RESUMO
Central poststroke pain (CPSP) is a type of central neuropathic pain whose mechanisms remain unknown. Recently, we showed that activated astrocytes and microglial cells are present in the spinal cord of CPSP model mice. Activated glial cells exacerbate cerebral ischemic pathology by increasing the expression of inflammatory factors. However, the involvement of spinal glial cells in CPSP remains unknown. We hypothesized that spinal glial cell-derived molecules cause hyperexcitability or promoted the development of CPSP. In this study, we identified glial cell-derived factors involved in the development of CPSP using a bilateral common carotid occlusion (BCAO)-induced CPSP mouse model. Male ddY mice were subjected to BCAO for 30 min. The von Frey test assessed mechanical hypersensitivity in the right hind paw of mice. BCAO mice showed hypersensitivity to mechanical stimuli and astrocyte activation in the spinal cord 3 days after treatment. DNA microarray analysis revealed a significant increase in lipocalin 2 (LCN2), is known as neutrophil gelatinase-associated lipocalin, in the superficial dorsal horns of BCAO-induced CPSP model mice. LCN2 colocalized with GFAP, an astrocyte marker. Spinal GFAP-positive cells in BCAO mice co-expressed signal transducer and activator of transcription 3 (STAT3). The increase in the fluorescence intensity of LCN2 and GFAP in BCAO mice was suppressed by intrathecal injection of AG490, an inhibitor of JAK2 and downstream STAT3 activation, or anti-LCN2 antibody. Our findings indicated that LCN2 in spinal astrocytes may be a key molecule and may be partly involved in the development of CPSP.
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Astrócitos , Modelos Animais de Doenças , Lipocalina-2 , Medula Espinal , Acidente Vascular Cerebral , Animais , Masculino , Lipocalina-2/metabolismo , Camundongos , Medula Espinal/metabolismo , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/complicações , Astrócitos/metabolismo , Fator de Transcrição STAT3/metabolismo , Neuralgia/metabolismo , Neuralgia/etiologia , Janus Quinase 2/metabolismo , Tirfostinas/farmacologia , Proteína Glial Fibrilar Ácida/metabolismoRESUMO
Chronic pain occurs at epidemic levels throughout the population. Hypersensitivity to touch, is a cardinal symptom of chronic pain. Despite dedicated research for over a century, quantifying this hypersensitivity has remained impossible at scale. To address these issues, we developed the Chainmail Sensitivity Test (CST). Our results show that control mice spend significantly more time on the chainmail portion of the device than mice subject to neuropathy. Treatment with gabapentin abolishes this difference. CST-derived data correlate well with von Frey measurements and quantify hypersensitivity due to inflammation. Our study demonstrates the potential of the CST as a standardized tool for assessing mechanical hypersensitivity in mice with minimal operator input.
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Psychosocial stress is a risk factor for psychiatric disorders, including depression and anxiety, and chronic pain, whereas chronic pain is also closely related to the development of psychiatric disorders. However, the pathological mechanisms of stress-triggered psychiatric disorders and chronic pain are unknown, and their effective treatments have not been established. Recently, the advances in analytical techniques for fatty acids and their metabolites have made it possible to comprehensively measure changes in fatty acid composition in various cells and organs using the lipidomics approach, and to visualize the localization of phospholipids, fatty acids, and other lipid mediators using imaging mass spectrometry. Many researchers have focused on understanding the differences in the distribution of phospholipids, fatty acids, their lipid metabolites in cells and organs, and the changes of fatty acid composition in various diseases. More recently, changes in the fatty acid composition and its distribution during chronic pain and stress have also been reported. We also proposed that modulation of brain fatty acid signaling could be a new therapeutic target for stress-induced chronic pain. In this review, we summarize the latest basic and clinical findings on the role of fatty acid signaling in stress-induced psychiatric disorders and chronic pain.
