Neuroscience
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The globus pallidus (GP) plays an important role in basal ganglia circuitry. In contrast to the well-characterized actions of dopamine on striatal neurons, the functional role of the dopamine innervation of GP is still not clearly determined. The present study aimed to investigate the effects of intrapallidal injection of 6-hydroxydopamine (6-OHDA) on rotational behavior induced by apomorphine, on the loss of dopamine cell bodies in the substantia nigra pars compacta (SNc) and fibers in the GP and striatum and on in vivo extracellularly-recorded GP neurons in the rat. ⋯ Electrophysiological recordings show that 6-OHDA injection in GP induced a significant decrease of the firing rate of GP neurons (16.02+/-1.11 versus 24.14+/-1.58 spikes/sec in control animals and 22.83+/-1.28 in sham animals, one-way ANOVA, P<0.0001) without any change in the firing pattern (chi(2)=1.03, df=4, P=0.90). Our results support the premise of the existence of collaterals of SNc dopaminergic axons projecting to the striatum and GP and that dopamine plays a role in the modulation of the firing rate but not the firing pattern of GP neurons. Our data provide important insights into the functional role of the SNc-GP dopaminergic pathway suggesting that dopamine depletion in GP may participate in the development of motor disabilities.
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Effective treatment of chronic pain with morphine is limited by decreases in the drug's analgesic action with chronic administration (antinociceptive tolerance). Because opioids are mainstays of pain management, restoring their efficacy has great clinical importance. We have recently reported that formation of peroxynitrite (ONOO(-), PN) in the dorsal horn of the spinal cord plays a critical role in the development of morphine antinociceptive tolerance and have further documented that nitration and enzymatic inactivation of mitochondrial superoxide dismutase (MnSOD) at that site provides a source for this nitroxidative species. ⋯ The more lipophilic analogue, MnTnHex-2-PyP5+ was able to cross the blood-brain barrier at higher levels than its lipophylic counterpart MnTE-2-PyP5+ and was about 30-fold more efficacious. Collectively, these data suggest that PN-mediated enzymatic inactivation of supraspinal MnSOD provides a source of nitroxidative stress, which in turn contributes to central sensitization associated with the development of morphine antinociceptive tolerance. These results support our general contention that PN-targeted therapeutics may have potential as adjuncts to opiates in pain management.
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The present study is aimed at testing the hypothesis that an enriched environment (EE) induces sex-dependent changes in stress hormone release and in markers of increased brain plasticity. The focus was on hypothalamic-pituitary-adrenocortical (HPA) axis activity, plasma levels of stress hormones, gene expression of glutamate receptor subunits and concentrations of brain-derived neurotrophic factor (BDNF) in selected brain regions. Rats exposed to EE were housed in groups of 12 in large cages with various objects, which were frequently changed, for 6 weeks. ⋯ Moreover, a negative association between corticosterone and BDNF was observed in both sexes. The results demonstrate that the association between hormones and changes in brain plasticity is sex related. In particular, testosterone seems to be involved in the regulatory processes related to neuroplasticity in females.
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Gephyrin is a tubulin-binding protein that acts as a scaffold for clustering glycine and GABA(A) receptors at postsynaptic sites. In this study, the role of gephyrin on GABA(A) receptor function was assessed at the post-translational level, using gephyrin-specific single chain antibody fragments (scFv-gephyrin). When expressed in cultured rat hippocampal neurons as a fusion protein containing a nuclear localization signal, scFv-gephyrin were able to remove endogenous gephyrin from GABA(A) receptor clusters. ⋯ In addition, hampering gephyrin function with scFv-gephyrin induced a significant reduction in GABA(A) receptor-mediated tonic conductance. This effect was probably dependent on the decrease in GABAergic innervation and in GABA release from presynaptic nerve terminals. These results indicate that gephyrin is essential not only for maintaining synaptic GABA(A) receptor clusters in the right position but also for regulating both phasic and tonic inhibition.
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Randomized Controlled Trial
Abnormal expression of voltage-gated sodium channels Nav1.7, Nav1.3 and Nav1.8 in trigeminal neuralgia.
Voltage-gated sodium channels have been implicated in acute and chronic neuropathic pain. Among subtypes, Nav1.7 single mutations can cause congenital indifference to pain or chronic neuropathic pain syndromes, including paroxysmal ones. This channel is co-expressed with Nav1.8, which sustains the initial action potential; Nav1.3 is an embrionary channel which is expressed in neurons after injury, as in neuropathic conditions. ⋯ We found that Nav1.7 was downregulated in TN (P=0.017) and Nav1.3 was upregulated in these patients (P=0.043). We propose a physiopathological mechanism for these findings. Besides vascular compression of TN, this disease might be also a channelopathy.