促代谢型谷氨酸受体mGluR5参与膀胱的生理与伤害性感受

Metabotropic Glutamate Receptor 5 Contributes to Physiological and Nociceptive Sensory Processes in the Urinary Bladder

促代谢型谷氨酸受体(mGluRs)是一类G蛋白偶联受体,参与中枢神经系统的突触可塑性和学习记忆等过程。一些研究资料表明,mGluRs还在躯体痛的外周信号转导和信号传递中起重要作用,但其在内脏感受中的作用尚不清楚。本研究的目的在于考察Ⅰ组促代谢型谷氨酸受体(mGluR5)是否参与膀胱的生理与伤害性感受。在用戊巴比妥钠(50mg/kg,ip)麻醉的大鼠,mGluR5拮抗剂MPEP(3.0mg/kgiv)能明显提高排尿反射的容积阈值,并能减弱快速充胀膀胱引起的腹肌收缩反应,提示mGluR5参与膀胱的生理和伤害性感受过程。在取自正常小鼠的膀胱/盆神经模型,MPEP(0.1￣100μM)对充胀膀胱引起的传入神经活动没有明显影响,而在环磷酰胺(125mg/kgip)致间质性膀胱炎(IC)的小鼠,MPEP(0.3μm)能抑制高阈值膀胱传入神经放电。在清醒、自由活动的IC小鼠,MPEP(1μmol/kg,ip)还明显抑制其后肢对机械刺激的反应。上述结果表明,mGluR5可能并不参与正常膀胱的外周机械性感受的信号转导,但可能参与膀胱生理和伤害性感受信息向脊髓和在中枢内的传递过程;外周和中枢mGluR5在实验性间质性膀胱炎时有上调现象,故可能是治疗内脏感觉过敏的一个潜在药物作用靶点。

Metabotropic glutamate receptors （mGluRs1-8） are members of the G protein-coupled receptor （GPCR） supefamily and they have been implicated in processes requiring synaptie plasticity such as learning and memory, neuronal development and neurodegeneration, mGluR5 is distributed throughout the eeatral nervous system including areas involved in nociception and in unmyelinated sensory afferent terminals as well, suggesting that mGluR may play a role in pain sensation. The present study aims to delineate the role of mGluR5 in physiological and nociceptive sensory processes of the urinary bladder, In vivo eystometry observations in the rat showed that the mGluR5 antagonist, MPEP, significantly raised the voiding threshoht, In pentobarbital-anesthetized rat, MPEP attenuated the motor responses of the abdominal muscle induced by rapid noxious distension of the urinary bladder. The effect oceurred in a dose-dependent manner and was reversible, In the isolated mouse bladder/pelvic nerve preparation, we recorded the bladder afferent nerve discharge in respnnse to nump distension of the bladder, tn preparations taken from control mice, MPEP （0.1 to 100 μM） failed to induce siguificant changes in the pressure- nerve response curve. In preparations （n=5） taken from mice pre-treated with cyclophosphamide （125 mg/kg, ip, 24 hr before experiment）, MPEP （0.3 M） depressed the high threshoht afferent discharge. In in vivo studies, MPEP （1 mol/kg, ip） significantly attenuated the leg withdrawal frequency in response to yon Frey hair stimulation of the paw in cyclophophamide-treated mice but not in normal control miee. These observations indicate that mGluR5 is unlikely to be involved in peripheral mechanosensory transduction in normal bladder, but rather may play a role in central processing of the peripheral afferent inputs, Peripheral and central mGluR5 appears to be up-regulated in cyclophosphanide-induced cystitis and may therefore be potential therapeutic targets for visceral hyperalgesia and functional disorders.