Neuropathic pain is refractory against conventional analgesics, and thus novel medicaments are desired for the treatment. Glycinergic neurons are localized in specific brain regions, including the spinal cord, where they play an important role in the regulation of pain signal transduction. Glycine transporter (GlyT)1, present in glial cells, and GlyT2, located in neurons, play roles in modulating glycinergic neurotransmission by clearing synaptically released glycine or supplying glycine to the neurons and thus could modify pain signal transmission in the spinal cord. In this study, we demonstrated that i.v. or intrathecal administration of GlyT1 inhibitors, cis-N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-yl methyl)amino methylcarboxylic acid (ORG25935) or sarcosine, and GlyT2 inhibitors, 4-benzyloxy-3,or knockdown of spinal GlyTs by small interfering RNA of GlyTs mRNA produced a profound antiallodynia effect in a partial peripheral nerve ligation model and other neuropathic pain models in mice. The antiallodynia effect is mediated through spinal glycine receptor ␣3. These results established GlyTs as the target molecules for the development of medicaments for neuropathic pain. However, these manipulations to stimulate glycinergic neuronal activity were without effect during the 4 days after nerve injury, whereas manipulations to inhibit glycinergic neuronal activity protected against the development of allodynia in this phase. The results implied that the timing of medication with their inhibitors should be considered, because glycinergic control of pain was reversed in the critical period of 3 to 4 days after surgery. This may also provide important information for understanding the underlying molecular mechanisms of the development of neuropathic pain.Neuropathic pain arising from peripheral or spinal nerve injury and diabetes or infection with herpes virus is a result of the final product of an altered peripheral, spinal, and supraspinal process for which the usual analgesics are not effective and novel analgesics are desired. Recent progress of research on the underlying mechanism of the pathology revealed more complexity, depending on the cause and stage of ongoing neuropathy. Among various mechanisms involved in the pathology, alterations of synaptic transmission within the spinal cord dorsal horn as well as peripheral nerves after peripheral nerve injury play key roles. In addition to the activation of stimulatory spinal neurotransmission, disinhibition of inhibitory neurotransmission has been implicated in the generation of inflammatory and neuropathic pain (Woolf and Mannion, 1999). Glycine as well as GABA serve as major inhibitory neurotransmitters in the spinal cord of vertebrates. In fact, relief from glycinergic inhibition by an inhib-
Recently, multiple neurotrophic/growth factors have been proposed to play an important role in the therapeutic action of antidepressants. In this study, we prepared astrocyte- and neuron-enriched cultures from the neonatal rat cortex, and examined the changes in neurotrophic/growth factor expression by antidepressant treatment using real-time PCR. Treatment with amitriptyline (a tricyclic antidepressant) significantly increased the expression of fibroblast growth factor-2 (FGF-2), brain-derived neurotrophic factor, vascular endothelial growth factor and glial cell line-derived neurotrophic factor mRNA with a different time course in astrocyte cultures, but not in neuron-enriched cultures. Only the expression of FGF-2 was higher in astrocyte cultures than in neuron-enriched cultures. We focused on the FGF-2 production in astrocytes. Several different classes of antidepressants, but not non-antidepressants, also induced FGF-2 mRNA expression. Noradrenaline (NA) is known to induce FGF-2 expression in astrocyte cultures, as with antidepressants. Therefore, we also assessed the mechanism of NA-induced FGF-2 expression, in comparison to amitriptyline. NA increased the FGF-2 mRNA expression via α1 and β-adrenergic receptors; however, the amitriptyline-induced FGF-2 mRNA expression was not mediated via these adrenergic receptors. Furthermore, the amitriptyline-induced FGF-2 mRNA expression was completely blocked by cycloheximide (an inhibitor of protein synthesis), while the NA-induced FGF-2 mRNA was not. These data suggest that the regulation of FGF-2 mRNA expression by amitriptyline was distinct from that by NA. Taken together, antidepressant-stimulated astrocytes may therefore be important mediators that produce several neurotrophic/growth factors, especially FGF-2, through a monoamine-independent and a de novo protein synthesis-dependent mechanism.
Brain imaging studies have revealed that both the hippocampus and prefrontal cortex undergo selective volume reduction in major depressive disorder (MDD).2 One of the most consistent findings, associated with the volume reduction, in postmortem studies of MDD is a decrease in the density and number of glia in several cortical areas (1). The decreases in glial density are accompanied by a reduction of astrocytic markers, such as glial fibrillary acidic protein and glutamine synthetase (1, 2), thus suggesting that glia, especially astrocytes might be involved in the pathophysiology of MDD.One of the major role of astrocytes is the production of neurotrophic factors, such as nerve growth factor (NGF), brainderived neurotrophic factor, fibroblast growth factor (FGF), and glial cell line-derived neurotrophic factor (GDNF), which support neurogenesis, gliogenesis, development, plasticity, and survival (3).GDNF, a member of the transforming growth factor- superfamily, was originally purified from a rat glial cell line supernatant as a trophic factor for midbrain dopamine neurons and was later found to have pronounced effects on other neuronal populations and glia (4). GDNF improves cognitive function (5, 6) while also inhibiting drug-induced dependence (7). These results suggest that GDNF plays a crucial role in not only neuronal development but also neuronal and glial plasticity in higher-ordered brain function.A growing body of evidence suggests that GDNF as well as brain-derived neurotrophic factor is involved in the pathophysiology of . GDNF has been shown to decrease in the peripheral blood of patients with MDD (8). In addition, the decreased blood level of GDNF in MDD has been reported to increase after antidepressant treatment (13). We have also previously shown that antidepressants increase the GDNF production in C6 glioma cells (C6 cells), rat astrocytes, and normal human astrocytes (NHA) (14,15). Treatment with antidepressants alters the GDNF levels in rodents in vivo and glial cell culture in vitro (16 -18). These findings suggest that an increase of GDNF production may be involved in the therapeutic effect *
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