Ketogenic diet combined with intermittent fasting: an option for type 2 diabetes remission?

With increasing attention to diabetes remission, various special dietary patterns have been found to be effective in achieving diabetes remission. The effect of a single dietary pattern on lowering blood glucose is clear, but studies on the synergistic effects of different dietary patterns are limited. This article describes the types of intermittent fasting and ketogenic diets, potential mechanisms, contraindications of combination diets, recommendations for combination diets, and their health outcomes. This paper aims to illustrate the evidence for intermittent fasting combined with a ketogenic diet on outcomes of diabetes remission and effect on blood glucose control. Knowledge of these findings can help doctors and patients determine dietary patterns for achieving diabetes remission and understanding their application.

Exploring the novel SNPs in neuroticism and birth weight based on GWAS datasets.

OBJECTIVES: Epidemiological studies have confirmed that low birth weight (BW) is related to neuroticism and they may have a common genetic mechanism based on phenotypic correlation research. We conducted our study on a European population with 159,208 neuroticism and 289,142 birth weight samples. In this study, we aimed to identify new neuroticism single nucleotide polymorphisms (SNPs) and pleiotropic SNPs associated with neuroticism and BW and to provide more theoretical basis for the pathogenesis of the disease. METHODS: We estimated the pleiotropic enrichment between neuroticism and BW in two independent Genome-wide association studies (GWAS) when the statistical thresholds were Conditional False Discovery Rate (cFDR) < 0.01 and Conjunctional Conditional False Discovery Rate (ccFDR) < 0.05. We performed gene annotation and gene functional analysis on the selected significant SNPs to determine the biological role of gene function and pathogenesis. Two-sample Mendelian Randomization (TSMR) analysis was performed to explore the causal relationship between the neuroticism and BW. RESULTS: The conditional quantile-quantile plots (Q-Q plot) indicated that neuroticism and BW have strong genetic pleiotropy enrichment trends. With the threshold of cFDR < 0.001, we identified 126 SNPs related to neuroticism and 172 SNPs related to BW. With the threshold of ccFDR < 0.05, we identified 62 SNPs related to both neuroticism and BW. Among these SNPs, rs8039305 and rs35755513 have eQTL (expressed quantitative trait loci) and meQTL (methylation quantitative trait loci) effects simultaneously. Through GO enrichment analysis we also found that the two pathways of positive regulation of "mesenchymal cell proliferation" and "DNA-binding transcription factor activity" were significantly enriched in neuroticism and BW. Mendelian randomization analysis results indicate that there is no obvious causal relationship between neuroticism and birth weight. CONCLUSION: We found 126 SNPs related to neuroticism, 172 SNPs related to BW and 62 SNPs associated with both neuroticism and BW, which provided a theoretical basis for their genetic mechanism and novel potential targets for treatment/intervention development.

A convenient paper-based fluorescent aptasensor for high-throughput detection of Pb2+ in multiple real samples (water-soil-food).

Lead ion (Pb2+) is one of the most toxic and widely polluted heavy metal ions. Given the potential health risks and economic losses associated with Pb2+, the rapid detection of Pb2+ using fluorescent aptasensors is of significant importance in evaluating food safety. A rapid, facile and economic fluorescent aptasensor using convenient paper as the sensing substrate was designed to high-throughput detect Pb2+ in complex samples within about 45 min. The Pb2+ changed the conformation of FAM-modified Apt from a random coil to a stable G-quadruplex structure. And then Dabcyl-labeled cDNA was added to form double-stranded DNA with the Apt that did not form a G-quadruplex structure, resulting in a weak fluorescence due to the fluorescence resonance energy transfer (FRET). The fluorescent aptasensor showed a positive correlation with Pb2+ concentration, and a linear relationship was obtained in the range of 0.01-10 µM with LOD of 6.1 nM. In addition, this method has been successfully used for the determination of Pb2+ in water, soil and various foods containing complex substrates. Meanwhile, the high-throughput detection of Pb2+ has also reached an acceptable level. Therefore, this convenient strategy has potential application value for on-site rapid detection of Pb2+.

Gut microbiota accelerates obesity in peri-/post-menopausal women via Bacteroides fragilis and acetic acid.