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Dor Crônica , Humanos , Dor Crônica/etiologia , Ácidos Graxos/metabolismo , Ácidos Graxos/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Encéfalo/metabolismoRESUMO
Early life stress, such as child abuse and neglect, and psychosocial stress in adulthood are risk factors for psychiatric disorders, including depression and anxiety. Furthermore, exposure to these stresses affects the sensitivity to pain stimuli and is associated with the development of chronic pain. However, the mechanisms underlying the pathogenesis of stress-induced depression, anxiety, and pain control remain unclear. Endogenous opioid signaling is reportedly associated with analgesia, reward, addiction, and the regulation of stress responses and anxiety. Stress alters the expression of various opioid receptors in the central nervous system and sensitivity to opioid receptor agonists and antagonists. µ-opioid receptor-deficient mice exhibit attachment disorders and autism-like behavioral expression patterns, while those with δ-opioid receptor deficiency exhibit anxiety-like behavior. In contrast, deficiency and antagonists of the κ-opioid receptor suppress the stress response. These findings strongly suggest that the expression and dysfunction of the endogenous opioid signaling pathways are involved in the pathogenesis of stress-induced psychiatric disorders and chronic pain. In this review, we summarize the latest basic and clinical research studies on the effects of endogenous opioid signaling on early-life stress, psychosocial stress-induced psychiatric disorders, and chronic pain.
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Dor Crônica , Regulação Emocional , Camundongos , Animais , Analgésicos Opioides/efeitos adversos , Dor Crônica/etiologia , Receptores Opioides/metabolismo , Peptídeos Opioides/fisiologia , Receptores Opioides mu/agonistas , Antagonistas de Entorpecentes/farmacologiaRESUMO
Central post-stroke pain (CPSP) is a type of central neuropathic pain, whose underlying mechanisms remain unknown. We previously reported that bilateral carotid artery occlusion (BCAO)-induced CPSP model mice showed mechanical hypersensitivity and decreased mRNA levels of preproorexin, an orexin precursor, in the hypothalamus. Recently, nicotine was shown to regulate the neuronal activity of orexin in the lateral hypothalamus (LH) and suppress inflammatory and neuropathic pain. In this study, we evaluated whether nicotine could suppress BCAO-induced mechanical allodynia through the activation of orexinergic neurons. Mice were subjected to BCAO for 30 min. Mechanical hypersensitivity was assessed by the von Frey test. BCAO mice showed hypersensitivity to mechanical stimuli three days after BCAO surgery. The intracerebroventricular injection of nicotine suppressed BCAO-induced mechanical hypersensitivity in a dose-dependent manner. These effects were inhibited by α7 or α4ß2-nicotinic receptor antagonists. After nicotine injection, the level of c-fos, a neuronal activity marker, increased in the LH and locus coeruleus (LC) of Sham and BCAO mice. Increased number of c-Fos-positive cells partly colocalized with orexin A-positive cells in the LH, as well as tyrosine hydroxylase-positive cells in the LC. Orexinergic neurons project to the LC area. Nicotine-induced antinociception tended to cancel by the pretreatment of SB334867, an orexin receptor1 antagonist into the LC. Intra-LH microinjection of nicotine attenuated BCAO-induced mechanical hypersensitivity. Nicotine-induced antinociception was inhibited by intrathecal pre-treatment with yohimbine, an α2 adrenergic receptor antagonist. These results indicated that nicotine may suppress BCAO-induced mechanical hypersensitivity through the activation of the descending pain control system via orexin neurons.
