Pharmacokinetics of trans-resveratrol in its aglycone (RES AGL )and glucuronide (RES GLU ) forms were studied following intravenous (15 mg/kg i.v.) and oral (50 mg/kg p.o.) administration of trans-resveratrol in a solution of ␤-cyclodextrin to intact rats. In addition, the enterohepatic recirculation of RES AGL and RES GLU was assessed in a linked-rat model. Multiple plasma and urine samples were collected and concentrations of RE-S AGL and RES GLU were determined using an electrospray ionization-liquid chromatography/tandem mass spectrometry method. After i.v. administration, plasma concentrations of RE-S AGL declined with a rapid elimination half-life (T 1/2 , 0.13 h), followed by sudden increases in plasma concentrations 4 to 8 h after drug administration. These plasma concentrations resulted in a significant prolongation of the terminal elimination half-life of RES AGL (T 1/2TER , 1.31 h). RES AGL and RES GLU also displayed sudden increases in plasma concentrations 4 to 8 h after oral administration, with T 1/2TER of 1.48 and 1.58 h, respectively. RES AGL bioavailability was 38% and its exposure was approximately 46-fold lower than that of RES GLU (AUC inf , 7.1 versus 324.7 mol⅐ h/l). Enterohepatic recirculation was confirmed in the linked-rat model since significant plasma concentrations of RES AGL and RES GLU were observed in bilerecipient rats at 4 to 8 h. The percentages of the exposures of RES AGL and RES GLU that were due to enterohepatic recirculation were 24.7 and 24.0%, respectively. The fraction of drug excreted in the urine over a period of 12 h was negligible. These results confirm that RES AGL is bioavailable and undergoes extensive first-pass glucuronidation, and that enterohepatic recirculation contributes significantly to the exposure of RES AGL and RES GLU in rats.Interest in the study of phenolic compounds present in red wine has grown since epidemiological studies have shown an inverse correlation between red wine consumption and the incidence of cardiovascular diseases (Nanji and French, 1986;Hegsted and Ausman, 1988). Resveratrol (3,5,4Ј-trihydroxystilbene), a molecule from the viniferin family of polymers, was identified as a biologically active compound in red wine in 1992 (Siemann and Creasy, 1992). Since then, numerous in vivo and in vitro studies have assessed the ability of resveratrol in preventing multiple pathophysiological processes. Resveratrol has the ability to inhibit the peroxidation of lipid membranes (Fauconneau et al., 1997), to decrease the concentration of low-and very-low-density lipoproteins (Frankel et al., 1993), and to inhibit platelet aggregation (Kimura et al., 1985), three conditions that help prevent cardiovascular diseases. Although significant estrogenic-like activity of resveratrol has been demonstrated in vitro (Gehm et al., 1997;Bhat et al., 2001), this was not proven in vivo in rats (Turner et al., 1999). Finally, trans-resveratrol was shown to have cancer chemoprotective properties and to induce apoptosis in leukemia and human breast carcinom...

Changes in brain structure and cortical function are associated with many chronic pain conditions including low back pain and fibromyalgia. The magnitude of these changes correlates with the duration and/or the intensity of chronic pain. Most studies report changes in common areas involved in pain modulation, including the prefrontal cortex (PFC), and pain-related pathological changes in the PFC can be reversed with effective treatment. While the mechanisms underlying these changes are unknown, they must be dynamically regulated. Epigenetic modulation of gene expression in response to experience and environment is reversible and dynamic. Epigenetic modulation by DNA methylation is associated with abnormal behavior and pathological gene expression in the central nervous system. DNA methylation might also be involved in mediating the pathologies associated with chronic pain in the brain. We therefore tested a) whether alterations in DNA methylation are found in the brain long after chronic neuropathic pain is induced in the periphery using the spared nerve injury modal and b) whether these injury-associated changes are reversible by interventions that reverse the pathologies associated with chronic pain. Six months following peripheral nerve injury, abnormal sensory thresholds and increased anxiety were accompanied by decreased global methylation in the PFC and the amygdala but not in the visual cortex or the thalamus. Environmental enrichment attenuated nerve injury-induced hypersensitivity and reversed the changes in global PFC methylation. Furthermore, global PFC methylation correlated with mechanical and thermal sensitivity in neuropathic mice. In summary, induction of chronic pain by peripheral nerve injury is associated with epigenetic changes in the brain. These changes are detected long after the original injury, at a long distance from the site of injury and are reversible with environmental manipulation. Changes in brain structure and cortical function that are associated with chronic pain conditions may therefore be mediated by epigenetic mechanisms.