OBJECTIVE: Many animal experiments and epidemiological studies have shown that the gut microbiota (GM) plays an important role in the development of obesity, but the specific biological mechanism involved in the pathogenesis of disease remain unknown. We aimed to examine the relationships and functional mechanisms of GM on obesity in peri- and post-menopausal women. METHODS: We recruited 499 Chinese peri- and post-menopausal women and performed comprehensive analyses of the gut microbiome, targeted metabolomics for short-chain fatty acids in serum, and host whole-genome sequencing by various association analysis methods. RESULTS: Through constrained linear regression analysis, we found that an elevated abundance of Bacteroides fragilis (B. fragilis) was associated with obesity. We also found that serum levels of acetic acid were negatively associated with obesity, and that B. fragilis was negatively associated with serum acetic acid levels by partial Spearman correlation analysis. Mendelian randomization analysis indicated that B. fragilis increases the risk of obesity and may causally down-regulate acetic acid levels. CONCLUSIONS: We found the gut with B. fragilis may accelerate obesity, in part, by suppressing acetic acid levels. Therefore, B. fragilis and acetic acid may represent important therapeutic targets for obesity intervention in peri- and post-menopausal women.

A low-noise ratiometric fluorescence biosensor for detection of Pb2+ based on DNAzyme and exonuclease III-assisted cascade signal amplification.

As a common heavy metal ion with strong toxicity and wide distribution, lead ions (Pb2+) had great harm to the human body. In this work, a low-noise ratiometric fluorescence biosensor was developed based on Pb2+-dependent DNAzyme and exonuclease III (Exo III)-assisted cascade signal amplification. Firstly, the substrate chain of DNAzyme (S-DNA) was modified on the surface of magnetic beads (MBs) through the combination of biotin and streptavidin, and then the enzyme chain of DNAzyme (E-DNA) was connected to the MBs by forming a double-stranded DNA (dsDNA) with S-DNA. A hairpin DNA (HP) labelled with Cy3 and Cy5 respectively at both ends was used as a fluorescence probe. The emission peaks of Cy3 and Cy5 can appear at 562 nm and 665 nm respectively, and their fluorescence intensity ratio (F562/F665) was chosen as the acquisition signal. The ratiometric sensor can reduce the interference of detection environment and avoid false positive reactivity. Due to the cleavage of DNAzyme and the release of single-stranded DNA (ssDNA) in the presence of Pb2+, the hairpin structure of HP was opened and the FRET between two fluorophores disappeared, resulting in the strengthened signal of Cy3 and the weakened signal of Cy5. Furthermore, the ratio [Formula: see text] signal increased gradually with the increase of Pb2+ concentration. When the concentration of Pb2+ was in the range of 0.1-1000 nM, [Formula: see text] had a good linear relationship with [Formula: see text], the correlation coefficient (R2) was 0.997, and the limit of detection (LOD) was 77 pM. The presented ratiometric fluorescence biosensor had lower LOD and wider detection range via comparing with other methods. At the same time, the sensor also obtained the satisfactory results for detection of Pb2+ in tap water, tea, and rice flour samples. The provided ratiometric biosensor has great potential in the monitoring of various targets. A low-noise ratiometric fluorescence biosensor based on the FRET between two fluorophores was developed, and the DNAzyme and exonuclease III-assisted cascade signal amplification was used to improve the sensitivity of the method. The biosensor had a detection limit as low as 77 pM.

A fluorescent aptasensor for Pb2+ detection based on gold nanoflowers and RecJf exonuclease-induced signal amplification.

A fluorescent aptasensor was constructed to detect lead ion (Pb2+). Complementary DNA with sulfhydryl group (SH-cDNA) were loaded on gold nanoflowers materials (Au NFs) through Au-S bonds. Then, based on complementary base pairing between FAM modified Pb2+ aptamer (FAM-Apt) and Au NFs/SH-cDNA system, an Au NFs/SH-cDNA/FAM-Apt aptasensor was constructed. The fluorescence of FAM was quenched by Au NFs due to the fluorescence resonance energy transfer (FRET). Upon addition of Pb2+ and RecJf exonuclease (RecJf Exo) for 1.5 h, the Apt changed to a G-quadruplex structure due to the high affinity between Pb2+ and its aptamer, which lead to a large recovery in the fluorescence intensity. Under the optimized conditions, the presented aptasensor revealed high selectivity toward Pb2+ in the concentration range of 0.5 nM-1 µM, with a limit of detection (LOD) of 0.285 nM. Besides, the designed aptasensor was successfully used to recognize Pb2+ with excellent selectivity, reproducibility and stability in tap water and tea, providing a potential platform for Pb2+ detection in actual samples.