Assuntos
Neurônios Adrenérgicos , Neuralgia , Camundongos , Animais , Orexinas/farmacologia , Nicotina/farmacologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Receptores de OrexinaRESUMO
INTRODUCTION: Our previous study demonstrated that docosahexaenoic acid (DHA), an endogenous G protein-coupled receptor 120 (GPR120)/free fatty acid receptor (FFAR) 4 agonist, attenuated the liver inflammation in nonalcoholic steatohepatitis (NASH), while exacerbated liver inflammation was observed in the GPR120/FFAR4 knockout (GPR120/FFAR4KO) mice. Recently, abdominal adiposity has been reported to correlate with the severity of inflammation and fibrosis in patients with NASH. In this study, we investigated whether the activation of GPR120/FFAR4 suppressed the inflammation of the adipose tissue and whether these suppressive effects attenuated the development of NASH. METHODS: A choline-deficient and 0.1% methionine-containing high-fat (CDAHF) diet was used to create a mouse model of NASH. DHA was orally administered to the mice for 1 week. Epididymal fat pads which collected from the control-fed wild-type (WT) or GPR120/FFAR4KO mice were used as ex vivo white adipose tissue (WAT) culture systems. RESULTS: The mice fed a CDAHF diet for 2 weeks showed NASH-like liver diseases. In the WAT of mice fed with the CDAHF diet, inflammation and fibrosis were significantly increased, and the administration of DHA suppressed these phenomena. In an ex vivo adipocyte culture study, DHA dose-dependently suppressed the lipopolysaccharide-induced inflammation in the adipocyte tissue of WT mice, which was reversed by pretreatment with AH7614, a GPR120/FFAR4 antagonist, but not GPR40 or peroxisome proliferator-activated receptor γ antagonist. CONCLUSIONS: These findings suggest that the activation of GPR120/FFAR4 may suppress the inflammation of adipocytes, which could be a key pathway to prevent the development of NASH.
Assuntos
Ácidos Docosa-Hexaenoicos , Hepatopatia Gordurosa não Alcoólica , Adipócitos/metabolismo , Animais , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácidos Graxos não Esterificados/metabolismo , Ácidos Graxos não Esterificados/farmacologia , Fibrose , Humanos , Inflamação/metabolismo , Fígado , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismoRESUMO
AIMS: Fatty acid-binding protein (FABP) regulates polyunsaturated fatty acid (PUFA) intracellular trafficking and signal transduction. Our previous studies demonstrated that the alteration of PUFA in the hypothalamus is involved in pain process. However, how FABP subtypes change during pain remain unclear. Here, we examined the expression changes and localization in the hypothalamic FABP subtype in postoperative pain model mice. METHODS: Paw incision-induced postoperative methods were adopted as a pain model in male ddY mice. Mechanical allodynia was examined using the von Frey test. The analysis of several FABPs mRNA was measured by real-time PCR, and cellular localization of its protein level was measured by immunofluorescent study. RESULTS: Postoperative pain mouse elicited mechanical allodynia on Day 2 after paw incision, and mRNA expression of FABP3 increased significantly in the hypothalamus in the postoperative pain mouse model compared to that in control mice. FABP3 protein expressed in the median eminence and the arcuate nucleus, and colocalized with Iba-1, which is a microglial cell marker. Its protein level significantly increased in the median eminence on Day 2 after incision and returned to the control level on Day 4 after incision. CONCLUSIONS: Our findings indicate that FABP3 in the median eminence may change in pain stimuli and may represent a molecular link controlling pain.
Assuntos
Proteínas de Ligação a Ácido Graxo , Eminência Mediana , Animais , Modelos Animais de Doenças , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Hiperalgesia/genética , Hiperalgesia/metabolismo , Masculino , Eminência Mediana/metabolismo , Camundongos , Dor/genéticaRESUMO
The free fatty acid receptor 1 (FFAR1) is suggested to function as a G protein-coupled receptor (GPR40) for medium-to-long-chain free fatty acids. Previous studies on the expression of FFAR1 revealed that the nigrostriatal region is one of the areas which express abundant FFAR1 mRNA/protein in the central nervous system (CNS). However, the role of FFAR1 in the CNS has been still largely unclarified. Here, we examined a possible functional role of FFAR1 in the control of extracellular concentrations of striatal monoamines and cocaine-induced locomotor activity. Microdialysis analysis revealed that the basal level of extracellular dopamine (DA) was significantly elevated, while the basal serotonin (5-HT) level tended to be reduced in the striatum of FFAR1 knockout (-/-) mice. Interestingly, local application of a FFAR1 agonist, GW9508, markedly augmented the striatal 5-HT release in FFAR1 wild-type (+/+) mice, whereas topical application of a FFAR1 antagonist, GW1100, significantly reduced the 5-HT release. However, the enhanced 5-HT release was completely lost in -/- mice. Although acute administration of cocaine enhanced the locomotor activity in both +/+ and -/- mice, the magnitude of the enhancement was significantly reduced in -/- mice. In addition, intraperitoneal injection of GW1100 significantly decreased the cocaine-induced locomotor enhancement. These results suggest that FFAR1 has a facilitatory role in striatal 5-HT release, and the evoked 5-HT release might contribute to enhance cocaine-induced locomotor activity.
