Neuroscience
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Comparative Study
A greater role for the norepinephrine transporter than the serotonin transporter in murine nociception.
Norepinephrine and serotonin involvement in nociceptive functions is supported by observations of analgesic effects of norepinephrine transporter (NET) and serotonin transporter (SERT) inhibitors such as amitriptyline. However, the relative contribution of NET and SERT to baseline nociception, as well as amitriptyline analgesia, is unclear. Amitriptyline and morphine analgesia in wild-type (WT) mice and littermates with gene knockout (KO) of SERT, NET or both transporters was conducted using the hotplate and tail-flick tests. ⋯ Furthermore, in the acetic acid writhing test of visceral nociception pronounced hypoalgesia was again found in NET KO mice, but no change in SERT KO mice. As some of these effects may have resulted from developmental consequences of NET KO, the effects of the selective NET blocker nisoxetine and the selective SERT blocker fluoxetine were also examined in WT mice: only nisoxetine produced analgesia in these mice. Collectively these data suggest that NET has a far greater role in determining baseline analgesia, and perhaps other analgesic effects, than SERT in mice.
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Comparative Study
Different effects of zolpidem and diazepam on hippocampal sharp wave-ripple activity in vitro.
Sharp waves and the concurrent high-frequency "ripple" oscillation (100-200 Hz) is a prominent intrinsic hippocampal network activity that occurs during slow-wave sleep and resting wakefulness with an important role in memory processes. Present data suggest that the generation of sharp wave-ripple (SWRs) requires a complex interaction between the various components of the hippocampal network with the important involvement of GABA(A) receptor (GABA(A)R)-mediated transmission. The positive modulators of GABA(A)Rs zolpidem and diazepam differ in their selectivity for the various subtypes of GABA(A)Rs. ⋯ It was also observed that at low concentrations both drugs increased the rate of initiation of episodes of SWR. At high concentration zolpidem but not diazepam continued to increase the rate of episodes of SWRs. We propose that an accurate yet dynamic balance between excitation and inhibition in specific sites of the hippocampal network distinctly regulates the generation of basic features of SWRs such as ripples and sequential activation of the neuronal assemblies which have particular functional roles.
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In larval lamprey, spinal locomotor activity can be initiated by pharmacological microstimulation from the following higher order brain locomotor areas [Paggett et al. (2004) Neuroscience 125:25-33; Jackson et al. (2007) J Neurophysiol 97:3229-3241]: rostrolateral rhombencephalon (RLR); ventromedial diencephalon (VMD); or dorsolateral mesencephalon (DLM). In the present study, pharmacological microstimulation with excitatory amino acids (EAAs) or their agonists in the brains of in vitro brain/spinal cord preparations was used to determine the sizes, pharmacology, and organization of these locomotor areas. First, the RLR, DLM and VMD locomotor areas were confined to relatively small areas of the brain, and stimulation as little as 50 μm outside these areas was ineffective or elicited tonic or uncoordinated motor activity. ⋯ Third, with synaptic transmission blocked only in the brain, stimulation in the RLR, VMD, or DLM no longer initiated spinal locomotor activity, suggesting that these locomotor areas do not directly activate spinal locomotor networks. Fourth, following a complete transection at the mesencephalon-rhombencephalon border, stimulation in the RLR no longer initiated spinal motor activity. Thus, the RLR locomotor area does not appear able to initiate spinal locomotor activity by neural circuits confined entirely within the rhombencephalon but requires more rostral neural centers, such as those in the VMD and DLM, as previously proposed [Paggett et al. (2004) Neuroscience 125:25-33].
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The ventral bed nuclei of the stria terminalis (BST) and medial preoptic nucleus (MPN) of gerbils contain cells that regulate male sex behavior via a largely uncrossed pathway to the retrorubral field (RRF). Our goal was to learn more about cells at the pathway source and target. To determine if the pathway uses GABA as its transmitter, we used immunocytochemistry (ICC) to study glutamic acid decarboxlyase(67) (GAD(67)) colocalization with fluoro-gold (FG) in the ventral BST and MPN after applying FG to the RRF. ⋯ Their activation may reflect arousal and anticipation of sexual reward. Among ventral BST cells that project to the RRF, 14% were activated with mating, consistent with how much of this pathway is needed for mating. The activated GABAergic cells that do not project to the RRF may release GABA locally and inhibit ejaculation.
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Botulinum neurotoxin serotype A (BoNT/A) acts by cleaving synaptosome-associated-protein-25 (SNAP-25) in nerve terminals to inhibit neuronal release and shows long-lasting antinociceptive action in neuropathic pain. However, its precise mechanism of action remains unclear. Our study aimed to characterize BoNT/A-induced neuroimmunological changes after chronic constriction injury (CCI) of the sciatic nerve. ⋯ BoNT/A also diminished the injury-induced upregulation of SNAP-25 expression in both structures. We provide evidence that BoNT/A impedes injury-activated neuronal function in structures distant from the injection site, which is demonstrated by its influence on NOS1, prodynorphin and pronociceptin mRNA levels in the DRG. Moreover, the silence of microglia/macrophages after BoNT/A administration could be secondary to the inhibition of neuronal activity, but this decrease in neuroimmune interactions could be the key to the long-lasting BoNT/A effect on neuropathic pain.