Masuda Hitoshi, Hayashi Yukio, Chancellor Michael B, Kihara Kazunori, de Groat William C, de Miguel Fernando, Yoshimura Naoki
Department of Urology, University of Pittsburgh School of Medicine, 3471 Fifth Avenue, Pittsburgh, PA 15213, USA.
J Urol. 2006 Jul;176(1):374-9. doi: 10.1016/S0022-5347(06)00581-7.
We investigated the effects of nicotinic acetylcholine receptor activation in the bladder and central nervous system on the micturition reflex in urethane anesthetized rats.
The effects of nicotinic acetylcholine receptor activation on bladder activity were examined during continuous infusion cystometrogram. Nicotine with or without the nicotinic acetylcholine receptor antagonist mecamylamine (Sigma Chemical Co., St. Louis, Missouri) was administered intravesically, intrathecally or intracerebroventricularly in normal or capsaicin pretreated rats. We also examined nicotine induced responses in dissociated bladder afferent neurons from L6 to S1 dorsal root ganglia that were sensitive to capsaicin using whole cell patch clamp recordings.
Intravesical nicotine (1 to 10 mM) significantly decreased intercontraction intervals in dose dependent fashion. This excitatory effect was abolished by co-application of mecamylamine (3 mM) as well as by capsaicin pretreatment. On patch clamp recordings 300 muM nicotine evoked rapid inward currents that were antagonized by mecamylamine in capsaicin sensitive bladder afferent neurons. Intrathecal and intracerebroventricular administration of nicotine (10 mug) decreased and increase intercontraction intervals, respectively. Each effect was antagonized by mecamylamine (50 mug) administered intrathecally and intracerebroventricularly. The spinal excitatory effect was significantly inhibited by the N-methyl-D-aspartate receptor antagonist (+)-MK-801 hydrogen maleate (20 mug) given intrathecally or by capsaicin pretreatment, although the effects of capsaicin pretreatment were significantly smaller than those of (+)-MK-801 hydrogen maleate.
These results indicate that nicotinic acetylcholine receptor activation in capsaicin sensitive C-fiber afferents in the bladder can induce detrusor overactivity. In the central nervous system nicotinic acetylcholine receptor activation in the spinal cord and brain has an excitatory and an inhibitory effect on the micturition reflex, respectively. In addition, the nicotine induced spinal excitatory effect may be mediated by the activation of glutamatergic mechanisms.
我们研究了膀胱和中枢神经系统中烟碱型乙酰胆碱受体激活对乌拉坦麻醉大鼠排尿反射的影响。
在连续输注膀胱测压图期间，检测烟碱型乙酰胆碱受体激活对膀胱活动的影响。在正常或辣椒素预处理的大鼠中，将含有或不含有烟碱型乙酰胆碱受体拮抗剂美加明（西格玛化学公司，密苏里州圣路易斯）的尼古丁经膀胱内、鞘内或脑室内给药。我们还使用全细胞膜片钳记录，检测了来自L6至S1背根神经节的对辣椒素敏感的离体膀胱传入神经元中尼古丁诱导的反应。
膀胱内给予尼古丁（1至10 mM）以剂量依赖性方式显著缩短收缩间期。美加明（3 mM）共同给药以及辣椒素预处理可消除这种兴奋作用。在膜片钳记录中，300 μM尼古丁在对辣椒素敏感的膀胱传入神经元中诱发快速内向电流，该电流被美加明拮抗。鞘内和脑室内给予尼古丁（10 μg）分别缩短和延长收缩间期。鞘内和脑室内给予美加明（50 μg）可拮抗每种效应。鞘内给予N-甲基-D-天冬氨酸受体拮抗剂（+）-马来酸MK-801氢盐（20 μg）或辣椒素预处理可显著抑制脊髓兴奋作用，尽管辣椒素预处理的效果明显小于（+）-马来酸MK-801氢盐。
这些结果表明，膀胱中对辣椒素敏感的C纤维传入神经中的烟碱型乙酰胆碱受体激活可诱导逼尿肌过度活动。在中枢神经系统中，脊髓和脑中的烟碱型乙酰胆碱受体激活分别对排尿反射具有兴奋和抑制作用。此外，尼古丁诱导的脊髓兴奋作用可能由谷氨酸能机制的激活介导。
