Interferon-gamma is a critical modulator of CB(2) cannabinoid receptor signaling during neuropathic pain.

Nerve injuries often lead to neuropathic pain syndrome. The mechanisms contributing to this syndrome involve local inflammatory responses, activation of glia cells, and changes in the plasticity of neuronal nociceptive pathways. Cannabinoid CB(2) receptors contribute to the local containment of neuropathic pain by modulating glial activation in response to nerve injury.

Crucial role of CB(2) cannabinoid receptor in the regulation of central immune responses during neuropathic pain.

Neuropathic pain is a clinical manifestation of nerve injury difficult to treat even with potent analgesic compounds. Here, we used different lines of genetically modified mice to clarify the role played by CB(2) cannabinoid receptors in the regulation of the central immune responses leading to the development of neuropathic pain. CB(2) knock-out mice and wild-type littermates were exposed to sciatic nerve injury, and both genotypes developed a similar hyperalgesia and allodynia in the ipsilateral paw.

Manipulation of fatty acid amide hydrolase functional activity alters sensitivity and dependence to ethanol.

The aim of this study was to examine the role of fatty acid amide hydrolase (FAAH) on ethanol sensitivity, preference, and dependence. The deletion of FAAH gene or the inhibition of FAAH by carbamoyl-biphenyl-3-yl-cyclohexylcarbamate (URB597) (0.1 mg/kg) markedly increased the preference for ethanol.

Ageing introduces a complex pattern of changes in several rat brain transcription factors depending on gender and anatomical localization.

As ageing changes the activity of several transcription factors in the rat cortex, we were interested in determining whether similar changes also appear in the hippocampus of old rats. We determined by electrophoretic gel shift assays the binding activity of nuclear factor kappa B (NFkappaB), activator protein-1 (AP-1), peroxisome proliferator-activated receptor (PPAR), and liver X receptor (LXR) in cortex and hippocampus samples from young (3-month-old), and old (18-month-old) male and female Sprague-Dawley rats. NFkappaB activity increased in old male and female rats, though only in cortex samples, while AP-1 activity decreased only in the cortex and hippocampus of old female animals.

Different response of senescent female Sprague-Dawley rats to gemfibrozil and rosiglitazone administration.

Eighteen-month-old Sprague-Dawley rats present age-related alterations in lipid and glucose metabolism and are resistant to the effect of PPARalpha-activating hypolipidemic drugs, such as gemfibrozil. We tested if these animals were responsive to the administration of rosiglitazone, an insulin-sensitizer acting on PPARgamma. We determined in 18-month-old female Sprague-Dawley rats treated for 21 days with a daily dose of 3mg gemfibrozil/kg or 3mg rosiglitazone/kg: (i) plasma concentrations of total cholesterol (TC), triglycerides (TG), nonesterified fatty acids (NEFA), glucose, insulin and leptin, (ii) hepatic concentrations of TG, NEFA and cholesteryl esters (CE), and (iii) the liver expression and binding activity of peroxisome proliferator-activated receptor alpha (PPARalpha), and several of its target genes, hepatic nuclear factor-4 (HNF-4), and liver X receptor alpha (LXRalpha).

Atorvastatin reverses age-related reduction in rat hepatic PPARalpha and HNF-4.

Old rats are resistant to fibrate-induced hypolipidemia owing to a reduction in hepatic peroxisome proliferator-activated receptor alpha (PPARalpha). We tested whether the age-related decrease in PPARalpha is prevented by atorvastatin (ATV), a hypolipidemic statin. We determined the activity and expression of Liver X receptor alpha (LXRalpha) and PPARalpha in the liver of 18-month-old rats treated with 10 mg kg(-1) of ATV for 21 days.

Prevention of age-related changes in rat cortex transcription factor activator protein-1 by hypolipidemic drugs.

We sought to investigate if, similar to what has been described in other rodent tissues, ageing changes the activity of several transcription factors, namely signal transducer and activator of transcription, nuclear factor-kappa B (NFkappaB), activated protein-1 (AP-1) and peroxisome proliferator-activated receptor (PPAR), in cortex of Sprague-Dawley rats. We also investigated if the administration of two hypolipidemic drugs, gemfibrozil (GFB) and atorvastatin (ATV), could prevent those changes. To this purpose, we determined the expression and binding activity of these transcription factors in cortex samples from 3-month and 18-month old male and female rats, and in 18-month old rats of both sexes treated for 21 days with a daily dose of 3mg GFB/kg or 10mg ATV/kg.

Lack of hypotriglyceridemic effect of gemfibrozil as a consequence of age-related changes in rat liver PPARalpha.

We have investigated if changes in hepatic lipid metabolism produced by old age are related to changes in liver peroxisome proliferator-activated receptor alpha (PPARalpha). Our results indicate that 18-month-old rats showed a marked decrease in the expression and activity of liver PPARalpha, as shown by significant reductions in PPARalpha mRNA, protein and binding activity, resulting in a reduction in the relative mRNA levels of PPARalpha target genes, such as liver-carnitine-palmitoyl transferase-I (CPT-I) and mitochondrial medium-chain acyl-CoA dehydrogenase (MCAD). Further, in accordance with a liver PPARalpha deficiency in old rats, treatment of old animals with a therapeutic dose of gemfibrozil (GFB) (3mg/kg per day, 21 days) was ineffective in reducing plasma triglyceride concentrations (TG), despite attaining a 50% reduction in TG when GFB was administered to young animals at the same dose and length of treatment.

Gemfibrozil increases the specific binding of rat-cortex nuclear extracts to a PPRE probe.

PPAR agonists have been shown to elicit beneficial responses in several cell- and tissue-models of neurotoxicity. To determine if brain PPARs are responsive to the in vivo administration of PPAR agonists in a similar way to those receptors present in other anatomical localizations, such as liver, we fed rats with gemfibrozil incorporated in the diet at a dose that activates hepatic PPARalpha and produces its typical hypolipidemic effect. Rat cortex nuclear extracts presented a pattern of two specific shifted bands when incubated with a PPRE oligonucleotide.

Atorvastatin treatment induced peroxisome proliferator-activated receptor alpha expression and decreased plasma nonesterified fatty acids and liver triglyceride in fructose-fed rats.

We aimed to investigate the effect of atorvastatin (5 and 30 mg/kg/day for 2 weeks) on hepatic lipid metabolism in a well established model of dietary hypertriglyceridemia, the fructose-fed rat. Fructose feeding (10% fructose in drinking water for 2 weeks) induced hepatic lipogenesis and reduced peroxisome proliferator-activated receptor alpha (PPARalpha) expression and fatty acid oxidation. As a result, plasma and liver triglyceride and plasma apolipoprotein B (apoB) levels were increased.