RF9, a potent and selective neuropeptide FF receptor antagonist, prevents opioid-induced tolerance associated with hyperalgesia - PubMed (original) (raw)

. 2006 Jan 10;103(2):466-71.

doi: 10.1073/pnas.0502090103. Epub 2006 Jan 3.

Martine Schmitt, Jean-Paul Laulin, Emilie Laboureyras, Jack H Jhamandas, David MacTavish, Audrey Matifas, Catherine Mollereau, Patrick Laurent, Marc Parmentier, Brigitte L Kieffer, Jean-Jacques Bourguignon, Guy Simonnet

Affiliations

RF9, a potent and selective neuropeptide FF receptor antagonist, prevents opioid-induced tolerance associated with hyperalgesia

Frédéric Simonin et al. Proc Natl Acad Sci U S A. 2006.

Erratum in

Abstract

Neuropeptide FF (NPFF) has been proposed to play a role in pain modulation, opioid tolerance, and several other physiological processes. However, pharmacological agents that would help define physiological roles for this peptide are still missing. Here we report the discovery of a potent and selective NPFF receptor antagonist, RF9, that can be administered systemically. This compound does not show any effects by itself but can block efficiently the increase in blood pressure and heart rate evoked by NPFF. When chronically coinjected with heroin, RF9 completely blocks the delayed and long-lasting paradoxical opioid-induced hyperalgesia and prevents the development of associated tolerance. Our data indicate that NPFF receptors are part of a bona fide antiopioid system and that selective antagonists of these receptors could represent useful therapeutic agents for improving the efficacy of opioids in chronic pain treatment.

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Figures

Fig. 1.

Fig. 1.

Screening of RFamide derivatives on hNPFF2R. (A) hNPFF2R membranes were labeled with [125I]Tyr-NPFF, and three concentrations of RFamide derivatives were tested in competition experiments. Each concentration was tested in duplicate. Results for the reference and the six most active compounds are shown. Arrowheads indicate compounds that were selected for further characterization. (B) Structures of RF2, RF9, RF48, RF49, and BIBP3226.

Fig. 2.

Fig. 2.

In vitro characterization of compounds selected from the screening. (A) Stimulation of [35S]GTPγS binding to hNPFF2R by NPFF (▪), RF2 (▴), RF48 (▾) and RF49 (♦). (B) Stimulation of [35S]GTPγS binding to hNPFF2R by NPFF alone (▪) or NPFF in presence of 7.5 μM RF9 (▴). RF9 shifted the concentration-effect curve of NPFF to the right by ≈160-fold. Data are expressed as percentage of basal [35S]GTPγS binding and represent mean ± SE from at least two separate experiments in triplicate. (C) RF9 (black bars) reversed the inhibition of forskolin-induced cAMP by NPVF in CHO-hNPFF1R cells. RF9 alone was inactive, whereas NPVF (white bar) inhibited ≈60% of the stimulated cAMP. Error bars represent the mean ± SEM of data from three experiments performed in duplicate.

Fig. 3.

Fig. 3.

RF9 blocks blood pressure effects of NPFF. (A) Changes in MAP [expressed in mmHg (1 mmHg = 133 Pa)] in rats receiving either i.c.v. saline (♦), NPFF (▪), RF9 (×), or NPFF and RF9 applied together (▴). Time 0 indicates the injection point for i.c.v. saline or drug applications. (B) Heart rate changes that accompany MAP alterations in A. Pooled MAP and heart rate data are from five animals. *, significant difference in MAP or heart rate compared with control (P < 0.05).

Fig. 4.

Fig. 4.

Coadministration of RF9 with heroin prevents heroin-induced delayed hyperalgesia and tolerance. (A) Delayed effects of 14 once-daily coadministrations of saline or RF9 (0.1 mg/kg, s.c.) 30 min before 0.3 mg/kg heroin or saline on basal nociceptive threshold in rats (n = 8 rats per group). The basal nociceptive threshold was determined once daily 60 min before each heroin or saline administration and after the heroin treatment was stopped. When rats in the saline/heroin group had recovered their predrug nociceptive threshold (D28), changes in nociceptive threshold induced by 0.3 mg/kg heroin in the saline/heroin and RF9/heroin groups were estimated for several days. Mean paw-pressure values for triggering vocalization (±SEM) are expressed in grams. #, P < 0.05 with a Newman-Keuls test when the RF9/heroin and saline/heroin groups were compared. (B) Analgesic effect induced by 0.3 mg/kg heroin (or saline) in the saline/saline (○), RF9/saline (•), saline/heroin (⋄), and RF9/heroin (♦) groups on D1,D14, and D28 (n = 8 rats per group). The nociceptive threshold of animals was measured 30 min after heroin injection and then every 30 min until the end of the pharmacological effect. (Inset) Comparison of AUC. Mean paw-pressure values for triggering vocalization (±SEM) are expressed in grams. *, P < 0.05 with Dunnett's test as compared with basal nociceptive value; #, P < 0.05 with a Newman-Keuls test comparing the RF9/heroin group with the saline/heroin group.

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