The activation of supraspinal GPR40/FFA1 receptor signalling regulates the descending pain control system.

Abstract

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: K Nakamoto, T Nishinaka, N Sato, F Aizawa, T Yamashita, M Mankura, Y Koyama, F Kasuya, S Tokuyama
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 172 Issue 5 Pg. 1250-62 (Mar 2015) ISSN: 1476-5381 [Electronic] England
• PMID: 25362997 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The British Pharmacological Society.

Chemical References

• Ffar1 protein, mouse
• GW9508
• Methylamines
• Propionates
• Receptors, G-Protein-Coupled
• Formaldehyde
• Fenclonine

Topics

• Animals
• Fenclonine (pharmacology)
• Formaldehyde (antagonists & inhibitors)
• Male
• Methylamines (antagonists & inhibitors, pharmacology)
• Mice
• Mice, Inbred Strains
• Pain (chemically induced, drug therapy)
• Pain Measurement
• Propionates (antagonists & inhibitors, pharmacology)
• Receptors, G-Protein-Coupled (agonists, metabolism)
• Signal Transduction (drug effects)