Neuroscience
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Immunoreactivity to pituitary adenylate cyclase activating polypeptide-38 was detected in numerous nerve fibres in layers I and II of the dorsal horn of the rat and some of these fibres extended into the deeper layers of all segments of the spinal cord. Immunoreactivity was also detected in the lateral funiculus projecting into the intermediolateral cell column of the lower cervical and thoracic segments and in the lateral pathway terminating in the intermediate gray area of the lower lumbar and sacral segments. Neurons in the lateral horn area were not immunoreactive nor were the ventral horn motoneurons. ⋯ A few weakly-labelled cells were occasionally seen in the dorsal motor nucleus of vagus. A population of neurons in the trigeminal, nodose and dorsal root ganglia from all segments of the spinal cord displayed low to intense immunoreactivity. The presence of immunoreactivity in nodose and dorsal root ganglia, dorsal horn, spinal autonomic nuclei, solitary tract and in certain areas of the medulla suggests that this peptide may participate in a variety of sensory and autonomic functions.
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Repetitive firing of nerve fibres results in the slowing of their conduction velocity. The extent of conduction velocity slowing throughout a standard electrical stimulus (20 s, 20 Hz, 2 x electrical threshold) was examined in identified C-fibres dissected from the saphenous nerve of anaesthetized rats. The aim of this study was to establish whether the different functional classes of C-fibre could be identified on the basis of their activity-dependent slowing of conduction velocity. ⋯ Moreover, it is possible to use this axonal property to separate the two classes of non-nociceptive afferent C-fibre (i.e. mechanoreceptors and cold thermoreceptors). In addition, one can also use this parameter to differentiate between the afferent and non-afferent populations of inexcitable C-fibres. The ability to identify a particular fibre type on the basis of an axonal property provides a useful tool for the functional classification of fibres in experiments where axons are separated from their terminals.
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To investigate the mechanism of vincristine-induced pain in humans undergoing chemotherapy we have established a model of vincristine-induced hyperalgesia in rat. Vincristine (100 micrograms/kg) was administered daily over a period of two weeks. An acute dose-dependent decrease in mechanical nociceptive threshold and an increased response to non-noxious mechanical stimuli ("hyperalgesia") occurred after the second day of administration. ⋯ At a dose that produced hyperalgesia (100 micrograms/kg), vincristine did not cause a significant motor deficit. Peripheral administration of a mu-opioid agonist did not reduce vincristine-induced acute hyperalgesia. Hyperalgesia induced by vincristine in the rat provides a good model for the experimental study of painful peripheral neuropathies in human patients receiving vincristine as a chemotherapeutic agent.
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The effect of etomidate, an imidazole general anesthetic, on GABAA receptor function was studied in cultured hippocampal neurons. At a clinically relevant concentration of 4.1 microM, etomidate shifts the GABA dose response to the left (ED50 shift from 10.2 to 5.2 microM), with no change in the maximum current evoked by saturating concentrations of GABA. At a higher concentration of 82 microM, etomidate directly induces current in the absence of GABA. ⋯ Analysis of single channels opened by GABA indicates that 8.2 microM etomidate increases the probability of channels being open 13-fold and increases the effective channel open time two-fold. Given the present understanding of central inhibitory synapses, the effect of etomidate on channel kinetics is most likely to be the predominant mechanism which influences the synaptic function. In addition, etomidate, through its modulation of both channel kinetics and open probability, is likely to have a large impact on extrasynaptic GABAA receptor function.
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A long line of studies emphasizes the contribution of serotonergic fibres descending from the rostral ventromedial medulla in the control of spinal nociceptive information processing. A growing body of evidence, however, suggests that the relative contribution of serotonin to the mediation of spinal neuronal activity from the rostral ventromedial medulla may require re-evaluation. It has recently been substantiated that, in addition to the serotonergic fibres, the spinal dorsal horn receives an abundant non-serotonergic projection from the rostral ventromedial medulla. ⋯ We show that the majority of the labelled raphe-spinal terminals in laminae I-IIo and IV-V contain GABA and some of the GABA-immunoreactive terminals are also immunoreactive for glycine. We also disclose that GABA-immunoreactive raphe-spinal terminals establish synaptic contacts primarily with GABA- and glycine-negative, presumably excitatory, spinal neurons, including Calbindin-D28k- as well as parvalbumin-immunoreactive cells in both laminae I-IIo and IV-V. The results suggest that volleys in fibres descending from the rostral ventromedial medulla may evoke GABA release from raphe-spinal terminals, and the released GABA, in some cases probably acting together with glycine, might play a crucial, as yet mostly unidentified, role in the inhibition of nociceptive information processing in the dorsal horn of the spinal cord.