Identification of novel functional CpG-SNPs associated with Type 2 diabetes and birth weight.

Genome-wide association studies (GWASs) have identified hundreds of genetic loci for type 2 diabetes (T2D) and birth weight (BW); however, a large proportion of the total trait heritability remains unexplained. The previous studies were generally focused on individual traits and largely failed to identify the majority of the variants that play key functional roles in the etiology of the disease. Here, we aim to identify novel functional loci for T2D, BW and the pleiotropic variants shared between them by performing a targeted conditional false discovery rate (cFDR) analysis that integrates two independent GWASs with summary statistics for T2D (n = 26,676 cases and 132,532 controls) and BW (n = 153,781) which entails greater statistical power than individual trait analyses. In this analysis, we considered CpG-SNPs, which are SNPs that may influence DNA methylation status, and are therefore considered to be functionally important. We identified 103 novel CpG-SNPs for T2D, 182 novel CpG-SNPs for BW (cFDR < 0.05), and 52 novel pleiotropic loci for both (conjunction cFDR [ccFDR] < 0.05). Among the identified novel CpG-SNPs, 33 were annotated as methylation quantitative trait loci (meQTLs) in whole blood, and 145 displayed at least some effects on meQTL, metabolic QTL (metaQTL), and/or expression QTL (eQTL). These findings may provide further insights into the shared biological mechanisms and functional genetic determinants that overlap between T2D and BW, thereby providing novel potential targets for treatment/intervention development.

[A comparative study of cerebellar development between appropriate-for-gestational age infants and small-for-gestational-age infants].

OBJECTIVE: To investigate whether there is a difference in cerebellar development between appropriate -for-gestational-age (AGA) infants and small-for-gestational-age (SGA) infants. METHODS: A total of 165 AGA infants and 105 SGA infants, with a gestational age of 26-40+6 weeks, were enrolled in this study. Within 24-48 hours after birth, ultrasound examination was performed to measure the transverse diameter of the cerebellum, the height of the vermis, the area of the vermis, the perimeter of the vermis, and the area and perimeter of the cerebellum on transverse section. A Pearson correlation analysis was used to investigate the correlation between cerebellar measurements and gestational age. RESULTS: In both AGA and SGA infants, all cerebellar measurements were positively correlated with gestational age (r=0.50-0.81, P<0.05). In AGA and SGA infants, there were no significant differences in the measurements between the 25-27+6 weeks, 28-30+6 weeks, and 31-33+6 weeks of gestational age subgroups (P>0.05), while in the 34-36+6 weeks and 37-40+6 weeks subgroups, the SGA infants had significantly lower measurements than the AGA infants (P<0.05). CONCLUSIONS: The SGA infants with a gestational age of <34 weeks have intrauterine cerebellar development similar to AGA infants, but those with a gestational age of ≥34 weeks have poorer intrauterine cerebellar development than AGA infants.

Plasma glucose to glycated hemoglobin ratio: Method of differentiating fulminant type 1 diabetes from diabetic ketoacidosis.

