Spinal cord injury-induced attenuation of GABAergic inhibition in spinal dorsal horn circuits is associated with down-regulation of the chloride transporter KCC2 in rat: Silent spinal circuits speak up after SCI

Most spinal cord injury (SCI) patients suffer from chronic pain. Effective therapy for this pain is lacking, and the underlying mechanisms are poorly understood. The spinal superficial dorsal horn (SDH) contains neuronal circuits capable of modulating primary afferent information involved in pain processing. KCC2 is an isoform of the K+–Cl− cotransporter that contributes to the regulation of transmembrane anion gradient which plays a key role in shaping GABAA receptor-mediated signalling in the CNS. We tested the hypothesis that SCI causes down-regulation of KCC2 distal to the injury and contributes to the neuronal hyperresponsiveness and pain-related behaviours. SCI was a hemisection at T13 level of adult Sprague–Dawley rats. Spinal sagittal slices with attached dorsal roots (DR) were prepared from L4 to L6 level. The reversal potentials of GABA responses (EGABA) and DR-evoked IPSPs and EPSPs of L4-6 SDH neurones in sham-operated and SCI rats were compared using gramicidin-perforated patch-clamp recordings. Here we report that thoracic SCI-induced down-regulation of KCC2 in the lumbar SDH parallels the development of allodynia. The subsequent changes of EGABA in SDH neurones attenuate the GABAA receptor-mediated inhibitory synaptic transmission. These changes cause certain normally subthreshold primary A and C fibre inputs to evoke action potential output in SDH neurones. We conclude that SCI induces KCC2 down-regulation and subsequent changes of EGABA in the SDH below the injury site. The resulting disinhibition unmasks normally ineffective SDH neuronal circuits and may contribute to the below-level central pain-related behaviours after incomplete SCI

FDTD Modelling of Silver Nanoparticles Embedded in Phase Separation Interface of H-PDLC

We report localized surface plasmon resonance (LSPR) of silver nanoparticles (NPs) embedded in interface of phase separation of holographic polymer-dispersed liquid crystal (H-PDLC) gratings using Finite-Difference Time Domain method. We show that silver NPs exhibit double resonance peak at the interface, and these peaks are influenced by the angle of incident light. We observe a blue shift of the wavelength of resonance peak as the incident angle increases. However, the location of silver NPs at the interface has nearly no effect on the wavelength of resonance peak. Also we show near-field and far-field properties surrounding silver NPs and find that field distribution can be controlled through rotation of incident angle. Therefore, LSPR properties of silver NPs within H-PDLC gratings can be excited by appropriate wavelength and angle of the incident light

Degradation of difenoconazole in water and soil: Kinetics, degradation pathways, transformation products identification and ecotoxicity assessment

Difenoconazole is a widely used triazole fungicide that has been frequently detected in the environment, but comprehensive study about its environmental fate and toxicity of potential transformation products (TPs) is still lacking. Here, laboratory experiments were conducted to investigate the degradation kinetics, pathways, and toxicity of transformation products of difenoconazole. 12, 4 and 4 TPs generated by photolysis, hydrolysis and soil degradation were identified via UHPLC-QTOF/MS and the UNIFI software. Four intermediates TP295, TP295A, TP354A and TP387A reported for the first time were confirmed by purchase or synthesis of their standards, and they were further quantified using UHPLC-MS/MS in all tested samples. The main transformation reactions observed for difenoconazole were oxidation, dechlorination and hydroxylation in the environment. ECOSAR prediction and laboratory tests showed that the acute toxicities of four novel TPs on Brachydanio rerio, Daphnia magna and Selenastrum capricornutum are substantially lower than that of difenoconazole, while all the TPs except for TP277C were predicted chronically very toxic to fish, which may pose a potential threat to aquatic ecosystems. The results are important for elucidating the environmental fate of difenoconazole and assessing the environmental risks, and further provide guidance for scientific and reasonable use.acceptedVersio

Peptidergic CGRPα Primary Sensory Neurons Encode Heat and Itch and Tonically Suppress Sensitivity to Cold

Calcitonin gene-related peptide (CGRP) is a classic molecular marker of peptidergic primary somatosensory neurons. Despite years of research, it is unknown if these neurons are required to sense pain or other sensory stimuli. Here, we found that genetic ablation of CGRPα-expressing sensory neurons reduced sensitivity to noxious heat, capsaicin and itch (histamine and chloroquine) and impaired thermoregulation but did not impair mechanosensation or β-alanine itch—stimuli associated with nonpeptidergic sensory neurons. Unexpectedly, ablation enhanced behavioral responses to cold stimuli and cold mimetics without altering peripheral nerve responses to cooling. Mechanistically, ablation reduced tonic and evoked activity in postsynaptic spinal neurons associated with TRPV1/heat, while profoundly increasing tonic and evoked activity in spinal neurons associated with TRPM8/cold. Our data reveal that CGRPα sensory neurons encode heat and itch and tonically cross-inhibit cold-responsive spinal neurons. Disruption of this crosstalk unmasks cold hypersensitivity, with mechanistic implications for neuropathic pain and temperature perception

Study on Formulation, in vivo Exposure, and Passive Targeting of Intravenous Itraconazole Nanosuspensions

The pharmacokinetic profile of a drug can be different when delivered as a nanosuspension compared with a true solution, which may in turn affect the therapeutic effect of the drug. The goal of this study was to prepare itraconazole nanosuspensions (ITZ-Nanos) stabilized by an amphipathic polymer, polyethylene glycol-poly (benzyl aspartic acid ester) (PEG-PBLA), by the precipitation-homogenization, and study the pharmacokinetic profile of the ITZ-Nanos. The particle size and morphology of nanosuspensions were determined by Zetasizer and field emission scanning electron microscope (SEM), respectively. The dissolution profile was evaluated using a paddle method according to Chinese Pharmacopoeia 2015. The level of ITZ in plasma and tissues was measured by a HPLC method. The optimized ITZ-Nanos had an average particle size of 268.1 ± 6.5 nm and the particles were in a rectangular form. The dissolution profile of ITZ-Nanos was similar to that of commercial ITZ injections, with nearly 90% ITZ released in the first 5 min. The ITZ-Nanos displayed different pharmacokinetic properties compared with the commercial ITZ injections, including a decreased initial drug concentration, increased plasma half-life and mean residence time (MRT), and increased concentration in the liver, lung, and spleen. The ITZ-Nanos can change the in vivo distribution of ITZ and result in passive targeting to the organs with mononuclear phagocyte systems (MPS)