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Reduction by gabapentin of K+-evoked release of [3H]-glutamate from the caudal trigeminal nucleus of the streptozotocin-treated rat.

ABSTRACT: Recently, we showed that gabapentin can inhibit a facilitatory effect of substance P (SP) on K(+)-evoked glutamate release in rat trigeminal slices (Maneuf et al., 2001), and we have now examined the effect of gabapentin on glutamate release in the trigeminal slice from the streptozotocin (STZ)-treated rat. 1. At 4 weeks following STZ treatment (50 mg kg(-1) i.p.), blood glucose was increased in the majority of cases, compared to the control level. All the treated animals showed a significant degree (P<0.001) of tactile allodynia (assessed using von Frey filaments) that did not appear to correlate with blood glucose levels. 2. In this study, we demonstrated that, after STZ treatment, 30 microM gabapentin reduced K(+)-evoked release of [(3)H]-glutamate in either normal (11 mM) or high (30 mM) glucose conditions by 24 and 22%, respectively. In the normal rat, gabapentin (up to 100 microM) is ordinarily unable to affect release of glutamate from the trigeminal slice. 3. The uptake of glutamate in Sp5C punches from streptozotocin-treated rats was reduced under normal glucose conditions (41.7% of control), whereas high glucose restored uptake to normal (84.7% of control). 4. The addition of 1 microm substance P potentiated the evoked release of glutamate in both normal (40% increase) and high glucose (28%), and this was blocked by gabapentin (30 microM) in both conditions. It is interesting to speculate that this ability of gabapentin to reduce the release of glutamate in the trigeminal nucleus after streptozotocin treatment may be of relevance to the antihyperalgesic-allodynic actions of the drug.

SUBMITTER: Maneuf YP

PROVIDER: S-EPMC1574225 | biostudies-other | 2004 Feb

REPOSITORIES: biostudies-other

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Project description:Trigeminal neuralgia (TN) is a severe chronic neuropathic pain. Despite numerous available medical interventions, the therapeutic effects are not ideal. To control the pain attacks, the need for more contemporary drugs continues to be a real challenge. Our previous study reported that Ca2+-activated K+ channels (BK Ca ) channels modulated by mitogen-activated protein kinases (MAPKs) in the trigeminal ganglia (TG) neurons play crucial roles in regulating TN, and some research studies demonstrated that inflammatory cytokine tumor necrosis factor alpha (TNF-α) could promote neuropathic pain. Meanwhile, the trigeminal nucleus caudalis (TNC), the first central site of the trigeminal nociceptive pathway, is responsible for processing sensory and pain signals from the peripheral orofacial area. Thus, this study is aimed to further investigate whether TNF-α and MAPKs phosphorylation in the TNC could mediate the pathogenesis of TN by modulating BK Ca channels. The results showed that TNF-α of the TNC region is upregulated significantly in the chronic constriction injury of infraorbital nerve (ION-CCI) rats model, which displayed persistent facial mechanical allodynia. The normal rats with target injection of exogenous TNF-α to the fourth brain ventricle behaved just like the ION-CCI model rats, the orofacial mechanical pain threshold decreased clearly. Meanwhile, the exogenous TNF-α increased the action potential frequency and reduced the BK Ca currents of TNC neurons significantly, which could be reversed by U0126 and SB203580, the inhibitors of MAPK. In addition, U0126, SB203580, and another MAPK inhibitor SP600125 could relieve the facial mechanical allodynia by being injected into the fourth brain ventricle of ION-CCI model rats, respectively. Taken together, our work suggests that the upregulation of TNF-α in the TNC region would cause the increase of MAPKs phosphorylation and then the negative regulation of BK Ca channels, resulting in the TN.

Project description:Clinical imaging studies have revealed that the hypothalamus is activated in migraine patients prior to the onset of and during headache and have also shown that the hypothalamus has increased functional connectivity with the spinal trigeminal nucleus. The dopaminergic system of the hypothalamus plays an important role, and the dopamine-rich A11 nucleus may play an important role in migraine pathogenesis. We used intraperitoneal injections of glyceryl trinitrate to establish a model of acute migraine attack and chronicity in mice, which was verified by photophobia experiments and von Frey experiments. We explored the A11 nucleus and its downstream pathway using immunohistochemical staining and neuronal tracing techniques. During acute migraine attack and chronification, c-fos expression in GABAergic neurons in the A11 nucleus was significantly increased, and inhibition of DA neurons was achieved by binding to GABA A-type receptors on the surface of dopaminergic neurons in the A11 nucleus. However, the expression of tyrosine hydroxylase and glutamic acid decarboxylase proteins in the A11 nucleus of the hypothalamus did not change significantly. Specific destruction of dopaminergic neurons in the A11 nucleus of mice resulted in severe nociceptive sensitization and photophobic behavior. The expression levels of the D1 dopamine receptor and D2 dopamine receptor in the caudal part of the spinal trigeminal nucleus candalis of the chronic migraine model were increased. Skin nociceptive sensitization of mice was slowed by activation of the D2 dopamine receptor in SP5C, and activation of the D1 dopamine receptor reversed this behavioral change. GABAergic neurons in the A11 nucleus were activated and exerted postsynaptic inhibitory effects, which led to a decrease in the amount of DA secreted by the A11 nucleus in the spinal trigeminal nucleus candalis. The reduced DA bound preferentially to the D2 dopamine receptor, thus exerting a defensive effect against headache.

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Reduction by gabapentin of K+-evoked release of [3H]-glutamate from the caudal trigeminal nucleus of the streptozotocin-treated rat.

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