OBJECTIVES: In fulminant type 1 diabetes mellitus (fT1DM), plasma glucose (PG) levels are strongly increased, unlike glycated hemoglobin (HbA1C) levels, resulting in a sharply increased PG/HbA1C ratio. We investigated the PG/HbA1C ratio in fT1DM and tested the accuracy of cutoff points to easily and efficiently differentiate fT1DM from diabetic ketoacidosis (DKA). METHODS: We report 41 cases of fT1DM in which PG/HbA1C ratio was studied as a novel clinical parameter to predict fT1DM. Clinical and biochemical characteristics were analyzed in 41 fT1DM and 51 DKA patients in China. Receiver-operating characteristic curve analysis was used to identify PG/HbA1C ratio cutoff points to differentiate fT1DM from DKA. RESULTS: PG/HbA1C ratio was significantly higher in fT1DM patients (7.24±2.49mmol/L/%; i.e., 0.88±0.36L/mol) than in DKA patients (2.60±0.69mmol/L/%; i.e., 0.06±0.01L/mol) (P<0.001). PG/HbA1C ratio exceeded 4.2mmol/L/% (i.e., 0.6 l/mol) in 39 of the 41 fT1DM patients (95.1%), versus only 1 of the 51 DKA patients (1.9%). CONCLUSIONS: PG/HbA1C ratio is a simple tool that may be useful to identify DKA patients at high risk of fT1DM. PG/HbA1C ratio with a threshold of≥4.2mmol/L/% (i.e., 0.6L/mol) can be adopted as a new clinical parameter in predicting fT1DM.

Prognostic value of pretreatment prognostic nutritional index in non-small cell lung cancer: A systematic review and meta-analysis.

BACKGROUND:: The pretreatment prognostic nutritional index has been considered a potential prognostic biomarker in patients with non-small cell lung cancer (NSCLC), but this remains controversial. Therefore, we performed a meta-analysis to systematically assess the prognostic value of the prognostic nutritional index in patients with NSCLC. METHODS:: We systematically searched PubMed, EMBASE, Web of Science, and CNKI. The hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs) were used to evaluate the link between the prognostic nutritional index and the oncological outcomes of patients with NSCLC, including overall survival, disease-free survival/recurrence-free survival, and progression-free survival. RESULTS:: Fifteen studies were included in this meta-analysis. Twelve of these studies explored the association between the prognostic nutritional index and the overall survival of patients with NSCLC. Our pooled analysis indicated that a low prognostic nutritional index was significantly related to adverse overall survival (HR 1.61; 95% CI 1.44, 1.81; P < 0.001). Our results also showed that the prognostic nutritional index was a negative predictor for disease-free survival/recurrence-free survival, and progression-free survival in patients with NSCLC. CONCLUSION:: Our meta-analysis demonstrated that there was a close association between the prognostic nutritional index value and prognosis in NSCLC patients and that the prognostic nutritional index may act as a useful prognostic biomarker in NSCLC patients.

Lack of coordination between partners: investigation of Physician-Preferred and Patient-Preferred (4P) basal insulin titration algorithms in the real world.

BACKGROUND: Patient-centered care is respectful to a patient's preference. All prior clinical trials on patient self-titration algorithms for basal insulin were decided by physicians. We hypothesized that patients and physicians have different preferences. PATIENTS AND METHODS: Physicians and diabetes patients were asked to choose their preferred insulin glargine self-titration algorithm among 5 algorithms. Algorithm 1, 1 U increase once daily; algorithm 2, 2 U increase every 3 days; algorithm 3, 3 U increase every 3 days; algorithm 4, titration every 3 days according to fasting blood glucose, and algorithm 5, weekly titration 2-8 U based on 3-day mean fasting blood glucose levels. RESULTS: Eleven (5.2%) out of 210 physicians and 180 (90.9%) out of 198 patients preferred algorithm 1 (χ2=300.4, p=0.000). In contrast, 195 (92.9%) physicians and 18 (9.1%) patients preferred algorithm 2 (χ2=286.6, p=0.000). In addition, 4 (1.9%) physicians but no patients preferred algorithm 3 (χ2=2.099, p=0.124). Neither physicians nor patients chose algorithms 4 or 5. Most physicians preferred algorithm 2 since it is recommended by guidelines, but most patients preferred algorithm 1 for its simplicity. CONCLUSION: Patients had different preferences compared with physicians. Attention should be given to patients' preferences to increase adherence and improve glycemic control.

Clinical study of pregnancy-associated fulminant type 1 diabetes.

