Opposite Effects of Neuropeptide FF on Central Antinociception Induced by Endomorphin-1 and Endomorphin-2 in Mice

Abstract

Neuropeptide FF (NPFF) is known to be an endogenous opioid-modulating peptide. Nevertheless, very few researches focused on the interaction between NPFF and endogenous opioid peptides. In the present study, we have investigated the effects of NPFF system on the supraspinal antinociceptive effects induced by the endogenous µ-opioid receptor agonists, endomorphin-1 (EM-1) and endomorphin-2 (EM-2). In the mouse tail-flick assay, intracerebroventricular injection of EM-1 induced antinociception via µ-opioid receptor while the antinociception of intracerebroventricular injected EM-2 was mediated by both µ- and κ-opioid receptors. In addition, central administration of NPFF significantly reduced EM-1-induced central antinociception, but enhanced EM-2-induced central antinociception. The results using the selective NPFF1 and NPFF2 receptor agonists indicated that the EM-1-modulating action of NPFF was mainly mediated by NPFF2 receptor, while NPFF potentiated EM-2-induecd antinociception via both NPFF1 and NPFF2 receptors. To further investigate the roles of µ- and κ-opioid systems in the opposite effects of NPFF on central antinociception of endomprphins, the µ- and κ-opioid receptors selective agonists DAMGO and U69593, respectively, were used. Our results showed that NPFF could reduce the central antinociception of DAMGO via NPFF2 receptor and enhance the central antinociception of U69593 via both NPFF1 and NPFF2 receptors. Taken together, our data demonstrate that NPFF exerts opposite effects on central antinociception of endomorphins and provide the first evidence that NPFF potentiate antinociception of EM-2, which might result from the interaction between NPFF and κ-opioid systems.

Intracerebroventricular Neuropeptide FF Diminishes the Number of Apneas and Cardiovascular Effects Produced by Opioid Receptors’ Activation

“…Considering the opposite situation, we can speculate that activation of NPFF receptors in the NTS could via unknown mechanism inhibit or downregulate opioid receptors and prevent apnea appearance. In the similar manner to our study it was also previously shown that central antinociception produced by EM-1 can be reduced by icv pretreatment with NPFF [ 43 ].…”

“…EM-1 control iv administration after icv saline injection evoked immediate arrest of breathing in 6 of 7 tested rats ( Figure 3 a and Figure 4 a) and a significant decrease in MAP and heart rate ( Table 2 ). The tested doses of NPFF we used were selected on the basis of earlier studies where NPFF was applied intracerebroventricularly [ 37 , 42 , 43 ]. NPFF was injected icv slowly for 5 min and remained without influence on cardiovascular and respiratory variables.…”

BN‐9, a chimeric peptide with mixed opioid and neuropeptide FF receptor agonistic properties, produces nontolerance‐forming antinociception in mice

“…Previously, a number of studies have shown that NPFF itself has no significant effect on nociceptive threshold but attenuates the central antinociception induced by endogenous or exogenous opioids after i.c.v. co‐administration (Roumy and Zajac, ; Fang et al , ; Li et al , ; Wang et al , ). In theory, BN‐9 containing both NPFF and opioid agonist activities could partially exert anti‐opioid activities of the NPFF moiety and reduce its antinociception after supraspinal administration.…”

The multifunctional peptide DN‐9 produced peripherally acting antinociception in inflammatory and neuropathic pain via μ‐ and κ‐opioid receptors

“…DN‐9 was obtained from Hybio Pharmaceutical Co., Ltd. (Shenzhen, China). NPFF and https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1486 were synthesized on Rink MBHA resin using the N ‐fluorenylmethoxycarbonyl (Fmoc)‐based solid‐phase synthesis (Wang et al, ) and purified using preparative reversed‐phase HPLC with a gradient of 30–75% solvent A (solvent A: 0.1% CF 3 COOH in CH 3 CN/water 9:1) and solvent B (solvent B: 0.1% CF 3 COOH in water). The purities of these compounds were confirmed using analytical HPLC and an electrospray ionization mass spectrometer (ESI‐Q‐TOF maXis‐4G, Bruker Daltonics, Bremen, Germany).…”