The Journal of neuroscience : the official journal of the Society for Neuroscience
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This study addresses the hypothesis that the previously described capacity of D1 dopamine receptors (D1Rs) to regulate dendritic growth in developing cortical neurons may involve alterations in the phosphorylation state of microtubule-associated protein-2 (MAP2). The changes in phosphorylation of this protein are known to affect its ability to stabilize the dendritic cytoskeleton. The study involved two systems: primary cultures of mouse cortical neurons grown in the presence of the D1R agonists, SKF82958 or A77636, and the cortex of neonatal transgenic mice overexpressing the D1A subtype of D1R. ⋯ Moreover, MAP2 phosphorylation underwent a substantial increase between 24 and 72 hr of exposure to these drugs. Our findings are consistent with the idea that D1Rs can modulate growth and maintenance of dendrites in developing cortical cells by regulating the phosphorylation of MAP2. In addition, our observations suggest that MAP2 phosphorylation by long-term activation of D1Rs (and PKA) can be divided into two phases: the initial approximately 24-hr-long phase of a relatively weak elevation in phosphorylation and the delayed phase of a much more robust phosphorylation increase taking place during the next approximately 48 hr.
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Pain and hyperalgesia from deep somatic tissue (i.e., muscle and joint) are processed differently from that from skin. This study examined differences between deep and cutaneous tissue allodynia and the role of cAMP in associated behavioral changes. Capsaicin was injected into the plantar aspect of the skin, plantar muscles of the paw, or ankle joint, and responses to mechanical and heat stimuli were assessed until allodynia resolved. ⋯ Spinally administered 8-bromo-cAMP resulted in a similar pattern, with heat hypoalgesia and mechanical allodynia occurring simultaneously. Thus, injection of capsaicin into deep tissues results in a longer-lasting mechanical allodynia and heat hypoalgesia compared with injection of capsaicin into skin. The mechanical allodynia depends on early activation of the cAMP pathway during the first 24 hr but is independent of the cAMP pathway by 1 week after injection of capsaicin.
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Although injury-induced afferent discharge declines significantly over time, experimental neuropathic pain persists unchanged for long periods. These observations suggest that processes that initiate experimental neuropathic pain may differ from those that maintain such pain. Here, the role of descending facilitation arising from developing plasticity in the rostral ventromedial medulla (RVM) in the initiation and maintenance of experimental neuropathic pain was explored. ⋯ These data distinguish mechanisms that initiate the neuropathic state as independent of descending supraspinal influences and additional mechanism(s) that require supraspinal facilitation to maintain such pain. In addition, the data indicate that these time-dependent descending influences can underlie some of the SNL-induced plasticity at the spinal level. Such time-dependent descending influences driving associated spinal changes, such as the upregulation of dynorphin, are key elements in the maintenance, but not initiation, of neuropathic states.
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High-frequency stimulation (HFS) of the subthalamic nucleus (STN) is now recognized as an effective treatment for advanced Parkinson's disease, but the molecular basis of its effects remains unknown. This study examined the effects of unilateral STN HFS (2 hr of continuous stimulation) in intact and hemiparkinsonian awake rats on STN neuron metabolic activity and on neurotransmitter-related gene expression in the basal ganglia, by means of in situ hybridization histochemistry and immunocytochemistry. In both intact and hemiparkinsonian rats, this stimulation was found to induce c-fos protein expression but to decrease cytochrome oxidase subunit I mRNA levels in STN neurons. ⋯ These data furnish the first evidence that STN HFS decreases the metabolic activity of STN neurons and antagonizes dopamine lesion-mediated cellular defects in the basal ganglia output structures. They provide molecular substrate to the therapeutic effects of this stimulation consistent with the current hypothesis that HFS blocks STN neuron activity. However, the differential impact of STN HFS on the effects of dopamine lesion among structures receiving direct STN inputs suggests that this stimulation may not cause simply interruption of STN outflow.
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Calcium/calmodulin-dependent protein kinase II (CaMK II) is found throughout the CNS. It regulates calcium signaling in synaptic transmission by phosphorylating various proteins, including neuronal membrane receptors and intracellular transcription factors. Inflammation or injuries to peripheral tissues cause long-lasting increases in the responses of central nociceptive neurons to innocuous and noxious stimuli. ⋯ Local administration of a CaMK II inhibitor in the spinal cord significantly inhibits the enhancement of responses of spinal nociceptive neurons and changes in exploratory behavior evoked by capsaicin injection. In addition, spinal CaMK II activity enhances phosphorylation of AMPA receptor GluR1 subunits during central sensitization produced by capsaicin injection. This study reveals that CaMK II contributes to central sensitization in a manner similar to its role in the processes underlying long-term potentiation.