BACKGROUND: Studies reported that fulminant type 1 diabetes (fT1DM) can occurred during pregnancy or within 2 weeks after delivery, and was defined as pregnancy-associated fulminant type 1 diabetes (PF). In PF patients, plasma glucose (PG) levels have an abrupt rise while glycated hemoglobin (HbA1C) levels are not markedly elevated, resulting in a sharply increased PG/HbA1C ratio. METHODS: We studied 30 PF patients, 21 non-pregnant fulminant type 1 diabetes (NPF) patients, and 26 female patients of child-bearing age (13-49 years) with diabetic ketoacidosis (DKA), all from China. We analyzed the PG/HbA1C ratio among these groups, with the goal of finding a method for predicting PF. The clinical and biochemical characteristics of the PF and NPF patients were analyzed and compared with the characteristics of the DKA patients. In order to detect PF in DKA patients, receiver-operating characteristic curves analysis was used to identify the cut-off points of the PG/HbA1C ratio. RESULTS: When we compared the clinical characteristics of these three groups, we found that the onset of hyperglycemic symptoms, arterial PH value, serum potassium, PG, HbA1C, fasting and postprandial serum C-peptide concentration, glutamic acid decarboxylase (GAD) antibodies positivity were all significantly different (P < 0.001). The PG/HbA1C ratio was significantly higher in PF and NPF patients (5.29 ± 1.39 and 6.38 ± 2.62) than in DKA patients (1.93 ± 0.55; P < 0.001). Receiver-operating characteristic (ROC) curves analyses showed that PG/HbA1C ratio at a cut-off value of 3.3 resulted in the highest Youden index, with corresponding sensitivity of 93 and 100% specificity for identifying PF from DKA. CONCLUSIONS: PF patients showed a more severe acidosis, with maternal and fetal mortality rates being high. PG/HbA1C ratio with a threshold of ≥3.3 can be used as a cut-off point in predicting PF from DKA in China. Elevated PG/HbA1C ratio at the time of diagnosis is predictive for more severe insulin secretion dysfunction and poor prognosis.

Whole-genome sequencing identification of a multidrug-resistant Salmonella enterica serovar Typhimurium strain carrying blaNDM-5 from Guangdong, China.

A carbapenem-resistant Salmonella enterica serovar Typhimurium (sequence type 34 [ST34]) strain was isolated from a fecal specimen from a child with acute diarrhea. Whole-genome sequencing revealed that the 84.5-kb IncFII plasmid pST41-NDM carrying the NDM-5 carbapenemase gene possesses a structure identical to that of the IncFII-type plasmid backbone. However, the blaNDM-5 flanking sequence found in this plasmid is identical to the blaNDM-5-positive IncX3 plasmids carried by 10 strains of Enterobacteriaceae identified in the same hospital.

[Correlation between growth rate of corpus callosum and neuromotor development in preterm infants].

OBJECTIVE: To investigate the growth rate of corpus callosum by cranial ultrasound in very low birth weight preterm infants and to provide a reference for early evaluation and improvement of brain development. METHODS: A total of 120 preterm infants under 33 weeks' gestation were recruited and divided into 26-29(+6) weeks group (n=64) and 30-32(+6) weeks group (n=56) according to the gestational age. The growth rate of corpus callosum was compared between the two groups. The correlation between the corpus callosum length and the cerebellar vermis length and the relationship of the growth rate of corpus callosum with clinical factors and the neuromotor development were analyzed. RESULTS: The growth rate of corpus callosum in preterm infants declined since 2 weeks after birth. Compared with the 30-32(+6) weeks group, the 26-29(+6) weeks group had a significantly lower growth rate of corpus callosum at 3-4 weeks after birth, at 5-6 weeks after birth, and from 7 weeks after birth to 40 weeks of corrected gestational age. There was a positive linear correlation between the corpus callosum length and the cerebellar vermis length. Small-for-gestational age infants had a low growth rate of corpus callosum at 2 weeks after birth. The 12 preterm infants with severe abnormal intellectual development had a lower growth rate of corpus callosum compared with the 108 preterm infants with non-severe abnormal intellectual development at 3-6 weeks after birth. The 5 preterm infants with severe abnormal motor development had a significantly lower growth rate of corpus callosum compared with the 115 preterm infants with non-severe abnormal motor development at 3-6 weeks after birth. CONCLUSIONS: The decline of growth rate of corpus callosum in preterm infants at 2-6 weeks after birth can increase the risk of severe abnormal neuromotor development.

[A contrastive study of corpus callosum area in very preterm and full-term infants].

