Involvement of neuropeptide FF receptors in neuroadaptive responses to acute and chronic opiate treatments

Br J Pharmacol. 2012 Jan;165(2):424-35. doi: 10.1111/j.1476-5381.2011.01563.x.


BACKGROUND AND PURPOSE Opiates remain the most effective compounds for alleviating severe pain across a wide range of conditions. However, their use is associated with significant side effects. Neuropeptide FF (NPFF) receptors have been implicated in several opiate-induced neuroadaptive changes including the development of tolerance. In this study, we investigated the consequences of NPFF receptor blockade on acute and chronic stimulation of opioid receptors in mice by using RF9, a potent and selective antagonist of NPFF receptors that can be administered systemically. EXPERIMENTAL APPROACH The effects of RF9 were investigated on opioid pharmacological responses including locomotor activity, antinociception, opioid-induced hyperalgesia, rewarding properties and physical dependence. KEY RESULTS RF9 had no effect on morphine-induced horizontal hyperlocomotion and slightly attenuated the decrease induced in vertical activity. Furthermore, RF9 dose-dependently blocked the long-lasting hyperalgesia produced by either acute fentanyl or chronic morphine administration. RF9 also potentiated opiate early analgesic effects and prevented the development of morphine tolerance. Finally, RF9 increased morphine-induced conditioned place preference without producing any rewarding effect by itself and decreased naltrexone-precipitated withdrawal syndrome following chronic morphine treatment. CONCLUSION AND IMPLICATIONS The NPFF system is involved in the development of two major undesirable effects: tolerance and dependence, which are clinically associated with prolonged exposure to opiates. Our findings suggest that NPFF receptors are interesting therapeutic targets to improve the analgesic efficacy of opiates by limiting the development of tolerance, and for the treatment of opioid dependence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adamantane / analogs & derivatives*
  • Adamantane / pharmacology
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Behavior, Animal / drug effects
  • Conditioning, Classical
  • Dipeptides / pharmacology*
  • Drug Tolerance / physiology*
  • Fentanyl / pharmacology
  • Hot Temperature
  • Hyperalgesia / chemically induced
  • Hyperalgesia / drug therapy
  • Hyperalgesia / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Morphine / pharmacology
  • Motor Activity / drug effects
  • Naltrexone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Opioid-Related Disorders / drug therapy
  • Opioid-Related Disorders / physiopathology*
  • Pain / drug therapy
  • Pain / physiopathology
  • Receptors, Neuropeptide / antagonists & inhibitors*
  • Receptors, Neuropeptide / physiology
  • Substance Withdrawal Syndrome / drug therapy
  • Substance Withdrawal Syndrome / physiopathology


  • Analgesics, Opioid
  • Dipeptides
  • Narcotic Antagonists
  • Receptors, Neuropeptide
  • adamantylcarbonyl-arginyl-phenylalaninamide
  • neuropeptide FF receptor
  • Naltrexone
  • Morphine
  • Adamantane
  • Fentanyl