Neuroscience
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Prior work has provided extensive documentation of threshold sensitivity and sensory hair cell losses after noise exposure. It is now clear, however, that cochlear synaptic loss precedes such losses, at least at low-moderate noise doses, silencing affected neurons. To address questions of whether, and how, cochlear synaptopathy and underlying mechanisms change as noise dose is varied, we assessed cochlear physiologic and histologic consequences of a range of exposures varied in duration from 15 min to 8 h and in level from 85 to 112 dB SPL. ⋯ With increasing noise dose, synapse loss grew to ∼50%, then declined for exposures yielding permanent hair cell injury/loss. All synaptopathic, but no non-synaptopathic exposures produced persistent neural response amplitude declines; those additionally yielding permanent OHC injury/loss also produced persistent reductions in OHC-based responses and exaggerated neural amplitude declines. Findings show that widespread cochlear synaptopathy can be present with and without noise-induced sensory cell loss and that differing patterns of cellular injury influence synaptopathic outcomes.
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Not all the people that consume drugs of abuse develop addiction. In this sense, just a percentage of rats express locomotor sensitization after repeated psychostimulant exposure. Neurochemical evidence has shown that locomotor sensitization is associated with changes in dorsolateral striatum (DLS) activity. ⋯ A decrease in MSNs baseline Lv accompanies the expression of AMPH locomotor sensitization. Moreover, a decrease in Lv after an acute AMPH 1.0 mg/kg injection was only observed in saline and sensitized rats. Our results show individual differences in DLS basal DA levels and firing pattern after repeated AMPH administration, suggesting that an hyperfunction of nigrostriatal pathway, accompanied by a decrease in DLS MSNs firing irregularity underlies the expression of AMPH locomotor sensitization.
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We reported recently that activators of AMP-activated protein kinase (AMPK) slow the rundown of current evoked by the D2 autoreceptor agonist quinpirole in rat substantia nigra compacta (SNC) dopamine neurons. The present study examined the effect of AMPK on current generated by dopamine, which unlike quinpirole, is a substrate for the dopamine transporter (DAT). Using whole-cell patch-clamp, we constructed current-voltage (I-V) plots while superfusing brain slices with dopamine (100 μM) for 25 min. ⋯ When D2 autoreceptors were blocked by sulpiride, I-V plots showed that dopamine evoked an inward current with an estimated slope conductance of 0.45 nS with an Erev of -57 mV. Moreover, this inward current was completely blocked by the trace amine-associated receptor 1 (TAAR1) antagonist EPPTB. These results suggest that dopamine activates a TAAR1-dependent non-selective cation current that is regulated by AMPK.
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Regular physical exercise has been described as a good strategy for prevention or reduction of musculoskeletal pain. The Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) has been investigated as a promising target for the control of inflammatory pain. Therefore, the aim of this study was to evaluate whether activation of PPARγ receptors is involved in the reduction of acute muscle pain by chronic exercise and, in this case, whether this process is modulated by inflammatory cytokines. ⋯ The results showed that swimming physical training prevented the onset of acute mechanical muscle hyperalgesia and the increase in muscle levels of Cytokine-induced neutrophil chemoattractant 1 (CINC-1) induced by carrageenan into gastrocnemius muscle. In addition, local pre-treatment with the selective PPARγ receptors antagonist GW9662 reversed the mechanical muscle hypoalgesia and the modulation of CINC-1 levels induced by swimming physical training. These data suggest that swimming physical training prevented the onset of acute mechanical muscle hyperalgesia by a mechanism dependent of PPARγ receptors, which seems to contribute to this process by modulation of the pro-inflammatory cytokine CINC-1, and highlight the potential of PPARγ receptors as a target to control musculoskeletal pain and to potentiate the reduction of musculoskeletal pain induced by exercise.
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The amphibian Bv8 and the mammalian prokineticin 1 (PROK1) and 2 (PROK2) are new chemokine-like protein ligands acting on two G protein-coupled receptors, prokineticin receptor 1 (PKR1) and 2 (PKR2), participating to the mediation of diverse physiological and pathological processes. Prokineticins (PKs), specifically activating the prokineticin receptors (PKRs) located in several areas of the central and peripheral nervous system associated with pain, play a fundamental role in nociception. In this paper, to improve the understanding of the prokineticin system in the neurobiology of pain, we investigated the role of PKR2 in pain perception using pkr2 gene-deficient mice. ⋯ This notion was supported by experiments in dorsal root ganglia (DRG) cultures from pkr1 and-pkr2-null mice, demonstrating that the percentage of Bv8-responsive DRG neurons which were also responsive to mustard oil was much higher in PKR1-/- than in PKR2-/- mice. Taken together, these findings suggest a functional interaction between PKR2 and TRP channels in the development of hyperalgesia. Drugs able to directly or indirectly block these targets and/or their interactions may represent potential analgesics.