analysis of bacterial metabolism of glutamate and GABA in the gut in a rat model of obesity and type 2 diabetes.

Dysbiosis of gut microbiota has adverse effects on host health. This study aimed to determine the effects of changes of faecal microbiota in obese and diabetic rats on the imputed production of enzymes involved in the metabolism of glutamate, gamma-aminobutyric acid (GABA), and succinate. The levels of glutamate decarboxylase, GABA transaminase, succinate-semialdehyde dehydrogenase, and methylisocitrate lyase were reduced or absent in diabetic rats compared with controls and obese rats.

Characterisation of gut microbiota of obesity and type 2 diabetes in a rodent model.

Various studies have suggested that the gut microbiome interacts with the host and may have a significant role in the aetiology of obesity and Type 2 Diabetes (T2D). It was hypothesised that bacterial communities in obesity and T2D differ from control and compromise normal interactions between host and microbiota. Obesity and T2D were developed in rats by feeding a high-fat diet or a high-fat diet plus a single low-dose streptozotocin administration, respectively.

Disrupted endothelial cell heterogeneity and network organization impair vascular function in prediabetic obesity.

Background: Obesity is a major risk factor for diabetes and cardiovascular diseases such as hypertension, heart failure, and stroke. Impaired endothelial function occurs in the earliest stages of obesity and underlies vascular alterations that give rise to cardiovascular disease. However, the mechanisms that link weight gain to endothelial dysfunction are ill-defined.

Adhesion G-protein coupled receptor 56 is required for 3T3-L1 adipogenesis.

Obesity-associated conditions represent major global health and financial burdens and understanding processes regulating adipogenesis could lead to novel intervention strategies. This study shows that adhesion G-protein coupled receptor 56 (GPR56) gene transcripts are reduced in abdominal visceral white adipose tissue derived from obese Zucker rats versus lean controls. Immunostaining in 3T3-L1 preadipocytes reveals both mitotic cell restricted surface and low level general expression patterns of Gpr56.

Genetic obesity increases pancreatic expression of mitochondrial proteins which regulate cholesterol efflux in BRIN-BD11 insulinoma cells.

Pancreatic β-cells are sensitive to fluctuations in cholesterol content, which can damage the insulin secretion pathway, contributing to the aetiology of type 2 diabetes mellitus. Cholesterol efflux to (apo)lipoproteins, via ATP-binding cassette (ABC) transporter A1 (ABCA1), can prevent intracellular cholesterol accumulation; in some peripheral cells, ABCA1-dependent efflux is enhanced by promotion of cholesterol trafficking to, and generation of Liver X receptor (LXR) ligands by, mitochondrial sterol 27-hydroxylase (Cyp27A1 (cytochrome P450 27 A1/sterol 27-hydroxylase)) and its redox partners, adrenodoxin (ADX) and ADX reductase (ADXR). Despite this, the roles of mitochondrial cholesterol trafficking (steroidogenic acute regulatory protein [StAR] and 18-kDa translocator protein [TSPO]) and metabolising proteins in insulin-secreting cells remain wholly uncharacterised.

Adiponectin-Mediated Analgesia and Anti-Inflammatory Effects in Rat.

The adipose tissue-derived protein, adiponectin, has significant anti-inflammatory properties in a variety of disease conditions. Recent evidence that adiponectin and its receptors (AdipoR1 and AdipoR2) are expressed in central nervous system, suggests that it may also have a central modulatory role in pain and inflammation. This study set out to investigate the effects of exogenously applied recombinant adiponectin (via intrathecal and intraplantar routes; 10-5000 ng) on the development of peripheral inflammation (paw oedema) and pain hypersensitivity in the rat carrageenan model of inflammation.

Intracellular cholesterol transporters and modulation of hepatic lipid metabolism: Implications for diabetic dyslipidaemia and steatosis.

Aims/hypotheses: To examine hepatic expression of cholesterol-trafficking proteins, mitochondrial StarD1 and endosomal StarD3, and their relationship with dyslipidaemia and steatosis in Zucker (fa/fa) genetically obese rats, and to explore their functional role in lipid metabolism in rat McArdle RH-7777 hepatoma cells.

Methods: Expression of StarD1 and StarD3 in rat liver and hepatoma samples were determined by Q-PCR and/or immunoblotting; lipid mass by colorimetric assays; radiolabelled precursors were utilised to measure lipid synthesis and secretion, and lipidation of exogenous apolipoprotein A-I.

