Dysfunctional GPR40/FFAR1 signaling exacerbates pain behavior in mice

Abstract

We previously showed that activation of G protein-coupled receptor 40/free fatty acid receptor 1 (GPR40/FFAR1) signaling modulates descending inhibition of pain. In this study, we investigated the involvement of fatty acid-GPR40/FFAR1 signaling in the transition from acute to chronic pain. We used GPR40/FFAR1-knockout (GPR40KO) mice and wild-type (WT) mice. A plantar incision was performed, and mechanical allodynia and thermal hyperalgesia were evaluated with a von Frey filament test and plantar test, respectively. Immunohistochemistry was used to localize GPR40/FFAR1, and the levels of free fatty acids in the hypothalamus were analyzed with liquid chromatography-tandem mass spectrometry. The repeated administration of GW1100, a GPR40/FFAR1 antagonist, exacerbated the incision-induced mechanical allodynia and significantly increased the levels of phosphorylated extracellular signal-regulated kinase in the spinal cord after low-threshold touch stimulation in the mice compared to vehicle-treated mice. The levels of long-chain free fatty acids, such as docosahexaenoic acid, oleic acid, and palmitate, which are GPR40/FFAR1 agonists, were significantly increased in the hypothalamus two days after the surgery compared to levels in the sham group. Furthermore, the incision-induced mechanical allodynia was exacerbated in the GPR40KO mice compared to the WT mice, while the response in the plantar test was not changed. These findings suggested that dysfunction of the GPR40/FFAR1 signaling pathway altered the endogenous pain control system and that this dysfunction might be associated with the development of chronic pain.

Palmitic Acid Reduces the Autophagic Flux and Insulin Sensitivity Through the Activation of the Free Fatty Acid Receptor 1 (FFAR1) in the Hypothalamic Neuronal Cell Line N43/5

“…Dragano et al also confirmed FFAR1 is expressed in hypothalamic neurons (both in neuropeptide Y (NPY) and POMC neurons) and acts to maintain whole body energy homeostasis by decreasing energy efficiency and reducing hypothalamic inflammation when FFAR1 is chemically activated by receptor specific agonists (38). Additional studies demonstrate that polyunsaturated fatty acids (PUFAs)-mediate FFAR1 activation in the hypothalamus to produce an anti-inflammatory and neuroprotective effect (37, 49–52). This apparent discrepancy in the effects of FFAR1 is most likely attributable to a ligand-dependent activation of distinct allosteric sites on the receptor by the different molecular structures (53).…”

Nonesterified Fatty Acids and Depression in Cancer Patients and Caregivers

“…GPR40 activation by the synthetic agonist GW9508 ( 36 ) has been associated with synaptic plasticity ( 37 ), a reduction in depressive behavior ( 38 ), and a reduction in pain symptoms and inflammation in mice ( 39 ). Moreover, knock-down experiments demonstrate mice lacking GPR40 protein receptors had higher pain and inflammation ( 40 , 41 ), and mice injected with inflammatory agents increased GPR40 expression compared with a control group ( 39 ). The underlying mechanisms are not well elucidated, but they may involve an upregulation of β-endorphins or regulation of cytokines ( 39 ).…”

Walking the Tightrope: A Proposed Model of Chronic Pain and Stress

“…The same group of researchers also found that repeating the administration of naloxone exacerbated mechanical allodynia due to postoperative pain. This suggests that the underlying mechanism for pain exacerbation induced by inhibition of the G protein-coupled receptor 40/free fatty acid receptor 1 may be associated with naloxone-induced exacerbation of postoperative pain (Nakamoto et al, 2017). Using a chronic pain mouse model, Wang et al (2017) investigated individual variance in two dimensions of pain behaviors: sensory and emotional.…”