Neuropeptide FF receptors have opposing modulatory effects on nociception
Lameh, Jelveh ; Bertozzi, Fabio ; Kelly, Nicholas ; Jacobi, Paula M. ; Nguyen, Derek ; Bajpai, Abhishek ; Gaubert, Gilles ; Olsson, Roger LU
and Gardell, Luis R.
(2010)
In Journal of Pharmacology and Experimental Therapeutics
334(1).
p.244-254
- Abstract
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... (More)
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.
(Less)
- author
- Lameh, Jelveh
; Bertozzi, Fabio
; Kelly, Nicholas
; Jacobi, Paula M.
; Nguyen, Derek
; Bajpai, Abhishek
; Gaubert, Gilles
; Olsson, Roger
LU
and Gardell, Luis R.
- publishing date
- 2010-07-01
- type
- Contribution to journal
- publication status
- published
- in
- Journal of Pharmacology and Experimental Therapeutics
- volume
- 334
- issue
- 1
- pages
- 11 pages
- publisher
- American Society for Pharmacology and Experimental Therapeutics
- external identifiers
-
- pmid:20354177
- scopus:77953791637
- ISSN
- 0022-3565
- DOI
- 10.1124/jpet.109.164384
- language
- English
- LU publication?
- no
- id
- f4d3e3c8-c3ce-4d39-be56-9f8544a95bb5
- date added to LUP
- 2019-10-02 10:13:29
- date last changed
- 2024-03-04 03:21:12
@article{f4d3e3c8-c3ce-4d39-be56-9f8544a95bb5,
abstract = {{<p>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.</p>}},
author = {{Lameh, Jelveh and Bertozzi, Fabio and Kelly, Nicholas and Jacobi, Paula M. and Nguyen, Derek and Bajpai, Abhishek and Gaubert, Gilles and Olsson, Roger and Gardell, Luis R.}},
issn = {{0022-3565}},
language = {{eng}},
month = {{07}},
number = {{1}},
pages = {{244--254}},
publisher = {{American Society for Pharmacology and Experimental Therapeutics}},
series = {{Journal of Pharmacology and Experimental Therapeutics}},
title = {{Neuropeptide FF receptors have opposing modulatory effects on nociception}},
url = {{http://dx.doi.org/10.1124/jpet.109.164384}},
doi = {{10.1124/jpet.109.164384}},
volume = {{334}},
year = {{2010}},
}