The Journal of neuroscience : the official journal of the Society for Neuroscience
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Analysis of the molecular basis of neuronal migration in the mammalian CNS relies critically on the discovery and identification of genetic mutations that affect this process. Here, we report the detailed cerebellar phenotype caused by a new autosomal recessive neurological mouse mutation, scrambler (gene symbol scm). The scrambler mutation results in ataxic mice that exhibit several neuroanatomic defects reminiscent of reeler. ⋯ However, the scrambler locus has been mapped to a site distinct from that of reelin (Reln), the gene responsible for the reeler defect. Here we find that there are normal levels of Reln mRNA in scrambler brain and that reelin protein is secreted normally by scrambler cerebellar cells. These findings imply that the scrambler gene product may function in a molecular pathway critical for neuronal migration that is tightly linked to, but downstream of, reelin.
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Acute superfusion of nerve growth factor (NGF; 1-100 ng/ml) through a naive rat spinal cord preparation did not alter basal or electrically evoked release of substance P-like immunoreactivity (SP-LI). In contrast, neurotrophin-3 (NT-3; 1-100 ng/ml), although not modifying SP-LI basal outflow, dose-dependently inhibited the electrically evoked, but not capsaicin (10 nM)-induced, release of the peptide. This NT-3 (10 ng/ml)-induced inhibition persisted even in the presence of 100 ng/ml NGF in the perfusion fluid and was still significant when the evoked release of SP-LI was enhanced by a prolonged in vivo treatment with NGF. ⋯ An identical treatment regimen with 1 mg/kg NGF induced a significant increase in evoked release of SP-LI. However, this was not associated with a significant hyperalgesia. Although finding that NGF-induced hyperalgesia does not clearly correlate with changes in the release of SP-LI in the spinal cord, this study shows that NT-3 is an inhibitor of SP-LI release and suggests that this mechanism may be responsible for NT-3-induced antinociception.
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The excitability of spinal neurons that transmit pain is modulated by glutamate and substance P (SP). Glutamate is an excitatory neurotransmitter in the dorsal horn, and its effects are enhanced by SP acting on neurokinin 1 receptors (NK1Rs). We assessed activation of NK1Rs by studying their internalization in spinal cord slices. ⋯ Internalization produced by the 100 Hz tetanus was mimicked by NMDA and blocked by an NMDA antagonist, 2-amino-5-phosphonopentanoic acid, but not by the AMPA and kainate antagonist CNQX. The NK1R antagonist L-703,606 abolished the internalization produced by 100 Hz stimulation or NMDA. Therefore, the release of SP in the dorsal horn appears to be controlled by NMDA receptors.
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D1 receptors located on striatonigral neurons and D2 receptors located, together with A2A receptors, on striatopallidal neurons are known to interact functionally. Using in situ hybridization, we examined the effects of D1 and D2 agonists and of an A2A antagonist on c-fos mRNA in identified striatal neurons and in globus pallidus. The full D1 agonist, SKF 82958 (1 mg/kg), induced a homogenous increase of c-fos mRNA in the striatum. ⋯ However, only the combination of D1 and D2 agonists modified the c-fos mRNA expression to a "patchy" distribution. Our data show that (1) c-fos expression can be activated through D1 and inhibited through A2A or D2 receptors in both striatal output pathways in normal rats, and (2) D2 receptor stimulation as well as A2A receptor blockade can interact with D1 receptor activation to potentiate c-fos expression in the striatum and the globus pallidus. The data also suggest that the topological alteration of c-fos expression after coadministration of D1 and D2 agonists involves D2 receptors located on interneurons or presynaptically on dopaminergic nerve terminals.
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Agonists acting at alpha2 adrenergic and opioid receptors have analgesic properties and act synergistically when co-administered in the spinal cord; this synergy may also contribute to the potency and efficacy of spinally administered morphine. The lack of subtype-selective pharmacological agents has previously impeded the definition of the adrenergic receptor subtype(s) mediating these effects. We therefore exploited a genetically modified mouse line expressing a point mutation (D79N) in the alpha2a adrenergic receptor (alpha2aAR) to investigate the role of the alpha2aAR in alpha2 agonist-evoked analgesia and adrenergic-opioid synergy. ⋯ In addition, the potency of spinally administered morphine was decreased in this test, suggesting that activation of descending noradrenergic systems impinging on the alpha2aAR contributes to morphine-induced spinal inhibition in this model. These results demonstrate that the alpha2aAR subtype is the primary mediator of alpha2 adrenergic spinal analgesia and is necessary for analgesic synergy with opioids. Thus, combination therapies targeting the alpha2aAR and opioid receptors may prove useful in maximizing the analgesic efficacy of opioids while decreasing total dose requirements.