BACKGROUND AND PURPOSE: The ω-3 polyunsaturated fatty acids exert antinociceptive effects in inflammatory and neuropathic pain; however, the underlying mechanisms remain unclear. Docosahexaenoic acid-induced antinociception may be mediated by the orphan GPR40, now identified as the free fatty acid receptor 1 (FFA1 receptor). Here, we examined the involvement of supraspinal FFA1 receptor signalling in the regulation of inhibitory pain control systems consisting of serotonergic and noradrenergic neurons. EXPERIMENTAL APPROACH: Formalin-induced pain behaviours were measured in mice. Antinociception induced by FFA1 receptor agonists was examined by intrathecal injections of a catecholaminergic toxin, 5-HT lowering drug or these antagonists. The expression of FFA1 receptor protein and c-Fos was estimated by immunohistochemistry, and the levels of noradrenaline and 5-HT in the spinal cord were measured by LC-MS/MS. KEY RESULTS: FFA1 receptors colocalized with NeuN (a neuron marker) in the medulla oblongata and with tryptophan hydroxylase (TPH; a serotonergic neuron marker) and dopamine β-hydroxylase (DBH; a noradrenergic neuron marker). A single i.c.v. injection of GW9508, a FFA1 receptor agonist, increased the number of c-Fos-positive cells and the number of neurons double-labelled for c-Fos and TPH and/or DBH. It decreased formalin-induced pain behaviour. This effect was inhibited by pretreatment with 6-hydroxydopamine, DL-p-chlorophenylalanine, yohimbine or WAY100635. Furthermore, GW9508 facilitated the release of noradrenaline and 5-HT in the spinal cord. In addition, GW1100, a FFA1 receptor antagonist, significantly increased formalin-induced pain-related behaviour. CONCLUSION AND IMPLICATIONS: Activation of the FFA1 receptor signalling pathway may play an important role in the regulation of the descending pain control system.
BACKGROUND AND PURPOSE: The ω-3 polyunsaturated fatty acids exert antinociceptive effects in inflammatory and neuropathic pain; however, the underlying mechanisms remain unclear. Docosahexaenoic acid-induced antinociception may be mediated by the orphan GPR40, now identified as the free fatty acid receptor 1 (FFA1 receptor). Here, we examined the involvement of supraspinal FFA1 receptor signalling in the regulation of inhibitory pain control systems consisting of serotonergic and noradrenergic neurons. EXPERIMENTAL APPROACH: Formalin-induced pain behaviours were measured in mice. Antinociception induced by FFA1 receptor agonists was examined by intrathecal injections of a catecholaminergic toxin, 5-HT lowering drug or these antagonists. The expression of FFA1 receptor protein and c-Fos was estimated by immunohistochemistry, and the levels of noradrenaline and 5-HT in the spinal cord were measured by LC-MS/MS. KEY RESULTS: FFA1 receptors colocalized with NeuN (a neuron marker) in the medulla oblongata and with tryptophan hydroxylase (TPH; a serotonergic neuron marker) and dopamine β-hydroxylase (DBH; a noradrenergic neuron marker). A single i.c.v. injection of GW9508, a FFA1 receptor agonist, increased the number of c-Fos-positive cells and the number of neurons double-labelled for c-Fos and TPH and/or DBH. It decreased formalin-induced pain behaviour. This effect was inhibited by pretreatment with 6-hydroxydopamine, DL-p-chlorophenylalanine, yohimbine or WAY100635. Furthermore, GW9508 facilitated the release of noradrenaline and 5-HT in the spinal cord. In addition, GW1100, a FFA1 receptor antagonist, significantly increased formalin-induced pain-related behaviour. CONCLUSION AND IMPLICATIONS: Activation of the FFA1 receptor signalling pathway may play an important role in the regulation of the descending pain control system.
