Neuroscience
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Interleukin-6 (IL-6) is a multifunctional cytokine that may have a role in energy regulation. Using a recombinant adeno-associated viral vector expressing murine interleukin-6 (rAAV-IL-6), we examined the chronic effects of centrally expressed IL-6 on food intake, body weight and adiposity in male Sprague-Dawley rats, and investigated the underlying mechanisms. Direct delivery of rAAV-IL-6 into rat hypothalamus suppressed weight gain and visceral adiposity without affecting food intake over a 5-week period. rAAV-IL-6 enhanced uncoupling protein 1 (UCP1) protein levels in interscapular brown adipose tissue (BAT). ⋯ These data demonstrate that chronic elevation of IL-6 in the CNS reduces body weight gain and visceral adiposity without affecting food intake. The mechanism involves sympathetic induction of UCP1 in BAT and, presumably, enhanced thermogenesis in BAT. Furthermore, chronic central IL-6 stimulation desensitizes IL-6 signal transduction characterized by reversal of elevated P-STAT3 levels.
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Galanin immunoreactive fibers hyperinnervate remaining cholinergic basal forebrain neurons in Alzheimer's disease, perhaps exacerbating the cholinergic deficit. The purpose of our study is to determine whether a similar phenomenon occurs following intraparenchymal injection of 192 IgG-saporin, a specific cholinergic neurotoxin, within the nucleus of the horizontal limb of the diagonal band of Broca. Immunotoxic lesion produced on average a 31% reduction in cholinergic cell counts ipsilateral to the lesion, compared to the contralateral side. ⋯ There was no statistically significant correlation between the extent of cholinergic cell loss and the increase in galanin immunoreactivity surrounding the lesion. Yet, since both of these changes persist over time, we suggest that galanin plasticity is triggered by neuronal damage. Our model can be useful to test the role that galanin plays in the regulation of acetylcholine and the efficacy of galanin inhibitors as potential therapeutic interventions in Alzheimer's disease.
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Physical dependence is a widely known consequence of morphine intake. Although commonly associated with prolonged or repeated morphine administration, withdrawal symptoms can be elicited even after a single prior morphine exposure. What remains contentious is the extent to which physical dependence following acute and chronic morphine treatment is mediated by common physiological substrates and, accordingly, represent distinct syndromes. ⋯ Substantial heritability was also observed for acute and both paradigms of chronic dependence, with estimates ranging from h(2)=0.53 to 0.70. The present demonstration of a strong genetic correlation between physical dependence to morphine following acute and chronic treatment implies that genes associated with variable sensitivity in the two traits are the same, and is suggestive of shared physiological substrates. The data also demonstrate that the differential genetic liability to morphine physical dependence begins with, and is predicted by, the first morphine exposure.
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Studies have shown that 5-hydroxytryptamine (5-HT) plays an important role in the descending pathway of pain modulation from brainstem to the spinal cord. Using selective 5-HT receptor antagonists, the present study investigated which type of 5-HT receptor(s) in the spinal cord was involved in the morphine-induced anti-nociception in intact rats, in rats with nerve injury and in rats with inflammation. The hindpaw withdrawal latencies decreased significantly after sciatic nerve injury and hindpaw inflammation compared with intact rats. ⋯ Intrathecal injection of the 5-HT(2) receptor antagonist RS 102221 and the 5-HT(3) receptor antagonist MDL 72222 had no significant effects on the increased hindpaw withdrawal latencies to both noxious stimulations induced by intra-periaqueductal gray injection of morphine. Furthermore, intrathecal administration of spiroxatrine, but not RS 102221 nor MDL 72222, significantly attenuated the increased hindpaw withdrawal latencies induced by intra-periaqueductal gray administration of morphine in rats with nerve injury and in rats with inflammation. The results demonstrate that the 5-HT(1A) receptor, not 5-HT(2) nor 5-HT(3) receptor, plays an important role in the descending pathway of anti-nociception from the brainstem to the spinal cord in intact rats, in rats with nerve injury and in rats with inflammation.
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To elucidate the mechanism of orphanin FQ on neuroimmune modulation, the relationship between orphanin FQ and interleukin-1beta in the rat CNS in vivo and in vitro was investigated. In our experiments, it was found that orphanin FQ and interleukin-1beta mRNA transcripts showed a similar distribution in cerebral cortex, hippocampus and hypothalamus. By using the in situ hybridization technique, down-regulation of interleukin-1beta mRNA transcripts by central administration of orphanin FQ was further identified in the traumatic animal model. ⋯ When analyzed by reverse transcription-polymerase chain reaction, interleukin-1beta gene expression was observed to be enhanced and inhibited in primary neuron and microglial cell cultures exposed to orphanin FQ respectively. Interleukin-1beta gene expression in astrocyte cultures was not affected by treatment with orphanin FQ. Our findings suggest that the neuroimmune function of orphanin FQ might be dependent on interleukin-1beta derived from microglia, and the interaction between microglia and neurons.