphine-induced reward. Bilateral intra-VTA (ventral tegmental area) and intra-NAc (nucleus accumbens) injections of NPFF both blocked the CPP caused by morphine in rats. This suggests that NPFF may act at both VTA and NAc to inhibit the sensitization of the mesocorticolimbic dopaminergic pathway. Neurochemical analyses support that NPFF could be acting through the inhibition of the mesocorticolimbic dopaminergic activity increased by morphine. We also determined the distribution of NPFF receptors in rat brains. Our results showed that both NPFF receptors were abundantly expressed in VTA but with less content in NAc. In fluorescent immunohistochemical staining, our results revealed that NPFF1 and NPFF2 receptors could be expressed at the TH (tyrosine hydroxylase)- or GAD67 (glutamic acid decarboxylase-67)-positive neurons in VTA, whereas some of them were present in the negative neurons. This implied a possible function of NPFF to modulate dopaminergic neurons directly and a possible indirect action of NPFF on GABAergic neurons to modulate dopamine release. Taken together, our study should be helpful for clarifying the possible mechanisms of NPFF system to modulate morphine-induced reward.