Results: Hepatic expression of StarD3 protein was repressed by genetic obesity in (fa/fa) Zucker rats, compared with lean (Fa/?) controls, suggesting a link with storage or export of lipids from the liver.

Bilobalide, a unique constituent of Ginkgo biloba, inhibits inflammatory pain in rats.

Standardized Ginkgo biloba extract EGb 761 has been shown to inhibit inflammatory hyperalgesia in rats; however, the mechanism of action is not known. This study set out to investigate the anti-inflammatory and analgesic potential of bilobalide, a unique G. biloba constituent, in three well-characterized models of acute inflammatory pain.

Increased central and peripheral inflammation and inflammatory hyperalgesia in Zucker rat model of leptin receptor deficiency and genetic obesity.

This study investigated whether sensitivity to nociceptive stimuli is altered in obese rats using established models of inflammatory pain, and using real-time PCR, profiled alterations in expression of key adipokine and inflammatory mediator mRNA (adiponectin, tumor necrosis factor-α, interleukin-1β, cyclooxygenase-2, inducible nitric oxide synthase (iNOS)) in spinal cord with obesity. Responses to thermal and mechanical stimulation of the hindpaw and paw oedema were assessed in adult male Zucker fatty rats (fa/fa) and their lean littermates (fa/-; n = 6-9 per group) in the absence of inflammation (acute nociception), then in response to intradermal hindpaw injection of carrageenan (3%; 50 μl) or capsaicin (10 μg; 50 μl) or hindpaw incision. The analgesic potency of morphine (1, 2.

Co-induction of cyclooxygenase-2 [correction of cyclooxyenase-2] and early growth response gene (Egr-1) in spinal cord in a clinical model of persistent inflammation and hyperalgesia.

Background: This study characterised the effects of persistent peripheral inflammation of the foot on pain and spinal cord expression of cyclooxygenase-1 and -2 (COX-1 and COX-2) and early growth response gene 1 (Egr-1), known markers of neuronal plasticity, in a clinical model of naturally-occurring inflammatory disease and hyperalgesia in sheep ('footrot'), before and after routine treatment (parenteral treatment with antibiotics and antiseptic footbathing). The temporal pattern of expression of COX-1, COX-2 and Egr-1 mRNA and protein were analysed using real-time PCR and Western blotting.

Results: Animals affected with persistent peripheral inflammation displayed significant hyperalgesia and lameness (a proxy indicator of spontaneous pain) restricted to the inflamed limb.

Activation of metabotropic glutamate receptor 7 in spinal cord inhibits pain and hyperalgesia in a novel formalin model in sheep.

This study set out to characterize the contribution of group III metabotropic glutamate receptor 7 activation to nociceptive behaviour and mechanical hypersensitivity in a novel formalin test in sheep. The mGlu receptor 7 allosteric agonist, N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082; 2-20 mM), the nonselective group III mGlu receptor agonist L-(+)-2-amino-4-phosphonobutyric acid (0.2-20 mM) and drug vehicle were injected intrathecally into naive subjects (n=7 per group), or 5 min preformalin (3%; 0.

Central and local administration of Gingko biloba extract EGb 761® inhibits thermal hyperalgesia and inflammation in the rat carrageenan model.

Background: Oral administration of the standardized Ginkgo biloba extract EGb 761® has been shown to inhibit thermal hyperalgesia in rodent models of inflammatory and postsurgical pain, but the mechanism underlying these effects is not known. We sought to determine the site of action of EGb 761 by investigating the antihyperalgesic and antiinflammatory properties of EGb 761 after local and central drug administration in the rat carrageenan model of inflammation.

Methods: Adult male Wistar rats received an intraplantar injection of carrageenan (3%) or saline into the left hindpaw followed 3 hours later by an intraplantar injection of EGb 761 (30, 100, or 300 μg) or vehicle into the left paw; or intrathecal injection of EGb 761 (0.

The selective metabotropic glutamate receptor 7 allosteric agonist AMN082 inhibits inflammatory pain-induced and incision-induced hypersensitivity in rat.