OBJECTIVE: To compare the differences between full-term and VLBW premature infants at term equivalent for the whole and sub-regional corpus callosum areas in order to provide reference for monitoring the extrauterine development of corpus callosum in VLBW premature infants. METHODS: Brain MR image data of 24 term infants with a gestational age of 39 weeks were collected within 24 hours after birth. Brain MR image of 30 VLBW neonates at 39 weeks' gestational age equivalent were successfully obtained. Routine T1WI, T2WI and DWI were applied. T1-weighted images on the mid-sagittal slice were selected, analyzed and measured. Forty-nine eligible MR images of them were chosen, 21 cases from the full-term infant group and 28 cases from the premature infant group. Corpus callosum and brain MR images were then sketched by two radiographic doctors. All data were analyzed by the Image Processing Function of MATLAB R2010a, and the whole corpus callosum and six sub-regions were obtained. RESULTS: The whole corpus callosum, anterior mid-body, posterior mid-body, isthmus and splenium area in the premature infant group were smaller than those in the full-term infant group (P<0.05), but the differences of Genu and rostral body area between the two groups was not statistically significant (P>0.05). CONCLUSIONS: The areas of the whole corpus callosum, anterior mid-body, posterior mid-body, isthmus and splenium in VLBW preterm infants at term are reduced, suggesting that the posterior end of the corpus callosum is probably most vulnerable to insults following pathogenic factors.

[Study on HPLC fingerprint of Tibetan herb Gymnadenia conopsea].

OBJECTIVE: To establish the HPLC fingerprint of Gymnadenia conopsea from different regions of Qinghai-Tibet Plateau. METHODS: 12 batches of Gymnadenia conopsea were measured by the RP-HPLC, and their fingerprints were obtained. Chromatographic condition: The sample was separated on column of Kromasil C18 (4.6 mm x 250 mm,5 microm) and gradiently eluted with a mixture of methanol and water (containing 0.04% phosphoric acid). The flow rate was 0.7 mL/min. The detection wavelength was set at 222 nm and the column temperature was 30 degrees C. RESULTS: The HPLC fingerprint of Gymnadenia conopsea was set up and 13 common peaks were selected,the results of method validation met technical requirement of fingerprint,the similarity of 12 batches Gymnadenia conopsea was 0.904 - 0.989. Principal components analysis and clustering analysis were used in the identification of the samples. CONCLUSION: The method is simple, practicable and reliable, which can be used for the quality control of Gymnadenia conopsea.

Effects of antidepressants on the exploration, spontaneous motor activity and isolation-induced aggressiveness in mice.

OBJECTIVE: To study the role of different antidepressants on exploration, spontaneous motor activity and isolation-induced aggressiveness in mice, further to discuss different mechanisms of their anti-aggression. METHODS: With an aggressive model induced by isolation housing in mice, antagonism of different antidepressants against isolation-induced aggression was evaluated. In the group-housed mice given the same treatment as aggressive test, exploration and spontaneous motor activity were measured. RESULTS: (1) Mianserin (0.5-5 mg/kg-1), buspirone (2.5-10 mg.kg-1) and meclobemide (2.5-10 mg.kg-1) significantly inhibited the exploration in the group-housed mice, but not fluoxetine (2.5-10 mg.kg-1), imipramine (2.5-10 mg.kg-1) and DOI (0.5-2 mg.kg-1); (2) Both mianserin and buspirone, but not fluoxetine, imipramine, meclobemide and DOI, obviously reduced spontaneous motor activity; (3) Fluoxetine, miaserin, imipramine and buspirone significantly and dose-dependently antagonized isolation-induced aggressive behavior, whereas meclobemide failed to attenuate aggression. DOI dual-regulated aggressiveness in isolation mice. CONCLUSION: Our findings suggest that the effects of fluoxetine, mianserin, buspirone, imipramine, meclobemide and DOI on exploration, spontaneous motor activity and isolation-induced aggression in mice are different, which may involve different pharmacological mechanisms underlying their anti-aggression in isolation mice. 5-HT1A and 5-HT2A/2C receptors may mediate isolation-induced aggressive behavior in mice. The involvement of 5-HT receptor subtypes needs further clarification.

L-type Ca(2+) channel blockers inhibit the development but not the expression of sensitization to morphine in mice.

