Abstract
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.
Highlights
Inflammatory chronic pain, such as arthritis pain, joint pain and inflammatory bowel disease, is a significant health problem, and is initiated by tissue damage or inflammation [1]
GPR40-positive cells were observed in the hypothalamus of the saline group, with GPR40 colocalized with NeuN-positive cells, but not with glial fibrillary acidic protein (GFAP) in the saline group (Fig. 3)
We use an inflammatory chronic pain mouse model to present the first evidence that hypothalamic GPR40 may contribute to the pain control system
Summary
Inflammatory chronic pain, such as arthritis pain, joint pain and inflammatory bowel disease, is a significant health problem, and is initiated by tissue damage or inflammation [1]. At present, such pain is generally treated with antidepressants, anticonvulsants and cyclooxygenase inhibitors, but negative side effects remain [2]. Endogenous n-3 series polyunsaturated fatty acids (PUFAs) or their derived lipid mediators have been found to have crucial roles in the local control and programming of acute inflammatory response and its resolution [3] Both basic and clinical studies have shown that a dietary intake of n-3 PUFAs results in a reduction of pain associated with rheumatoid and inflammatory joint pain [4,5], dysmenorrheal pain [6], fibromyalgia [7] and neuropathy [7]. There are several reports that resolvins D1 and E1, derived from docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), respectively, could effectively reduce inflammatory [8] and postoperative pain [9]
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