RF9, a potent and selective neuropeptide FF receptor antagonist, prevents opioid-induced tolerance associated with hyperalgesia.
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.
Simonin
Frédéric
F
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. simonin@esbs.u-strasbg.fr
Schmitt
Martine
M
Laulin
Jean-Paul
JP
Laboureyras
Emilie
E
Jhamandas
Jack H
JH
MacTavish
David
D
Matifas
Audrey
A
Mollereau
Catherine
C
Laurent
Patrick
P
Parmentier
Marc
M
Kieffer
Brigitte L
BL
Bourguignon
Jean-Jacques
JJ
Simonnet
Guy
G
D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000577:Amides / Q000737:chemistry; D000701:Analgesics, Opioid / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D019556:COS Cells; D002522:Chlorocebus aethiops; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology*; D004361:Drug Tolerance; D006339:Heart Rate / Q000187:drug effects; D003932:Heroin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D008024:Ligands; D015394:Molecular Structure; D051381:Rats; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000577:Amides; D000701:Analgesics, Opioid; D004151:Dipeptides; D008024:Ligands; D018013:Receptors, Neuropeptide; C508361:adamantylcarbonyl-arginyl-phenylalaninamide; C083929:neuropeptide FF receptor; D003932:Heroin; D000218:Adamantane