Neuroscience
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Thrombin and activated protein C (aPC) bound to the endothelial protein C receptor (EPCR) both activate protease-activated receptor 1 (PAR1) generating either harmful or protective signaling respectively. In the present study we examined the localization of PAR-1 and EPCR and thrombin activity in Schwann glial cells of normal and crushed peripheral nerve and in Schwannoma cell lines. In the sciatic crush model nerves were excised 1h, 1, 4, and 7days after the injury. ⋯ EPCR was found to be located at the microvilli of Schwann cells at the node of Ranvier and in cytoplasm surrounding the nucleus. Four days after sciatic injury, EPCR levels increased significantly (57,785±16602AU versus 4790±1294AU in the contralateral uninjured nerves, p<0.001 by t-test) mainly distal to the site of injury, where axon degeneration is followed by proliferation of Schwann cells which are diffusely stained for EPCR. EPCR seems to be located to cytoplasmic component of Schwann cells and not to compact myelin component, and is highly increased following injury.
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Propofol is a major intravenous anesthetic that facilitates GABAA receptor-mediated inhibitory synaptic currents and modulates inward current (Ih), K(+), and voltage-gated Na(+) currents. This propofol-induced modulation of ionic currents changes intrinsic membrane properties and repetitive spike firing in cortical pyramidal neurons. However, it has been unknown whether propofol modulates these electrophysiological properties in GABAergic neurons, which express these ion channels at different levels. ⋯ Using a low concentration of propofol clarified this tendency: 30μM propofol decreased the firing of pyramidal neurons but had little effect on GABAergic neurons. Pre-application of a GABAA receptor antagonist, picrotoxin (100μM), diminished the propofol-induced suppression of neural activities in both pyramidal and FS neurons. These results suggest that GABAergic neurons, especially FS neurons, are less affected by propofol than are pyramidal neurons and that propofol-induced modulation of the intrinsic membrane properties and repetitive spike firing are principally mediated by GABAA receptor-mediated tonic currents.
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The insular cortex (IC) plays a principal role in the regulation of pain processing. Although opioidergic agonists depress cortical excitatory synaptic transmission, little is known about opioidergic roles in inhibitory synaptic transmission. In the IC, the opioid receptors differentially regulate the excitatory propagation: agonists of the mu (MOR), delta (DOR), and kappa (KOR) exhibit suppressive, facilitative, and little effects, respectively. ⋯ The DOR agonist, [D-Pen(2,5)]-Enkephalin hydrate (DPDPE), reduced uIPSC amplitude by 39% in FS→FS and by 49% in FS→Pyr connections, which was antagonized by the DOR antagonist, naltrindole. However, DPDPE had little effect on non-FS→FS/Pyr connections. (±)-trans-U-50488 methanesulfonate salt (U50488), a KOR agonist, had little effect on uIPSC in FS→FS/Pyr connections. These results suggest that MOR-induced uIPSC depression in FS→FS and non-FS→FS, but not FS→Pyr and non-FS→Pyr connections, results in the depression of excitatory propagation in the IC, which may be an underlying mechanism of the powerful analgesic effects of MOR agonists.
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This study sought to determine the effects of chronic low back pain (LBP) on the cortical evoked potentials, muscle activation, and kinematics of postural responses to perturbations of standing balance. Thirteen subjects with chronic, recurrent, non-specific LBP and 13 subjects without LBP participated. The subjects responded to unpredictably timed postural perturbations while standing on a platform that randomly rotated either "toes up" or "toes down". ⋯ For the subjects with LBP, CoM displacements significantly and positively correlated with knee displacements as well as activity interference and fear scores. The P2 potentials significantly and negatively correlated with CoM displacements as well as activity interference, catastrophizing, and fear scores. These results demonstrate that people with LBP exhibit altered late-phase cortical processing of postural perturbations concomitant with altered kinematic and muscle responses, and these cortical and postural response characteristics correlate with each other as well as with clinical reports of pain-related fears and activity interference.
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Noradrenergic signaling, through the α2A and α2C adrenergic receptors modulates the cognitive and behavioral symptoms of disorders such as schizophrenia, attention deficit hyperactivity disorder (ADHD), and addiction. However, it is unknown whether the α2B receptor has any significant role in CNS function. The present study elucidates the potential role of the α2B receptor in CNS function via the discovery and use of the first subtype-selective α2B antagonist (AGN-209419), and behavioral analyses of α-receptor knockout (KO) mice. ⋯ However, α2B KO mice exhibited stereotypy at doses of amphetamine that were only locomotor stimulatory to all other genotypes. Following co-administration of AGN-209419 with low-dose amphetamine in WT mice, stereotypy was observed, mimicking the α2B KO phenotype. These findings suggest that the α2B receptor is involved in CNS behaviors associated with sensorimotor gating and compulsivity, and may be therapeutically relevant for disorders such as schizophrenia, ADHD, post-traumatic stress disorder, addiction, and obsessive compulsive disorder.