The Journal of neuroscience : the official journal of the Society for Neuroscience
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This study examined the acute actions of brain-derived neurotrophic factor (BDNF) in the rat dentate gyrus after seizures, because previous studies have shown that BDNF has acute effects on dentate granule cell synaptic transmission, and other studies have demonstrated that BDNF expression increases in granule cells after seizures. Pilocarpine-treated rats were studied because they not only have seizures and increased BDNF expression in granule cells, but they also have reorganization of granule cell "mossy fiber" axons. This reorganization, referred to as "sprouting," involves collaterals that grow into novel areas, i.e., the inner molecular layer, where granule cell and interneuron dendrites are located. ⋯ The results suggest a preferential action of BDNF at mossy fiber synapses, even after substantial changes in the dentate gyrus network. Moreover, the results suggest that activation of trkB receptors could contribute to the hyperexcitability observed in animals with sprouting. Because human granule cells also express increased BDNF mRNA after seizures, and sprouting can occur in temporal lobe epileptics, the results may have implications for understanding temporal lobe epilepsy.
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Repetitive noxious stimulation leads to permanent adaptive changes of central pathways involved in the genesis and integration of nociception. Several classes of neurotrophic factors that affect brain plasticity are also involved in the regulation of sensory functions in adulthood. To investigate a putative role of nerve growth factor (NGF) in central plasticity linked to chronic pain, modifications in immunoreactivity (IR) for the high-affinity NGF receptor, TrkA, were studied at spinal levels in a rat model of inflammatory chronic pain, adjuvant-induced arthritis (AIA). ⋯ Dual labeling with calcitonin gene-related peptide or substance P showed that TrkA-IR neurons were mainly located in projection fields of small- to medium-sized primary afferent fibers, which convey nociceptive inputs. These results suggest that TrkA-containing neurons of the spinal dorsal horn participate in the first central relay of transmission of nociceptive information to supraspinal centers. Enhanced numbers of TrkA-IR neurons during AIA strongly support the hypothesis of a participation of NGF in adaptive mechanisms of central nociceptive pathways observed in chronic pain states.
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The role of enkephalin and the opioid receptors in modulating GABA release within the rat globus pallidus (GP) was investigated using whole-cell patch recordings made from visually identified neurons. Two major GP neuronal subtypes were classified on the basis of intrinsic membrane properties, action potential characteristics, the presence of the anomalous inward rectifier (Ih), and anode break depolarizations. The mu opioid receptor agonist [D-Ala2-N-Me-Phe4-Glycol5]-enkephalin (DAMGO) (1 microM) reduced GABAA receptor-mediated IPSCs evoked by stimulation within the striatum. ⋯ However, spontaneous action potential-driven IPSCs were reduced in frequency by met-enkephalin and DAMGO, whereas DPDPE was without effect. Overall, these results indicate that presynaptic mu opioid receptors are located on striatopallidal terminals and pallidopallidal terminals of spontaneously firing GP neurons, whereas presynaptic delta opioid receptors are preferentially located on terminals of quiescent GP cells. Enkephalin, acting at both of these receptor subtypes, serves to reduce GABA release in the GP and may therefore act as an adaptive mechanism, maintaining the inhibitory function of the GP in basal ganglia circuitry.
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Central sensitization, the hyperexcitability of spinal processing that often accompanies peripheral injury, is a major component of many persistent pain states. Here we report that the neurotrophin, brain-derived neurotrophic factor (BDNF), is a modulator of excitability within the spinal cord and contributes to the mechanism of central sensitization. BDNF, localized in primary sensory neuron cell bodies and central terminals, potentiates nociceptive spinal reflex responses in an in vitro spinal cord preparation and induces c-fos expression in dorsal horn neurons. ⋯ Thus behavioral nociceptive responses induced by intraplantar formalin and by intraplantar carageenan are significantly attenuated by trkB-IgG. Hence BDNF is appropriately localized and regulated in inflammatory states and is sufficient and necessary for the expression of central sensitization in the spinal cord. We propose that BDNF may function as a modulator of central sensitization in pathological states, and our results suggest that pharmacological antagonism of BDNF may prove an effective and novel analgesic strategy for the treatment of persistent inflammatory pain states.
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Comparative Study
Relationships between the prefrontal cortex and the basal ganglia in the rat: physiology of the cortico-nigral circuits.
The prelimbic/medial orbital areas (PL/MO) of the rat prefrontal cortex are connected to substantia nigra pars reticulata (SNR) through three main circuits: a direct nucleus accumbens (NAcc)-SNR pathway, an indirect NAcc-SNR pathway involving the ventral pallidum (VP) and the subthalamic nucleus (STN), and a disynaptic cortico-STN-SNR pathway. The present study was undertaken to characterize the effect of PL/MO stimulation on SNR cells and to determine the contribution of these different pathways. The major pattern of responses observed in the SNR was an inhibition preceded by an early excitation and followed or not by a late excitation. ⋯ The early excitation, which was markedly decreased after blockade of the cortico-STN transmission by CNQX application into the STN, resulted from the activation of the disynaptic cortico-STN-SNR pathway. Finally, the blockade of the cortico-STN-VP circuit by CNQX application into STN or VP modified the influence of the trans-striatal circuits on SNR cells. This study suggests that, in the prefrontal cortex-basal ganglia circuits, the trans-subthalamic pathways, by their excitatory effects, participate in the shaping of the inhibitory influence of the direct striato-nigral pathway on SNR neurons.