RESUMO
Recent studies have shown that the endogenous opioid system is considerably affected by early life stress such as child abuse. Here, we investigated whether early life stress changes the endogenous opioid receptors and their peptides, and if such stress impacts morphine antinociception. We used mice affected by maternal separation and social isolation (MSSI) as an early life stress model. In the tail-flick test, 10-week-old MSSI mice showed a significant decrease in morphine antinociception compared to age-matched control mice. The number of c-Fos-positive cells increased in the periaqueductal gray (PAG), nucleus accumbens, and thalamus of control mice after the morphine injections, whereas hardly any positive cells were detected in the same areas of MSSI mice. The expression of µ- and κ-opioid receptor (MOR and KOR, respectively) messenger RNA (mRNA) was significantly decreased in the PAG of MSSI mice, whereas KOR expression was significantly increased in the amygdala of MSSI mice. The expression of δ-opioid receptor (DOR) mRNA was significantly reduced in the PAG and rostral ventromedial medulla of MSSI mice compared to control mice. Moreover, the lack of morphine antinociception was observed in 18-week-old MSSI mice. Our findings suggest that the supraspinal opioid system may be affected by early life stress exposure, and that this exposure may impact morphine antinociception.
Assuntos
Analgésicos Opioides/farmacologia , Encéfalo/efeitos dos fármacos , Morfina/farmacologia , Nociceptividade/efeitos dos fármacos , Dor Nociceptiva/prevenção & controle , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , Estresse Psicológico/metabolismo , Fatores Etários , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Masculino , Privação Materna , Camundongos , Dor Nociceptiva/metabolismo , Dor Nociceptiva/fisiopatologia , Dor Nociceptiva/psicologia , Gravidez , Proteínas Proto-Oncogênicas c-fos/metabolismo , Receptores Opioides delta/genética , Receptores Opioides delta/metabolismo , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Transdução de Sinais , Isolamento Social , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologiaRESUMO
This article [1] has been retracted at the request of the corresponding author because an Investigation Committee established by Kobe Gakuin University (Kobe, Japan) has found numerous discrepancies between the raw data and the data presented in Figs. 6b, d. Statistical analysis of the raw data showed no significant difference between conditions. Authors S. Harada, K. Nakamoto, W. Fujita-Hamabe, H.-H. Chen, M.-H. Chan, and S. Tokuyama agree with this retraction. Authors M. Kishimoto and M. Kobayashi could not be reached for comment about this retraction.
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Central post-stroke pain (CPSP) is a type of neuropathic pain for which the mechanism and relevant drug pathways remain unknown. Recently, it was reported that intracerebroventricular (ICV) administration of orexin-A suppresses pain and ischemia. In this study, we tested the role of orexin-A in CPSP induction in mice. Male ddY mice were subjected to 30 min of bilateral carotid artery occlusion (BCAO). CPSP was assessed by von Frey test. Colocalization of orexin 1 receptor (OX1R) with various neuron markers were determined by double-immunofluorescence. The hindpaw withdrawal responses to mechanical stimuli were significantly increased 3 days post-BCAO compared with those of sham groups. ICV injection of orexin-A dose-dependently suppressed BCAO-induced mechanical allodynia. These effects were inhibited by pre-treatment with SB334867 (an OX1R antagonist; ICV injection), yohimbine (a noradrenaline α2 receptor antagonist; intrathecal (IT) injection), and WAY100635 (a serotonin 5-HT1A receptor antagonist; IT injection), but not TCS OX2 29 (an OX2R antagonist; ICV injection). OX1R colocalized with TH (a noradrenergic neuron marker) and TPH (a serotonergic neuron marker) in the locus ceruleus (LC) and the rostral ventromedial medulla (RVM), respectively. The number of c-Fos positive cells in the LC and the RVM of BCAO mice was increased at 90 min after ICV injection of orexin-A compared to saline group. These results indicate that orexin-A/OX1R signaling plays an important role through activation of the descending pain control system in the induction of CPSP in mice.
