Neuroscience
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Na(+) currents were recorded using patch-clamp techniques from small-diameter (<25 micrometers) dorsal root ganglion neurons, cultured from adult rats (>150 g). Late Na(+) currents maintained throughout long-duration voltage-clamp steps (>/=200 ms) were of two types: a low-threshold, tetrodotoxin-sensitive (TTX-s) current that was largely blocked by 200 nM TTX, and a high-threshold, TTX-resistant (TTX-r) current. TTX-s late current was found in approximately 28% (10/36) of small-diameter neurons and was recorded only in neurons exhibiting TTX-s transient current. ⋯ We suggest that TTX-s late sodium current results from channel openings different from those generating transient current. As in large-diameter sensory neurons, TTX-s channels generating late openings may play a key role in controlling membrane excitability. In contrast, a single population of high-threshold TTX-r channels may account for both transient and late TTX-r currents.
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Comparative Study
A role for c-Jun N-terminal kinase in the inhibition of long-term potentiation by interleukin-1beta and long-term depression in the rat dentate gyrus in vitro.
Recent evidence has emphasised the importance of mitogen-activated protein kinase activation in the modulation of hippocampal synaptic plasticity. Whilst extracellular-regulated kinase activation is now regarded as a critical step in the induction of long-term potentiation (LTP), activation of p38 and c-Jun N-terminal kinase (JNK) is associated with its inhibition. Here, the effects of the novel JNK inhibitor anthra[1,9-cd]pyrazol-6(2H)-1 (SP600125) were investigated on the inhibition of LTP by cytokines interleukin-1beta, interleukin-18 and tumour necrosis factor-alpha in the dentate gyrus. ⋯ Perfusion of SP600125 prior to low-frequency stimulation of the perforant path resulted in a significant attenuation of induced LTD, which suggests that JNK activation is a critical mediator of LTD in the dentate gyrus. These results directly implicate, for the first time, differential activation of JNK in the modulation of distinct forms of hippocampal synaptic plasticity. Whereas acute over-activation of JNK by pathophysiological concentrations of cytokines is detrimental to LTP, physiologic activation of JNK appears necessary for the induction of LTD.
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Comparative Study
Glial cell line-derived neurotrophic factor contributes to delayed inflammatory hyperalgesia in adjuvant rat pain model.
Neurotrophic factors, such as nerve growth factor and brain-derived neurotrophic factor, are members of the structurally related neurotrophin family that play important roles in pain modulation. Although there are also indications for the involvement of glial cell line-derived neurotrophic factor (GDNF), it is unclear whether and how GDNF is involved in inflammatory pain. In the present study, we studied the expression pattern of GDNF in dorsal root ganglia (DRG) and spinal cord, using confocal microscopy. ⋯ To assess the impact of this down-regulation on pain transmission, we used a function-blocking antibody against GDNF delivered intrathecally in the same chronic-pain animal models. Injection of this antibody to GDNF produced no immediate effect, but decreased the delayed, bilateral hyperalgesia induced from a unilateral injection of complete Freund's adjuvant. The effect of this antibody coincided with the down-regulation of GDNF immunoreactivity in response to inflammation, suggesting that GDNF supports biochemical changes that contribute to hyperalgesia.
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Dynorphin A (1-17), an endogenous opioid neuropeptide, can have pathophysiological consequences at high concentrations through actions involving glutamate receptors. Despite evidence of excitotoxicity, the basic mechanisms underlying dynorphin-induced cell death have not been explored. To address this question, we examined the role of caspase-dependent apoptotic events in mediating dynorphin A (1-17) toxicity in embryonic mouse striatal neuron cultures. ⋯ AMPA/kainate receptor blockade significantly attenuated dynorphin A-induced cytochrome c release and/or caspase-3 activity, while NMDA or opioid receptor blockade typically failed to prevent the apoptotic response. Last, dynorphin-induced caspase-3 activation was mimicked by the ampakine CX546 [1-(1,4-benzodioxan-6-ylcarbonyl)piperidine], which suggests that the activation of AMPA receptor subunits may be sufficient to mediate toxicity in striatal neurons. These findings provide novel evidence that dynorphin-induced striatal neurotoxicity is mediated by a caspase-dependent apoptotic mechanism that largely involves AMPA/kainate receptors.
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The function of the second nuclear estrogen receptor, estrogen receptor beta (ERbeta), in the brain is largely unknown. The present study tested whether 1) ERbeta in the paraventricular nucleus (PVN) of the hypothalamus has a direct role in the hypothalamic-pituitary-adrenal (HPA) axis-mediated stress function, and 2) whether corticosterone (CORT) can regulate ERbeta gene expression in the PVN in the intact, cycling female rat. To test the first hypothesis a pure estrogen receptor antagonist, ICI182, 780, was microinjected into the PVN bilaterally and stress-induced CORT response to an acute stressor (15 min restraint) was measured at 0, 15, 30, 60 and 90 min time points. ⋯ Adrenalectomy reduced ERbeta mRNA expression in the PVN, whereas CORT replacement fully reversed this effect in a dose-dependent fashion. Both antagonist inhibition of CORT response and CORT-mediated regulation of ERbeta mRNA were found to be estrus cycle-dependent in the intact, cycling female. These data suggest that ERbeta in the PVN may critically modulate the HPA axis response to stress and is, in turn, regulated by circulating CORT.