Authors: Marta Zamarbide; Iñigo Etayo-Labiano; Ana Ricobaraza; Eva Martínez-Pinilla; María S Aymerich; José Luis Lanciego; Alberto Pérez-Mediavilla; Rafael Franco Journal: Hippocampus Date: 2014-02-27 Impact factor: 3.899
Authors: Celia P Briscoe; Mohammad Tadayyon; John L Andrews; William G Benson; Jon K Chambers; Michelle M Eilert; Catherine Ellis; Nabil A Elshourbagy; Aaron S Goetz; Dana T Minnick; Paul R Murdock; Howard R Sauls; Usman Shabon; Lisa D Spinage; Jay C Strum; Philip G Szekeres; Kong B Tan; James M Way; Diane M Ignar; Shelagh Wilson; Alison I Muir Journal: J Biol Chem Date: 2002-12-19 Impact factor: 5.157
Authors: Adam J Pawson; Joanna L Sharman; Helen E Benson; Elena Faccenda; Stephen P H Alexander; O Peter Buneman; Anthony P Davenport; John C McGrath; John A Peters; Christopher Southan; Michael Spedding; Wenyuan Yu; Anthony J Harmar Journal: Nucleic Acids Res Date: 2013-11-14 Impact factor: 16.971
Authors: Stephen P H Alexander; Helen E Benson; Elena Faccenda; Adam J Pawson; Joanna L Sharman; John C McGrath; William A Catterall; Michael Spedding; John A Peters; Anthony J Harmar; N Abul-Hasn; C M Anderson; C M H Anderson; M S Araiksinen; M Arita; E Arthofer; E L Barker; C Barratt; N M Barnes; R Bathgate; P M Beart; D Belelli; A J Bennett; N J M Birdsall; D Boison; T I Bonner; L Brailsford; S Bröer; P Brown; G Calo; W G Carter; W A Catterall; S L F Chan; M V Chao; N Chiang; A Christopoulos; J J Chun; J Cidlowski; D E Clapham; S Cockcroft; M A Connor; H M Cox; A Cuthbert; F M Dautzenberg; A P Davenport; P A Dawson; G Dent; J P Dijksterhuis; C T Dollery; A C Dolphin; M Donowitz; M L Dubocovich; L Eiden; K Eidne; B A Evans; D Fabbro; C Fahlke; R Farndale; G A Fitzgerald; T M Fong; C J Fowler; J R Fry; C D Funk; A H Futerman; V Ganapathy; B Gaisnier; M A Gershengorn; A Goldin; I D Goldman; A L Gundlach; B Hagenbuch; T G Hales; J R Hammond; M Hamon; J C Hancox; R L Hauger; D L Hay; A J Hobbs; M D Hollenberg; N D Holliday; D Hoyer; N A Hynes; K-I Inui; S Ishii; K A Jacobson; G E Jarvis; M F Jarvis; R Jensen; C E Jones; R L Jones; K Kaibuchi; Y Kanai; C Kennedy; I D Kerr; A A Khan; M J Klienz; J P Kukkonen; J Y Lapoint; R Leurs; E Lingueglia; J Lippiat; S J Lolait; S C R Lummis; J W Lynch; D MacEwan; J J Maguire; I L Marshall; J M May; C A McArdle; J C McGrath; M C Michel; N S Millar; L J Miller; V Mitolo; P N Monk; P K Moore; A J Moorhouse; B Mouillac; P M Murphy; R R Neubig; J Neumaier; B Niesler; A Obaidat; S Offermanns; E Ohlstein; M A Panaro; S Parsons; R G Pwrtwee; J Petersen; J-P Pin; D R Poyner; S Prigent; E R Prossnitz; N J Pyne; S Pyne; J G Quigley; R Ramachandran; E L Richelson; R E Roberts; R Roskoski; R A Ross; M Roth; G Rudnick; R M Ryan; S I Said; L Schild; G J Sanger; K Scholich; A Schousboe; G Schulte; S Schulz; C N Serhan; P M Sexton; D R Sibley; J M Siegel; G Singh; R Sitsapesan; T G Smart; D M Smith; T Soga; A Stahl; G Stewart; L A Stoddart; R J Summers; B Thorens; D T Thwaites; L Toll; J R Traynor; T B Usdin; R J Vandenberg; C Villalon; M Vore; S A Waldman; D T Ward; G B Willars; S J Wonnacott; E Wright; R D Ye; A Yonezawa; M Zimmermann Journal: Br J Pharmacol Date: 2013-12 Impact factor: 8.739