Assuntos
Isquemia Encefálica/metabolismo , Hiperalgesia/metabolismo , Proteínas Mitocondriais/metabolismo , Neuralgia/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Benzoxazóis/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Isoquinolinas/farmacologia , Masculino , Camundongos , Proteínas Mitocondriais/antagonistas & inibidores , Naftiridinas/farmacologia , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Orexinas/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Antagonistas da Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ureia/análogos & derivados , Ureia/farmacologia , Ioimbina/farmacologiaRESUMO
Nonalcoholic fatty liver disease (NAFLD) is characterized by the pathological accumulation of fat in the liver in the absence of any other disease related to liver steatosis, which includes a wide spectrum ranging from mild asymptomatic fatty liver to nonalcoholic steatohepatitis (NASH) and cirrhosis. However, the pathogenesis of NASH has not been established. In this study, we investigated the involvement of the G-protein-coupled receptor 120/free fatty acid receptor 4 (GPR120/FFAR4) in the pathogenesis of NASH. Mice fed a 0.1% methionine- and choline-deficient l-amino acid-defined, high-fat (CDAHF) diet showed a significant increase in plasma aspartate aminotransferase and alanine aminotransferase levels, fatty deposition, inflammatory cell infiltration, and slight fibrosis. Docosahexanoic acid (DHA, a GPR120/FFAR4 agonist) suppressed the inflammatory cytokines in hepatic tissues and prevented liver fibrosis. On the other hand, GPR120/FFAR4-deficient CDAHF-fed mice showed increments in the number of hepatic crown-like structures and immunoreactivity to F4/80-positive cells compared with wild-type mice. Furthermore, the levels of hepatic TNF-α mRNA expression increased in GPR120-deficient mice. These findings suggest that the GPR120/FFAR4-mediating system could be a key signaling pathway to prevent the development of NASH. In this review, we describe our recent data showing that GPR120/FFAR4 could be a therapeutic target in NASH/NAFLD.
Assuntos
Ácidos Docosa-Hexaenoicos/uso terapêutico , Terapia de Alvo Molecular , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/fisiologia , Animais , Ácidos Docosa-Hexaenoicos/farmacologia , Humanos , Camundongos , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaRESUMO
The pathophysiological mechanism of central post-stroke pain (CPSP) is complicated and not well understood. Recently, it has been reported that an increase in the levels of spinal nitric oxide synthetase (NOS) occurs in cerebral ischemia, and spinal NOS is involved in the development of neuropathic pain. The aim of this study was to elucidate the mechanism of spinal NOS signaling in the development of CPSP. Male ddY mice were subjected to 30-min long bilateral carotid artery occlusion (BCAO). The withdrawal responses to mechanical stimuli were significantly increased as determined with von Frey test on days 1 and 3 after BCAO. Protein expression of spinal N(G),N(G)-dimethylarginine dimethylaminohydralase 1 (DDAH1), a key enzyme involved in the metabolism of the endogenous NOS, increased on day 1 after BCAO, but not on day 3. Intrathecal (i.t.) injection of PD404182, a DDAH1 inhibitor, significantly suppressed mechanical allodynia on day 1, but not on day 3 after BCAO. In addition, i.t. administration of NG-nitro-L-arginine methyl ester (L-NAME), a non-selective NOS inhibitor, significantly blocked mechanical allodynia on days 1 and 3 after BCAO. Furthermore, BCAO-induced increment of spinal NOS activity was inhibited by the pretreatment with PD404182. These results suggest that mechanical allodynia in the early stage of CPSP is caused by increment of NOS activity through upregulated DDAH1 in the spinal cord.
