title: The activation of supraspinal GPR40/FFA1 receptor signalling regulates the descending pain control system.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  Activation of the FFA1 receptor signalling pathway may play an important role in the regulation of the descending pain control system.
authors.affiliation: Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nakamoto
authors.forename: T
authors.initials: T
authors.lastname: Nishinaka
authors.forename: N
authors.initials: N
authors.lastname: Sato
authors.forename: F
authors.initials: F
authors.lastname: Aizawa
authors.forename: T
authors.initials: T
authors.lastname: Yamashita
authors.forename: M
authors.initials: M
authors.lastname: Mankura
authors.forename: Y
authors.initials: Y
authors.lastname: Koyama
authors.forename: F
authors.initials: F
authors.lastname: Kasuya
authors.forename: S
authors.initials: S
authors.lastname: Tokuyama
mesh_terms: D000818:Animals; D010134:Fenclonine / Q000494:pharmacology; D005557:Formaldehyde / Q000037:antagonists & inhibitors; D008297:Male; D008744:Methylamines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010147:Pain Measurement; D011422:Propionates / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C473036:Ffar1 protein, mouse; C515630:GW9508; D008744:Methylamines; D011422:Propionates; D043562:Receptors, G-Protein-Coupled; D005557:Formaldehyde; D010134:Fenclonine