G-protein receptor (GPR) 40 is known to be activated by
docosahexaenoic acid (DHA). However, reports studying the role and functions (including
pain regulation) of GPR40 in the brain are lacking. We investigated the involvement of GPR40 in the brain on DHA-induced antinociceptive effects. Expression of GPR40
protein was observed in the olfactory bulb, striatum, hippocampus, midbrain, hypothalamus, medulla oblongata, cerebellum and cerebral cortex in the brain as well as the spinal cord, whereas GPR120
protein expression in these areas was not observed. Intracerebroventricular (i.c.v.), but not intrathecal (i.t.) injection of DHA (25 and 50μg/mouse) and
GW9508 (a GPR40- and GPR120-selective agonist; 0.1 and 1.0μg/mouse) significantly reduced
formalin-induced
pain behavior. These effects were inhibited by pretreatment with the μ
opioid receptor antagonist β-funaltrexamine (β-FNA),
naltrindole (δ
opioid receptor antagonist) and anti-β-
endorphin antiserum. The κ
opioid receptor antagonist norbinaltorphimine (
nor-BNI) did not affect the antinociception of DHA or
GW9508. Furthermore, the immunoreactivity of β-
endorphin in the hypothalamus increased
at 10 and 20min after i.c.v. injection of DHA and
GW9508. These findings suggest that DHA-induced antinociception via β-
endorphin release may be mediated (at least in part) through GPR40 signaling in the supraspinal area, and may provide valuable information on a novel therapeutic approach for
pain control.