Assuntos
Amidoidrolases/metabolismo , Isquemia Encefálica/complicações , Hiperalgesia/etiologia , Neuralgia/etiologia , Óxido Nítrico Sintase/metabolismo , Medula Espinal/enzimologia , Animais , Isquemia Encefálica/enzimologia , Hiperalgesia/enzimologia , Masculino , Camundongos Endogâmicos , Neuralgia/enzimologia , Transdução de SinaisRESUMO
N-3 fatty acids, including docosahexaenoic acid (DHA), have a beneficial effect in both pain and psychiatric disorders. In fact, we previously reported that stress-induced pain prolongation might be mediated through the suppression of the G-protein coupled-receptor 40/free fatty acid receptor 1 (GPR40/FFAR1), which is activated by DHA and long-chain fatty acids. However, the involvement of GPR40/FFAR1 ligands in the development of stress-induced chronic pain has not yet been described. In this study, we investigated the role of DHA in stress-evoked pain chronicity using diet-induced n-3 fatty acid deficient mice. The n-3 fatty acid deficient mice showed exacerbation of anxiety-like behavior after repeated exposure to social defeat stress. The intact n-3 fatty acid deficient mice showed a decrease in paw threshold values. On the other hand, paw withdrawal thresholds of defeated but not non-stressed, n-3 fatty acid deficient mice continued until day 49 after paw surgery. We evaluated changes in phosphatidylcholine composition in the brains of repeat stress-evoked chronic pain model mice which were not on n-3 fatty acid deficiency diets. On day 7 after paw surgery, phosphatidylcholines with DHA and other long-chain fatty acids were found to have decreased in the brains of stressed mice. Moreover, stress-induced persistent mechanical allodynia was improved by oral DHA supplementation. These results indicated that chronic stress may directly affect brain lipid composition; the related changes could be involved in chronic pain development. Our findings suggested that n-3 fatty acids, particularly DHA, are useful as a potential therapeutic target for stress-evoked chronic pain.
Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Graxos Ômega-3/metabolismo , Hiperalgesia/tratamento farmacológico , Animais , Ansiedade , Encéfalo/metabolismo , Dor Crônica/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Graxos/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Estresse PsicológicoRESUMO
RATIONALE: 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. RESULTS: 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. CONCLUSION: 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.
Assuntos
Dor Crônica/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Relações Interpessoais , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/fisiologia , Estresse Psicológico/metabolismo , Animais , Benzoatos/administração & dosagem , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Dor Crônica/psicologia , Ácidos Graxos não Esterificados/antagonistas & inibidores , Infusões Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Pirimidinas/administração & dosagem , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/psicologiaRESUMO
G-protein-coupled receptor 40 (GPR40)/free fatty acid receptor (FFAR) 1 is activated by long-chain fatty acids such as docosahexaenoic acid (DHA). Its receptor is expressed predominantly in the central nervous system (CNS) and in ß-cells in the pancreatic Islets. We have already demonstrated that the intracerebroventricular administration of DHA or GW9508, a GPR40/FFAR1 agonist, suppresses formalin-induced pain behavior. It also attenuates complete Freund's adjuvant-induced mechanical allodynia and thermal hyperalgesia, suggesting that these effects occur by increasing ß-endorphin release from propiomelanocortin neurons. Furthermore, we found that the brain GPR40/FFAR1 signaling may involve in the regulation of the descending pain control system, whereas the deletion of GPR40/FFAR1 might exacerbate mechanical allodynia in postoperative pain. Therefore, it is possible that the brain n-3 fatty acid-GPR40/FFAR1 signaling may play a key role in the modulation of the endogenous pain control system and emotional function. Here, we discuss the role of brain n-3 fatty acids-GPR40/FFAR1 signaling in a pain, and we review the current status and future prospects of the brain GPR40/FFAR1.
