gw1100 and Chronic-Pain

Depression and anxiety can cause the development of chronic pain. However, the mechanism of chronic pain induced by emotional dysfunction is still unknown. Previously, we demonstrated that the G protein-coupled receptor 40/free fatty acid receptor 1 (GPR40/FFAR1) signaling in the brain is related to regulation of both pain and emotion. In the present study, we proved that the role of GPR40/FFAR1 signaling in the development of chronic pain is induced by emotional dysfunction.. Repeated social defeat (SD)-stressed mice showed the impairment of social interaction and anxiety behavior. These mice also caused pain prolongation after paw-incision comparison with non-SD mice. This pain prolongation was markedly continued by infusion of the GPR40/FFAR1 antagonist, GW1100 during SD stress but not non-SD stress. Although, infusion of the GW1100 during SD stress did not cause deterioration of the emotional behavior. Furthermore, GW1100-treated SD-mice showed strong tendency of emotional dysfunction after paw incision.. Our findings indicate that the dysfunction of fatty acids-GPR40/FFAR1 signaling in the brain underlying stress condition might be related to the development of chronic pain.

Topics: Animals; Benzoates; Brain; Chronic Pain; Fatty Acids, Nonesterified; Infusions, Intraventricular; Interpersonal Relations; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Pyrimidines; Receptors, G-Protein-Coupled; Signal Transduction; Stress, Psychological

GPR40 has been reported to be activated by long-chain fatty acids, such as docosahexaenoic acid (DHA). However, reports studying functional role of GPR40 in the brain are lacking. The present study focused on the relationship between pain regulation and GPR40, investigating the functional roles of hypothalamic GPR40 during chronic pain caused using a complete Freund's adjuvant (CFA)-induced inflammatory chronic pain mouse model. GPR40 protein expression in the hypothalamus was transiently increased at day 7, but not at days 1, 3 and 14, after CFA injection. GPR40 was co-localized with NeuN, a neuron marker, but not with glial fibrillary acidic protein (GFAP), an astrocyte marker. At day 1 after CFA injection, GFAP protein expression was markedly increased in the hypothalamus. These increases were significantly inhibited by the intracerebroventricular injection of flavopiridol (15 nmol), a cyclin-dependent kinase inhibitor, depending on the decreases in both the increment of GPR40 protein expression and the induction of mechanical allodynia and thermal hyperalgesia at day 7 after CFA injection. Furthermore, the level of DHA in the hypothalamus tissue was significantly increased in a flavopiridol reversible manner at day 1, but not at day 7, after CFA injection. The intracerebroventricular injection of DHA (50 µg) and GW9508 (1.0 µg), a GPR40-selective agonist, significantly reduced mechanical allodynia and thermal hyperalgesia at day 7, but not at day 1, after CFA injection. These effects were inhibited by intracerebroventricular pretreatment with GW1100 (10 µg), a GPR40 antagonist. The protein expression of GPR40 was colocalized with that of β-endorphin and proopiomelanocortin, and a single intracerebroventricular injection of GW9508 (1.0 µg) significantly increased the number of neurons double-stained for c-Fos and proopiomelanocortin in the arcuate nucleus of the hypothalamus. Our findings suggest that hypothalamic GPR40 activated by free long chain fatty acids might have an important role in this pain control system.

Topics: Animals; Arcuate Nucleus of Hypothalamus; Astrocytes; Benzoates; beta-Endorphin; Chronic Pain; Disease Models, Animal; DNA-Binding Proteins; Docosahexaenoic Acids; Flavonoids; Freund's Adjuvant; Gene Expression; Glial Fibrillary Acidic Protein; Hyperalgesia; Injections, Intraventricular; Male; Methylamines; Mice; Nerve Tissue Proteins; Neuroglia; Nuclear Proteins; Pain Management; Piperidines; Pro-Opiomelanocortin; Propionates; Pyrimidines; Receptors, G-Protein-Coupled; Signal Transduction; Time Factors