The role of descending inhibitory pathways on chronic pain modulation and clinical implications.

The treatment and management of chronic pain is a major challenge for clinicians. Chronic pain is often underdiagnosed and undertreated, and there is a lack of awareness of the pathophysiologic mechanisms that contribute to chronic pain. Chronic pain involves peripheral and central sensitization, as well as the alteration of the pain modulatory pathways. Imbalance between the descending facilitatory systems and the descending inhibitory systems is believed to be involved in chronic pain in pathological conditions. A pharmacological treatment that could restore the balance between these 2 pathways by diminishing the descending facilitatory pain pathways and enhancing the descending inhibitory pain pathways would be a valuable therapeutic option for patients with chronic pain. Due to the lack of evidence for pharmacological options that act on descending facilitation pathways, in this review we summarize the role of the descending inhibitory pain pathways in pain perception. This review will focus primarily on monoaminergic descending inhibitory pain pathways and their contribution to the mechanism of chronic pain and several pharmacological treatment options that enhance these pathways to reduce chronic pain. We describe anatomical structures and neurotransmitters of the descending inhibitory pain pathways that are activated in response to nociceptive pain and altered in response to sustained and persistent pain which leads to chronic pain in various pathological conditions.

Evaluation of glycemic variability in well-controlled type 2 diabetes mellitus.

AIMS: It is necessary to evaluate glucose variability and postprandial hyperglycemia in patients with well-controlled type 2 diabetes mellitus because of the limitations associated with hemoglobin A1c (HbA1c) measurements. We evaluated parameters reflecting postprandial hyperglycemia and glycemic variability in patients with optimal HbA1c. PATIENTS AND METHODS: Thirty-nine patients with HbA1c levels below 7% were recruited to the study. A continuous glucose monitoring system (CGMS) was applied for two 72-h periods. 1,5-Anhydroglucitol (1,5-AG) and fructosamine (FA) were measured as parameters for postprandial hyperglycemia and glucose variability. Using CGMS data, the following postprandial hyperglycemia parameters were calculated: mean postprandial maximum glucose (MPMG) and area under the curve for glucose above 180 mg/dL (AUC-180). To measure glycemic variability, we calculated mean amplitude of glucose excursion (MAGE) using a classical (MAGEc) and new method (MAGE group of sign [MAGEgos]). RESULTS: The baseline HbA1c level was 6.3±0.3%. The mean MPMG was 10.34±1.84 mmol/L, and the mean AUC-180 was 0.17±0.23 mmol/L/day. The mean MAGEgos was 3.27±1.29 mmol/L, and MAGEc was 4.30±1.43 mmol/L, indicating glycemic variability in our patients. The mean levels of 1,5-AG and FA were 16.7±7.4 µg/mL and 273.0±22.5 µmol/L, respectively. In a correlation analysis, FA was significantly correlated with MPMG, AUC-180, MAGEgos, and MAGEc. In contrast, 1,5-AG was only correlated with AUC-180. CONCLUSIONS: This study demonstrated postprandial hyperglycemia and glycemic variability in subjects with well-controlled diabetes. FA may reflect postprandial hyperglycemia and glycemic variability, but 1,5-AG may be of limited value for assessing glucose variability in patients with well-controlled type 2 diabetes mellitus.

Kaempferol attenuates 2-deoxy-d-ribose-induced oxidative cell damage in MC3T3-E1 osteoblastic cells.

Reducing sugar, 2-deoxy-D-ribose (dRib), produces reactive oxygen species through autoxidation and protein glycosylation and causes osteoblast dysfunction. Kaempferol, a natural flavonoid, was investigated to determine whether it could influence dRib-induced cellular dysfunction and oxidative cell damage in the MC3T3-E1 mouse osteoblastic cell line. Osteoblastic cells were treated with 30 mM dRib in the presence or absence of kaempferol (10(-9)-10(-5) M) and markers of osteoblast function and lipid peroxidation were subsequently examined. Kaempferol (10(-9)-10(-5) M) significantly inhibited the dRib-induced decrease in growth of MC3T3-E1 osteoblastic cells. In addition, treatment with kaempferol resulted in a significant elevation of alkaline phosphatase (ALP) activity, collagen content, and mineralization in the cells. Treatment with kaempferol increased osteoprotegerin (OPG) secretion and decreased malondialdehyde (MDA) contents of MC3T3-E1 osteoblastic cells in the presence of 30 mM dRib. Taken together, these results suggest that kaempferol inhibits dRib-induced osteoblastic cell damage and may be useful for the treatment of diabetes-related bone disease.

Association between apolipoprotein E genetic polymorphism and the development of diabetic nephropathy in type 2 diabetic patients.

INTRODUCTION: In recent studies, apolipoprotein E (apo E) genetic polymorphism in association with dyslipidemia have been proposed as the one of the risk factors for the development of diabetic nephropathy. We found that type 2 diabetic patients with microalbuminuria (MA) had higher plasma triglyceride levels than those with normoalbuminuria (NA) in our previous study. Therefore, we aimed for investigating the association among apo E genetic polymorphism, dyslipidemia and the development of diabetic nephropathy in type 2 diabetic patients. METHOD: We included 58 subjects with normoalbuminuria and 36 subjects with microalbuminuria in analysis. They were all Korean and type 2 diabetic patients who had normal renal function, history of diabetes longer than 10 years and the data of urine albumin excretion rate at 10th year diabetes duration. Mean HbA1c, plasma total cholesterol and triglyceride levels for 10 years and several clinical characteristics were examined. Apo E genotypes were confirmed by real time PCR. RESULTS: The frequency of e3/e4 genotype (20.7% versus 5.6%, p=0.045) and E4 carrier (22.8% versus 5.9%, p=0.035) was significantly higher in NA group than in MA group. On logistic regression analysis, crude odds ratio of E2 carrier and E4 carrier were 0.833 (95% CI: 0.245-2.833) and 0.205 (95% CI: 0.043-0.986), respectively. However, after adjusted by HbA1c, hypertension, total cholesterol and triglyceride, odds ratio of E2 carrier and E4 carrier were 0.664 (95% CI: 0.134-3.289) and 0.365 (95% CI: 0.061-2.187) and the association became weak. There were no correlation between apo E carrier and lipid profile. HbA1c (7.6+/-1.3% versus 7.0+/-0.9%, p=0.012) and mean creatinine (1.2+/-0.7 mg/dL versus 1.0+/-0.2mg/dL, p=0.004) levels were significantly higher in MA group than in NA group as expected. CONCLUSIONS: These data suggest that E4 carrier might be associated with the protection for the development of diabetic nephropathy in type 2 diabetic patients without respect to dyslipidemia.