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Proc Natl Acad Sci U S A. 2006 Jan 10;103(2):466-71. Epub 2006 Jan 3.

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

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Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Universite Louis Pasteur, 67404 Illkirch Cedex, France.

Erratum in

  • Proc Natl Acad Sci U S A. 2006 Oct 24;103(43):16058.


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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