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Encéfalo/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Dor/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Animais , Humanos , Fosforilação , Receptores Acoplados a Proteínas G/antagonistas & inibidoresRESUMO
Nonalcoholic steatohepatitis (NASH) is one of the most common liver diseases involving chronic accumulation of fat and inflammation, often leading to advanced fibrosis, cirrhosis and carcinoma. However, the pathological mechanism for this is unknown. GPR120/FFAR4 has been recognized as a functional fatty acid receptor and an attractive therapeutic target for metabolic diseases. In this study, we investigated the involvement of GPR120/FFAR4 in the pathogenesis of NASH. Mice fed with a 0.1% methionine and choline deficient high-fat (CDAHF) diet showed a significant increase in plasma aspartate transaminase and alanine transaminase levels, fatty deposition, inflammatory cell infiltration, and mild fibrosis. Docosahexaenoic acid (DHA, GPR120/FFAR4 agonist) suppressed the inflammatory cytokines in the liver tissues and prevented fibrosis in the wild type (WT) mice fed CDAHF diet, but not GPR120/FFAR4 deficient (GPR120KO) mice. GPR120KO mice fed CDAHF diet showed increment of the number of crown like structures and the immunoreactivity for F4/80 positive cells, and increased TNF-α mRNA in the liver compared to WT mice fed CDAHF diet. GPR120 KO mice fed CDAHF diet showed more severe liver inflammation than that of WT mice fed CDAHF diet, but not fibrosis. Our findings suggest that DHA supplementation could be prevented the development of NASH via GPR120/FFAR4 signaling. Furthermore, decrease of GPR120/FFAR4 signaling could be facilitated an inflammatory response in the process of NASH progression.
Assuntos
Suplementos Nutricionais , Progressão da Doença , Ácidos Docosa-Hexaenoicos/farmacologia , Hepatopatia Gordurosa não Alcoólica/patologia , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Fibrose , Técnicas de Inativação de Genes , Fígado/efeitos dos fármacos , Fígado/lesões , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fenótipo , Receptores Acoplados a Proteínas G/deficiência , Receptores Acoplados a Proteínas G/genéticaRESUMO
The free fatty acid receptor 1 (GPR40/FFAR1) is activated by polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acids (DHA). This receptor has been the focus of many studies regarding physiological functions of the central nervous system. PUFAs are essential for neuronal development and maintenance of neuronal function; thus, the decrease of PUFAs in the brain is closely related to the induction of psychiatric diseases associated with emotional disorder, such as anxiety, depression, and schizophrenia. However, details of the mechanisms remain unclear. In this study, we investigated changes of maternal and/or emotional behavior caused by a deficiency of GPR40/FFAR1 signaling. GPR40/FFAR1 deficient (FFAR1-/-) female mice exhibited impaired maternal care such as retrieving behaviors and an increased rate of neglect and infanticide when compared to wild type (WT) female mice. Furthermore, FFAR1-/- female mice showed increased time spent in the open arms in an elevated plus maze test, reduction of locomotor activity and social interaction behavior, and decreased sucrose intake, when compared to WT female mice. In conclusion, these findings suggest that PUFAs-GPR40/FFAR1 signaling might function, at least in part, as a regulatory factor of emotional and maternal behavior in mice.
Assuntos
Comportamento Animal , Emoções , Comportamento Materno , Receptores Acoplados a Proteínas G/genética , Animais , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Comportamento SocialRESUMO
Our previous studies demonstrated that emotional dysfunction associated with early life stress exacerbated nerve injury-induced mechanical allodynia. Sex differences were observed in several anxiety tests, but not in mechanical allodynia. To elucidate the mechanism underlying these findings, we have now investigated the involvement of astrocytes in emotional dysfunction and enhancement of nerve injury-induced mechanical allodynia in mice subjected to maternal separation combined with social isolation (MSSI) as an early life stress. We measured expression of glial fibrillary acidic protein (GFAP), an astrocyte maker, in each brain area by immunohistochemistry. GFAP expression in the locus coeruleus (LC) of female, but not of male mice, significantly increased after MSSI, corresponding to the behavioral changes at 7 and 12 weeks of age. Lipopolysaccharide (LPS)-treated astrocyte-derived supernatant was administered to local brain regions, including LC. Intra-LC injection of conditioned medium from cultured astrocytes treated with LPS increased GFAP expression, anxiety-like behavior and mechanical allodynia in both male and female mice. Furthermore, increases in anxiety-like behavior correlated with increased mechanical allodynia. These findings demonstrate that emotional dysfunction and enhanced nerve injury-induced mechanical allodynia after exposure to MSSI are mediated, at least in part, by astrocyte activation in the LC. Male but not female mice may show resistance to MSSI stress during growth.
RESUMO
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.