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

Abstract

BACKGROUND AND PURPOSEThe 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 APPROACHFormalin-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 RESULTSFFA1 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 IMPLICATIONSActivation of the FFA1 receptor signalling pathway may play an important role in the regulation of the descending pain control system. Abbreviations

Serotonergic System Does Not Contribute to the Hypothermic Action of Acetaminophen

“…17) The inhibitory effect of PCPA on AcAP-induced analgesia in the formalin test is also consistent with the results of an earlier study. 7) Consistent with previous reports, 30,31) the PCPA treatment protocol used in the present study markedly reduced the serotonin content of the central nervous system. The basal rectal temperature of the PCPAtreated mice was normal, suggesting that the lack of serotonin can be compensated by other thermoregulatory mechanisms.…”

“…31) Mouse brains were homogenized in the solu- tion containing 0.05% Triton-X and 10 mM ammonium formate (pH 4.0, 1 mL per 100 mg tissue). An equal volume of ice-cold chloroform-methanol (2 : 1, v/v) containing 6.6 µM 3,4-dihydroxybenzylamine hydrobromide (DHBA, Sigma, St. Louis, MO, U.S.A.) as internal standard was added to the homogenate and centrifuged at 1500×g for 30 min at 4°C.…”

Regulation of prohormone convertase 2 protein expression via GPR40/FFA1 in the hypothalamus

“…In our previous study, we demonstrated that pretreatment with GW1100 exacerbates formalin or CFA-induced pain behavior (Nakamoto et al, 2014). Furthermore, we showed that free fatty acid levels rise in the hypothalamus during inflammatory pain induced by CFA (Nakamoto et al, 2013), suggesting that free fatty acids may be continuously released during pain.…”

Astrocytes Release Polyunsaturated Fatty Acids by Lipopolysaccharide Stimuli

“…Therefore, our results indicate that astrocytes might be involved in control of brain FFAs composition respond to LPS stimulation. Based on our previous reports, 32,33) it is thought that these FFAs released from astrocytes might maintain a neuronal function as a ligand of GPR40/FFAR1, one of a FFAs receptors.…”