PT  - JOURNAL ARTICLE
AU  - Jelveh Lameh
AU  - Fabio Bertozzi
AU  - Nicholas Kelly
AU  - Paula M. Jacobi
AU  - Derek Nguyen
AU  - Abhishek Bajpai
AU  - Gilles Gaubert
AU  - Roger Olsson
AU  - Luis R. Gardell
TI  - Neuropeptide FF Receptors Have Opposing Modulatory Effects on Nociception
AID  - 10.1124/jpet.109.164384
DP  - 2010 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 244--254
VI  - 334
IP  - 1
4099  - http://jpet.aspetjournals.org/content/334/1/244.short
4100  - http://jpet.aspetjournals.org/content/334/1/244.full
SO  - J Pharmacol Exp Ther2010 Jul 01; 334
AB  - The role of neuropeptide FF (NPFF) and its analogs in pain modulation is ambiguous. Although NPFF was first characterized as an antiopioid peptide, both antinociceptive and pronociceptive effects have been reported, depending on the route of administration. Currently, two NPFF receptors, termed FF1 and FF2, have been identified and cloned, but their roles in pain modulation remain elusive because of the lack of availability of selective compounds suitable for systemic administration in in vivo models. Ligand-binding studies confirm ubiquitous expression of both subtypes in brain, whereas only FF2 receptors are expressed spinally. This disparity in localization has served as the foundation of the hypothesis that FF1 receptors mediate the pronociceptive actions of NPFF. We have identified novel small molecule NPFF receptor agonists and antagonists with varying degrees of FF2/FF1 functional selectivity. Using these pharmacological tools in vivo has allowed us to define the roles of NPFF receptor subtypes as pertains to the modulation of nociception. We demonstrate that selective FF2 agonism does not modulate acute pain but instead ameliorates inflammatory and neuropathic pains. Treatment with a nonselective FF1/FF2 agonist potentiates allodynia in neuropathic rats and increases sensitivity to noxious thermal and to non-noxious mechanical stimuli in normal rats in an FF1 antagonist-reversible manner. Treatment with FF1 antagonists reversed established mechanical allodynia, indicating the possibility of increased NPFF tone through FF1 receptors. In conclusion, we provide evidence for the opposing roles of NPFF receptors and highlight selective FF2 agonism and/or selective FF1 antagonism as potential targets warranting further investigation. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics