Neuroscience
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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.
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The ventrobasal thalamus is the principal somatosensory thalamic relay nucleus, and it receives two major sources of excitatory input: firstly an input from ascending sensory afferents, and secondly a descending projection from the primary somatosensory cortex. There is considerable anatomical evidence to suggest that both of these projections utilise the excitatory amino acid L-glutamate as their neurotransmitter. Previous work from this laboratory has shown that the sensory input to the rat ventrobasal thalamus in vivo is mediated by ionotropic excitatory amino acid receptors of both the N-methyl-D-aspartate and non-N-methyl-D-aspartate type. ⋯ These data indicate that both N-methyl-D-aspartate receptors and Group I (possibly metabotropic glutamate receptors type I) metabotropic receptors are involved in the mediation of corticothalamic transmission. Such a transmitter mechanism would allow a modulatory system that could selectively enhance other excitatory inputs. Some of these data have been reported in abstract form.
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The regional distribution of the serotonin uptake system was studied in rat brain using a specific polyclonal antibody raised against the putative extracellular loop between transmembrane domains 7 and 8 of the cloned rat serotonin transporter. Light microscope analysis with fluorescence and avidin-biotin-peroxidase techniques revealed a punctate staining as well as numerous labelled thin fibres, which exhibited accumulation of reaction end-product deposit over varicosities. These immunopositive processes were widely and heterogeneously distributed in the rat brain. ⋯ In addition, some immunoreactive fibres were present in the molecular and granular layers of the cerebellum as well as in the cochlear and olivary nuclei. In none of the regions analysed was evidence for glial staining obtained. The present immunocytochemical data reveal a widespread and heterogeneous distribution of the serotonin transporter in rat brain and suggest that serotoni transporter is preferentially sorted into axons, where it appears concentrated at varicosities and terminal boutons.