The relationship between opioid actions and L-type Ca(2+) channel blockers has been well documented. However, there is no report relevant to L-type Ca(2+) channel blockers and morphine sensitization, which is suggested to be an analog of behaviors that are characteristic of drug addiction. We now studied systematically the effects of three L-type Ca(2+) channel blockers, nimodipine, nifedipine and verapamil, on morphine-induced locomotor activity, the development and the expression of sensitization to morphine. The results showed that both nimodipine and verapamil attenuated, while nifedipine had only a tendency to decrease morphine-induced locomotor activity. All three drugs inhibited the development of sensitization to morphine. However, none of them showed any effects on the expression of morphine sensitization. These results indicate that blocking L-type Ca(2+) channel attenuates the locomotor-stimulating effects of morphine and inhibits the development but not the expression of morphine sensitization.

Tramadol reduces the 5-HTP-induced head-twitch response in mice via the activation of mu and kappa opioid receptors.

Tramadol, an atypical opioid analgesic, stimulates both opiatergic and serotonergic systems. Here we have investigated the effect of tramadol in mice on 5-hydroxyptrytophan (5-HTP)-induced head twitch response (HTR), which is an animal model for the activation of the CNS 5-HT(2A) receptors in mice. Tramadol attenuated 5-HTP-induced HTR in a dose-dependent manner as morphine. Furthermore, the nonselective opioid receptor antagonists, naloxone and diprenorphine (M5050), reversed the effect of tramadol on 5-HTP-induced HTR dose-dependently. Interestingly, in contrast to the selective delta opioid receptor antagonist NTI, beta-FNA, a selective mu receptor antagonist, and nor-BNI, a selective kappa opioid receptor antagonist, antagonized the attenuation of 5-HTP-induced HTR by tramadol. In conclusion, administration of tramadol systemically inhibits 5-HTP-induced HTR in mice by activating opiatergic system in the CNS. Our findings show that mu and kappa opioid receptors, but not delta opioid receptor, play an important role in the regulation of serotonergic function in the CNS.

Buspirone-induced antinociception is mediated by L-type calcium channels and calcium/caffeine-sensitive pools in mice.

RATIONALE: Previous studies have shown that buspirone, a partial 5-HT(1A) receptor agonist, produces antinociceptive effects in rats and mice; Ca(2+) plays a critical role as a second messenger in mediating nociceptive transmission. 5-HT(1A) receptors have been proven to be coupled functionally with various types of Ca(2+) channels in neurons, including N-, P/Q-, T-, or L-type. It was of interest to investigate the involvement of extracellular/intracellular Ca(2+) in buspirone-induced antinociception. OBJECTIVES: To determine whether central serotonergic pathways participate in the antinociceptive processes of buspirone, and investigate the involvement of Ca(2+) mechanisms, particularly L-voltage-gated Ca(2+) channels and Ca(2+)/caffeine-sensitive pools, in buspirone-induced antinociception. METHODS: Antinociception was assessed using the hot-plate test (55 degrees C, hind-paw licking latency) in mice treated with either buspirone (1.25-20 mg/kg i.p.) alone or the combination of buspirone and fluoxetine (2.5-10 mg/kg i.p.), 5-HTP (25 mg/kg i.p.), nimodipine (2.5-10 mg/kg i.p.), nifedipine (2.5-10 mg/kg i.p.), CaCl(2) (25-200 nmol per mouse i.c.v.), EGTA (5-30 nmol per mouse i.c.v.), or ryanodine (0.25-2 nmol per mouse i.c.v.). RESULTS: Buspirone dose dependently increased the licking latency in the hot-plate test in mice. This effect of buspirone was enhanced by fluoxetine, 5-HTP, nimodipine, and nifedipine. Interestingly, central administration of Ca(2+) reversed the antinociceptive effects of buspirone. In contrast to these, ryanodine or EGTA administered centrally potentiated buspirone-induced antinociception. CONCLUSIONS: Decreasing neuronal Ca(2+) levels potentiated buspirone-induced antinociception; conversely, increasing intracellular Ca(2+) abolished the antinociceptive effects of buspirone. These results suggest that Ca(2+) influx from extracellular fluid and release of Ca(2+) from Ca(2+)/caffeine-sensitive microsomal pools may be involved in buspirone-induced antinociception.