This study characterized the contribution of metabotropic glutamate receptor 7 (mGlu7 receptor) activation to the development of inflammatory hyperalgesia and allodynia, using a novel, systemically active mGlu7 receptor allosteric agonist, N, N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082). The effects of AMN082 (0.1, 1 or 5 mg/kg, intraperitoneally; 5 or 50 nmol, intrathecally) or diclofenac (5 mg/kg, intraperitoneally) administered 30 min preprocedure or 3 h postprocedure on hindpaw withdrawal latency (in seconds) to thermal stimulation, and response threshold (in grams) to mechanical stimulation, were measured in adult rats (n = 6-8 per group) before and up to 24 h after intradermal injection of carrageenan into the hindpaw or hindpaw incision.

Enhanced short-latency responses in the ventral posterior medial (VPM) thalamic nucleus following whisker trimming in the adult rat.

This study examined the effects of whisker trimming on the functional organization of the adult somatosensory thalamus. In vivo extracellular unit recordings were made on ventral posterior medial (VPM) thalamic neurons in urethane anaesthetised adult rats. Neuronal response properties to controlled whisker deflection were recorded in untrimmed control animals and in animals where one row of whiskers had been trimmed for a median of 18 days.

Blockade of metabotropic glutamate receptor 5 activation inhibits mechanical hypersensitivity following abdominal surgery.

This study used the metabotropic glutamate 5 (mGlu5) receptor subtype-selective antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) to characterise the contribution of mGlu5 receptor activity to pain and hypersensitivity in an animal model of post-surgical pain. Adult female Wistar rats (200-250g) were anaesthetised with isoflurane (2%) and underwent a midline laparotomy with gentle manipulation of the viscera, and the effects of pre- (30min) or post- (5h) operative treatment with MPEP (1, 3 or 10mgkg(-1); i.p.

Differential expression of central metabotropic glutamate receptor (mGluR) subtypes in a clinical model of post-surgical pain.

Tissue damage during surgery can induce 'central sensitization' and the development of pain and hyperalgesia post-operatively. Metabotropic glutamate receptors (mGluRs) contribute to nociception, inflammatory pain and hyperalgesia. This study characterized the temporal expression of group I (mGluR(1), mGluR(5)) and II (mGluR(2), mGluR(3)) mGluRs in spinal cord following abdominal surgery.

Up-regulation of metabotropic glutamate receptor subtypes 3 and 5 in spinal cord in a clinical model of persistent inflammation and hyperalgesia.

Evidence from experimental pain research has revealed that metabotropic glutamate receptors (mGluRs) play a pivotal role in nociceptive processing, inflammatory pain and hyperalgesia. The aim of this study was to characterise expression of group I and II mGluRs in spinal cord in a model of naturally occurring persistent inflammation (sheep with unilateral lameness due to inflammation of the digital tissues of the feet, estimated to have been affected by the condition for >2 weeks) and an experimental model of acute inflammation (injection of intradermal carrageenan into lower forelimb in sheep). Animals with unilateral clinical inflammation displayed significant mechanical hyperalgesia on the affected limb.

Expression of gonadotropin-releasing hormone and gonadotropin-releasing hormone receptor in sheep spinal cord.

Consistent with its neuroendocrine role, gonadotropin-releasing hormone (GnRH) is located principally within the hypothalamus, although extra-hypothalamic expression has been reported. The present study characterized the expression of GnRH and GnRH receptor (GnRH-R) in sheep spinal cord using real-time PCR and immunocytochemistry. Both GnRH and GnRH-R mRNA were detected in sheep spinal cord.

Transient up-regulation of spinal cyclooxygenase-2 and neuronal nitric oxide synthase following surgical inflammation.

Background: Surgery induces pain and hyperalgesia postoperatively. The products of cyclooxygenases and nitric oxide synthase (NOS) have been implicated in the development of inflammatory pain and hyperalgesia experimentally, and the use of drugs clinically that modify cyclooxygenase activity has been advocated in the management of perioperative pain. However, regulation of these enzymes following surgery has not been studied.

The role of nitric oxide and prostaglandin signaling pathways in spinal nociceptive processing in chronic inflammation.

Both nitric oxide (NO) and prostaglandins (PG) and their associated enzymes nitric oxide synthases (NOS) and cyclooxygenases (COX) (specifically COX-2) have been implicated in the development of hyperalgesia. This study examined the effects of naturally occurring chronic inflammation, chronic mastitis, on spinal nociceptive processing in sheep and focused on potential alterations in spinal PG and NO signaling pathways. Mechanical withdrawal thresholds were significantly lower in animals suffering from chronic inflammation (n=6) compared to control animals (n=6).