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1.
Drug Res (Stuttg) ; 69(8): 428-433, 2019 Aug.
Article in English | MEDLINE | ID: mdl-30609433

ABSTRACT

Little is known about the role of 5-HT6 receptors in the pathophysiology of neuropathic pain. The aim of this study is firstly, to investigate the influence of spinal and systemic 5-HT6 receptors on thermal hyperalgesia, one of the most significant symptoms of neuropathy occurring in diabetes; and secondly to determine spinal lumbar serotonin and 5-HT6 receptor levels during development of diabetic neuropathy in mice. Diabetes was produced in Balb/c mice with a single injection of streptozocin (150 mg/kg, i.p.). Using the hot plate test, the 5-HT6 antagonist SB-258585 was given systemically (3, 10, 30 mg/kg) and intrathecally (0.01, 0.1, 1 nmol/mouse) to determine its effect on thermal hyperalgesia. Furthermore, on days 7 and 15 of diabetes, development of thermal hyperalgesia was evaluated in relation to changes in spinal serotonin and 5-HT6 receptor levels by using LC/MS/MS and Western blot analyses, respectively. Two-way analysis of variance and unpaired t-tests were used to evaluate data from hot-plate tests and 5-HT levels/ 5-HT6 receptor expression, respectively. Thermal hyperalgesia was observed in neuropathic mice, starting from day 5 after streptozocin administration. On day 15, systemic, but not intrathecal, SB-258585 attenuated thermal hyperalgesia in neuropathic mice. Spinal serotonin levels did not change during development of hyperalgesia after induction of diabetes, whereas spinal 5-HT6 receptor levels were significantly reduced on days 7 and 15. Our findings show that systemic, but not spinal, blockade of 5-HT6 receptors may exert antihyperalgesic effects in neuropathic mice and suggest that systemic 5-HT6 receptors contribute to the pathophysiology of diabetic neuropathy.


Subject(s)
Diabetic Neuropathies/etiology , Hyperalgesia/physiopathology , Receptors, Serotonin/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Serotonin/metabolism , Analysis of Variance , Animals , Blotting, Western , Diabetes Mellitus, Experimental/complications , Diabetic Neuropathies/metabolism , Gas Chromatography-Mass Spectrometry , Hyperalgesia/etiology , Locomotion/drug effects , Locomotion/physiology , Lumbar Vertebrae , Mice , Mice, Inbred BALB C , Psychomotor Performance , Serotonin/cerebrospinal fluid , Serotonin Plasma Membrane Transport Proteins/cerebrospinal fluid , Selective Serotonin Reuptake Inhibitors/pharmacology , Spinal Cord/metabolism , Tandem Mass Spectrometry
2.
Alcohol Clin Exp Res ; 35(5): 912-20, 2011 May.
Article in English | MEDLINE | ID: mdl-21294753

ABSTRACT

BACKGROUND: Moderate prenatal alcohol exposure can contribute to neurodevelopmental impairments and disrupt several neurotransmitter systems. We examined the timing of moderate level alcohol exposure, serotonin transporter gene polymorphic region variation (rh5-HTTLPR), and levels of primary serotonin and dopamine (DA) metabolites in cerebrospinal fluid (CSF) in rhesus monkeys. METHODS: Thirty-two 30-month old rhesus monkeys (Macaca mulatta) from 4 groups of females were assessed: (i) early alcohol-exposed group (n = 9), in which mothers voluntarily consumed 0.6 g/kg/d alcohol solution on gestational days 0 to 50; (ii) middle-to-late gestation alcohol-exposed group (n = 6), mothers consumed 0.6 g/kg/d alcohol solution on gestational days 50 to 135; (iii) a continuous-exposure group (n = 8), mothers consumed 0.6 g/kg/d alcohol solution on gestational days 0 to 135; and (iv) controls (n = 9), mothers consumed an isocaloric control solution on gestational days 0 to 50, 50 to 135, or 0 to 135. Serotonin transporter promoter region allelic variants (homozygous s/s or heterozygous s/l vs. homozygous l/l) were determined. We examined CSF concentrations of the 5-HT and DA metabolites, 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), respectively, at baseline and 50 hours after separation from cage-mates, when the monkeys were 30 months old. RESULTS: Early- and middle-to-late gestation-alcohol exposed monkeys carrying the short allele had lower concentrations of 5-HIAA in CSF relative to other groups. Concentrations of 5-HIAA in CSF were lower for s allele carriers and increased from baseline relative to pre-separation values, whereas 5-HIAA levels in l/l allele carriers were not affected by separation. Monkeys carrying the short allele had lower basal concentrations of HVA in CSF compared with monkeys homozygous for the long allele. CONCLUSION: Carrying the s allele of the 5-HT transporter increased the probability of reduced 5-HIAA in early- and middle-to-late gestation alcohol-exposed monkeys and reduced HVA at baseline. These findings that prenatal alcohol exposure altered central 5-HT activity in genetically sensitive monkeys raise questions about whether abnormal serotonin biological pathways could underlie some of the psychiatric disorders reported in fetal alcohol spectrum disorder.


Subject(s)
Central Nervous System/physiology , Ethanol/administration & dosage , Prenatal Exposure Delayed Effects/genetics , Serotonin Plasma Membrane Transport Proteins/genetics , Serotonin/genetics , Animals , Central Nervous System/drug effects , Female , Genotype , Hydroxyindoleacetic Acid/cerebrospinal fluid , Macaca mulatta , Male , Pregnancy , Prenatal Exposure Delayed Effects/cerebrospinal fluid , Random Allocation , Serotonin/cerebrospinal fluid , Serotonin Plasma Membrane Transport Proteins/cerebrospinal fluid
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