Background Gabapentin reduces acute postoperative and chronic neuropathic pain, but its sites and mechanisms of action are unclear. Based on previous electrophysiologic studies, we tested whether gabapentin reduced γ-Amino butyric acid (GABA) release in the locus coeruleus (LC), a major site of descending inhibition, rather than in the spinal cord. Methods Male Sprague-Dawley rats with or without L5-L6 spinal nerve ligation (SNL) were used. Immunostaining for glutamic acid decarboxylase and GABA release in synaptosomes and microdialysates were examined in the LC and spinal dorsal horn. Results Basal GABA release and expression of glutamic acid decarboxylase increased in the LC but decreased in the spinal dorsal horn following SNL. In microdialysates from the LC, intravenously administered gabapentin decreased extracellular GABA concentration in normal and SNL rats. In synaptosomes prepared from the LC, gabapentin and other α2δ ligands inhibited KCl-evoked GABA release in normal and SNL rats. In microdialysates from the spinal dorsal horn, intravenous gabapentin did not alter GABA concentrations in normal rats but slightly increased them in SNL rats. In synaptosomes from the spinal dorsal horn, neither gabapentin nor other α2δ ligands affected KCl-evoked GABA release in normal and SNL rats. Discussion These results suggest that peripheral nerve injury induces plasticity of GABAergic neurons differently in the LC and spinal dorsal horn, and that gabapentin reduces pre-synaptic GABA release in the LC but spinal dorsal horn. The present study supports the idea that gabapentin activates descending noradrenergic inhibition via disinhibition of LC neurons.
We have recently demonstrated that the glutamate transporter activator riluzole paradoxically enhanced glutamate-induced glutamate release from cultured astrocytes. We further showed that both riluzole and the α2δ subunit ligand gabapentin activated descending inhibition in rats by increasing glutamate receptor signaling in the locus coeruleus and hypothesized that these drugs share common mechanisms to enhance glutamate release from astrocytes. In the present study, we examined the effects of riluzole and gabapentin on glutamate uptake and release and glutamate-induced Ca2+ responses in primary cultures of astrocytes. Riluzole and gabapentin facilitated glutamate-induced glutamate release from astrocytes and significantly increased glutamate uptake, the latter being completely blocked by the non-selective glutamate transporter blocker DL-threo-β-benzyloxyaspartic acid (DL-TBOA). Riluzole and gabapentin also enhanced the glutamate-induced increase in intracellular Ca2+ concentrations. Some α2δ subunit ligands, pregabalin and L-isoleucine, enhanced the glutamate-induced Ca2+ response, whereas another, 3-exo-aminobicyclo[2.2.1]heptane-2-exo-carboxylic acid (ABHCA), did not. The enhancement of glutamate-induced intracellular Ca2+ response by riluzole and gabapentin was blocked by the DL-TBOA and an inhibitor of Na+/Ca2+ exchange, 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiurea (KB-R7943). Gabapentin’s enhancement of Ca2+ increase was specific to glutamate stimulation, as it was not mimicked with stimulation by ATP. These results suggest that riluzole and gabapentin enhance Na+-glutamate co-transport through glutamate transporters, induce subsequent Ca2+ influx via the reverse mode of Na+/Ca2+ exchange, and thereby facilitate Ca2+-dependent glutamate release by glutamate in astrocytes. The present study also demonstrates a novel target of gabapentinoid action in astrocytes other than α2δ subunits in neurons.
Objectives:To investigate the effects of insulin replacement on ejaculatory dysfunction in streptozotocin (STZ)-induced diabetic rats. Methods: Rats were divided into three groups: (i) STZ-treated group; (ii) STZ-treated + insulin replacement (5 and 2 international units [IU]) group; and (iii) control group. The ejaculatory function in rats was evaluated using the spontaneous seminal emission (SSE) test. The amount of seminal vesicle fluid (SVF) stored in seminal vesicle was measured after the SSE test. Blood glucose was measured using a simplified blood glucose meter. Results: In the SSE test, the ejaculatory capacity in STZ-induced diabetic rats deteriorated with time after the onset of diabetes, and the incidence of SSE and the amount of ejaculated seminal material (SM) were significantly decreased from 5 weeks after STZ administration. Likewise, the amount of SVF was also significantly decreased in a time-dependent manner. One week after STZ administration when ejaculatory capacity had not yet diminished , insulin replacement (for 4 weeks) completely prevented the decrease in frequency of SSE, the amount of SM and SVF. However, insulin replacement after the dysfunction had occurred (5 or 15 weeks after STZ administration) did not allow all parameters for ejaculatory function to be restored to the levels of the control group. Conclusion: This study demonstrates that at an early stage following the onset of diabetes, insulin replacement can prevent ejaculatory dysfunction in STZ-induced diabetic rats, but once the dysfunction occurs, treatment with insulin alone does not restore the ejaculatory capacity to normal levels. In addition, this study suggests that the loss of seminal emission that results from a decrease in SVF may be involved in the mechanism of ejaculatory dysfunction in diabetic rats.
Epithelial cells in the urinary bladder (urothelium) trigger sensory signals in micturition by releasing ATP in response to distention of the bladder wall. Our previous study revealed the distinct roles of extracellular Ca(2+) and the Ca(2+) stores in the endoplasmic reticulum (ER) in urothelial ATP release. In the present study, we investigated the regulation of urothelial ATP release by Ca(2+) influx from the extracellular space and Ca(2+) release from the ER using a distention assay of the mouse bladder wall in a small Ussing chamber. Stimulation of Ca(2+) release from the ER in the mucosal side of the bladder induced significant ATP release without distention. Blockade of the inositol 1,4,5-triphosphate receptor reduced distention-induced ATP release, suggesting that Ca(2+) release from the ER is essential for the induction of urothelial ATP release. On the other hand, blockade of store-operated Ca(2+) entry (SOCE) from the extracellular space significantly enhanced distention-induced ATP release. Thus Ca(2+) release from the ER causes urothelial ATP release and depletion of Ca(2+) stores in the ER, which in turn causes the depletion-inducing SOCE to suppress the amount of urothelial ATP released.
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