The Journal of neuroscience : the official journal of the Society for Neuroscience
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The possible involvement of p38 mitogen-activated protein kinase activation in spinal cord and dorsal root ganglion (DRG) cells in the development of peripheral neuropathic pain has been explored. Ligation of the L5 spinal nerve (SNL) on one side in adult rats produces an early onset and long-lasting mechanical allodynia. This lesion results in activation of p38 in the L5 segment of the spinal cord, most prominently in the ipsilateral dorsal horn, starting soon after the lesion (<1 d) and persisting for >3 weeks. ⋯ Post-treatment with SB203580 starting on day 1 or on day 10 after surgery also reduces established mechanical allodynia. Because the reduction in neuropathic pain by p38 inhibition occurs before the appearance of p38 activation in DRG neurons, p38 activation in spinal cord microglia is likely to have a substantial role in the earliest phase of neuropathic pain. Coactivation of p38 in DRG neurons and spinal microglia may contribute to later phases of neuropathic pain.
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Randomized Controlled Trial Clinical Trial
Conscious expectation and unconscious conditioning in analgesic, motor, and hormonal placebo/nocebo responses.
The placebo and nocebo effect is believed to be mediated by both cognitive and conditioning mechanisms, although little is known about their role in different circumstances. In this study, we first analyzed the effects of opposing verbal suggestions on experimental ischemic arm pain in healthy volunteers and on motor performance in Parkinsonian patients and found that verbally induced expectations of analgesia/hyperalgesia and motor improvement/worsening antagonized completely the effects of a conditioning procedure. ⋯ These findings indicate that verbally induced expectations have no effect on hormonal secretion, whereas they affect pain and motor performance. This suggests that placebo responses are mediated by conditioning when unconscious physiological functions such as hormonal secretion are involved, whereas they are mediated by expectation when conscious physiological processes such as pain and motor performance come into play, even though a conditioning procedure is performed.
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One of the first steps in the coding of olfactory information is the transformation of synaptic input to action potential firing in mitral and tufted (M/T) cells of the mammalian olfactory bulb. However, little is known regarding the synaptic mechanisms underlying this process in vivo. In this study, we examined odor-evoked response patterns of M/T and granule cells using whole-cell recording in anesthetized, freely breathing rats. ⋯ Odor-evoked, rhythmic M/T cell excitation is reliable during odor presentation (2-4 sec); in contrast, both excitatory responses of granule cells and M/T cell lateral inhibition adapt quickly after the first respiration cycle in the presence of odorants. We also find that the amplitude and initial slope of odor-evoked synaptic excitation play an important role in regulating the timing of M/T cell spikes. Furthermore, differences in odor concentration alter the shape of odor-evoked excitatory synaptic responses, the latency of M/T cell spikes, and the timing of M/T cell lateral inhibition.
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Nitric oxide (NO) has been implicated in some of the central pathways engaged in the regulation of the sleep-wake cycle. The existence of nitric oxide synthase (NOS) in the cholinergic basal forebrain (BF) cells projecting to the cortex suggests a role for NO in the activation induced by the BF during arousal. We tested, in the anesthetized cat, the hypothesis that inhibition of NOS would decrease the ability of BF cholinergic fibers to induce cortical activation. ⋯ After blocking NOS activity, the capacity of BF stimulation to induce cortical activation was strongly impaired. Furthermore, voltammetric measurements of NO levels revealed an increase in cortical NO after BF stimulation, also blocked by systemic NOS inhibition. These results indicate that the blockade of NOS activity significantly reduces the ability of BF stimulation to induce changes in the EEG pattern and suggest a role for NO in the BF-cholinergic system implicated in arousal mechanisms.
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We hypothesized that adenosine, acting via the A1 receptor, is a key factor in the homeostatic control of sleep. The increase in extracellular levels of adenosine during prolonged wakefulness is thought to facilitate the transition to sleep by reducing the discharge activity of wakefulness-promoting neurons in the basal forebrain. Adenosine A1 receptor control of the homeostatic regulation of sleep was tested by microdialysis perfusion of antisense oligonucleotides against the mRNA of the A1 receptor in the magnocellular cholinergic region of the basal forebrain of freely behaving rats. ⋯ Control experiments with microdialysis perfusion of nonsense (randomized antisense) oligonucleotides and with artificial CSF showed no effect during postdeprivation recovery sleep or spontaneously occurring behavioral states. Antisense to the A1 receptor suppressed A1 receptor immunoreactivity but did not show any neurotoxicity as visualized by Fluoro-Jade staining. These data support our hypothesis that adenosine, acting via the A1 receptor, in the basal forebrain is a key component in the homeostatic regulation of sleep.