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Epidemiological studies in patients with type 1 and type 2 diabetes show that hyperglycemia is associated with the development of long-term microvascular complications, including painful diabetic neuropathy (PDN). However, as the prevalence of type 2 diabetes in humans far exceeds that of type 1, the present study was undertaken as a 22-week longitudinal investigation commencing at 7 weeks of age, to assess the utility of the Zucker diabetic fatty (ZDF) rat model of type 2 diabetes for the study of PDN. Behavioral methods were used to characterize temporal changes in hindpaw sensitivity as well as morphine potency in these animals. The effect of long-term diabetes on µ-opioid receptor function and mRNA expression levels in the spinal cord was also assessed. Diabetes developed spontaneously in ZDF rats with marked hyperglycemia (blood glucose levels ≥ 15 mM) evident by 11 weeks of age, which was maintained until study completion at 29 weeks. In ZDF rats, there was progressive development of mechanical allodynia in the hindpaws such that it was fully developed by 6 months of age. Concurrently, there was temporal loss of opioid sensitivity in these animals such that marked morphine hyposensitivity was evident at 6 months. In the spinal cord, basal G-protein function was significantly impaired at 29 weeks of age, resulting in apparently reduced agonist-stimulated µ-opioid receptor function compared with the prediabetic state. Together, our findings suggest that impaired basal G-protein activity underpins morphine hyposensitivity in PDN. Clinical management of diabetic neuropathic pain has been challenging. This study provides a mechanistic explanation regarding the effectiveness, or lack thereof, of opioid analgesia in the treatment of diabetic neuropathic pain. [ABSTRACT FROM AUTHOR]

Our aim was to investigate the effect of several dietary polyphenols on uptake of 14C-butyrate (14C-BT) by Caco-2 cells and try to correlate this effect with the modulation of the anticarcinogenic effect of BT in these cells. Acutely, uptake of 14C-BT (10 μM) was decreased by resveratrol, quercetin, myricetin, and chrysin, and increased by xanthohumol, catechin, and epicatechin; and uptake of 14C-BT (20 mM) was reduced by resveratrol, quercetin, myricetin, chrysin, EGCG, and epicatechin. Resveratrol acts as a competitive inhibitor of 14C-BT uptake. Chronically, quercetin and EGCG increased uptake of 14C-BT (10 μM), whereas myricetin, rutin, chrysin, and xanthohumol decreased it. Moreover, catechin (1 μM), quercetin, myricetin, rutin, EGCG, and chrysin increased uptake of 14C-BT (20 mM), whereas catechin (0.1 μM) decreased it. EGCG, myricetin, and catechin decreased MCT1 mRNA expression, while chrysin increased it; quercetin, rutin, and xanthohumol had no effect. BT (5 mM; 48 h) markedly decreased cellular viability and proliferation and increased cell differentiation and apoptosis. In general, combination of polyphenolic compounds with BT did not significantly modify these changes. In conclusion, changes in uptake of BT induced by polyphenols do not correlate with changes on the effect of BT upon cell viability, cell proliferation, differentiation, and apoptosis. [ABSTRACT FROM AUTHOR]