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The activation of supraspinal GPR 40/ FFA 1 receptor signalling regulates the descending pain control system
Author(s) -
Nakamoto K,
Nishinaka T,
Sato N,
Aizawa F,
Yamashita T,
Mankura M,
Koyama Y,
Kasuya F,
Tokuyama S
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13003
Subject(s) - serotonergic , receptor , tyrosine hydroxylase , chemistry , pharmacology , neuron , docosahexaenoic acid , endocrinology , agonist , medicine , dopamine , serotonin , fatty acid , biology , polyunsaturated fatty acid , biochemistry , neuroscience
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 GPR 40, now identified as the free fatty acid receptor 1 ( FFA 1 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‐ F os 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 N eu N (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 GW 9508, a FFA1 receptor agonist, increased the number of c‐ F os‐positive cells and the number of neurons double‐labelled for c‐ F os 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 WAY 100635. Furthermore, GW 9508 facilitated the release of noradrenaline and 5‐HT in the spinal cord. In addition, GW 1100, 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.