Objective. To examine the concentration of glucosamine in the synovial fluid and its pharmacokinetics in serum in a large animal model following dosing with glucosamine HCl at clinically relevant levels.Methods. Eight adult female horses were studied. After an overnight fast, glucosamine HCl (20 mg/kg of body weight) was administered by either nasogastric (NG) intubation or intravenous (IV) injection. Blood samples were collected before dosing and at 5, 15, 30, 60, 120, 180, 240, 360, 480, and 720 minutes after dosing. Synovial fluid samples were collected from the radiocarpal joints 48 hours before dosing and at 1 and 12 hours after dosing. Glucosamine was assayed by fluorophoreassisted carbohydrate electrophoresis.Results. The maximum concentration of glucosamine in serum reached ϳ300 M (ϳ50 g/ml) following IV dosing and ϳ6 M (ϳ1 g/ml) following NG dosing. Synovial fluid concentrations reached 9-15 M with IV dosing and 0.3-0.7 M with NG dosing, and remained elevated (range 0.1-0.7 M) in most animals even at 12 hours after dosing. Following NG dosing, the median serum maximal concentration of 6.1 M (range 4.38-7.58) was attained between 30 minutes and 4 hours postdose. The mean apparent volume of distribution was 15.4 liters/kg, the mean bioavailability was 5.9%, and the mean elimination half-life was 2.82 hours.Conclusion. Clinically relevant dosing of glucosamine HCl in this large monogastric animal model results in serum and synovial fluid concentrations that are at least 500-fold lower than those reported to modify chondrocyte anabolic and catabolic activities in tissue and cell culture experiments. We conclude that the apparent therapeutic benefit of dietary glucosamine on pain and joint space width in humans and animals may be secondary to its effects on nonarticular tissues, such as the intestinal lining, liver, or kidney, since these may be exposed to much high levels of glucosamine following ingestion.Glucosamine is now widely taken in the US as a dietary supplement (recommended dosage 20 mg/kg/ day) to relieve the discomfort of osteoarthritis (OA)-related joint pain. In Europe, a patented formulation of glucosamine (glucosamine sulfate) is a prescription drug, which is also widely reported to achieve cartilageprotective effects in knee OA (1,2). A quality assessment and meta-analysis of 6 placebo-controlled clinical trials using both glucosamine HCl (2 studies) and glucosamine sulfate (4 studies) concluded that some degree of efficacy appears probable in treating symptoms of knee OA (3). More recently, 2 meta-analyses of a large number of randomized control trials with glucosamine sulfate consistently concluded that the drug is both safe and effective for the treatment of symptomatic OA (4,5).

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BackgroundIn animal models, the impact of social and environmental manipulations on chronic pain have been investigated in short term studies where enrichment was implemented prior to or concurrently with the injury. The focus of this study was to evaluate the impact of environmental enrichment or impoverishment in mice three months after induction of chronic neuropathic pain.MethodsThirty-four CD-1 seven to eight week-old male mice were used. Mice underwent surgery on the left leg under isoflurane anesthesia to induce the spared nerve injury model of neuropathic pain or sham condition. Mice were then randomly assigned to one of four groups: nerve injury with enriched environment (n = 9), nerve injury with impoverished environment (n = 8), sham surgery with enriched environment (n = 9), or sham surgery with impoverished environment (n = 8). The effects of environmental manipulations on mechanical (von Frey filaments) heat (hot plate) and cold (acetone test) cutaneous hypersensitivities, motor impairment (Rotarod), spontaneous exploratory behavior (open field test), anxiety-like behavior (elevated plus maze) and depression-like phenotype (tail suspension test) were assessed in neuropathic and control mice 1 and 2 months post-environmental change. Finally, the effect of the environment on spinal expression of the pro-nociceptive neuropeptides substance P and CGRP form the lumbar spinal cord collected at the end of the study was evaluated by tandem liquid chromatography mass spectrometry.ResultsEnvironmental enrichment attenuated nerve injury-induced hypersensitivity to mechanical and cold stimuli. In contrast, an impoverished environment exacerbated mechanical hypersensitivity. No antidepressant effects of enrichment were observed in animals with chronic neuropathic pain. Finally, environmental enrichment resulted lower SP and CGRP concentrations in neuropathic animals compared to impoverishment. These effects were all observed in animals that had been neuropathic for several months prior to intervention.ConclusionsThese results suggest that environmental factors could play an important role in the rehabilitation of chronic pain patients well after the establishment of chronic pain. Enrichment is a potentially inexpensive, safe and easily implemented non-pharmacological intervention for the treatment of chronic pain.