Lecci A, Giuliani S, Garret C, Maggi C A
Pharmacology Department, A. Menarini Pharmaceuticals, Florence, Italy.
Neuroscience. 1993 Jun;54(3):827-37. doi: 10.1016/0306-4522(93)90252-b.
The possible involvement of tachykinin neurokinin-1 and neurokinin-2 receptors in the activation of various micturition-related reflexes was assessed by the intrathecal administration of selective neurokinin-1 or neurokinin-2 receptor antagonists at lumbosacral spinal cord level in urethane-anaesthetized rats. The effect of the glutamate N-methyl-D-aspartate receptor antagonist, 2-amino-5-phosphonovaleric acid, was also investigated for comparison. The effect of antagonists was investigated on: (i) the chemonociceptive vesicovesical reflex activated by topical application of capsaicin onto the urinary bladder; (ii) the distension-induced micturition reflex produced by transvesical filling with saline; (iii) distension-induced rhythmic bladder contractions in isovolumetric conditions (urethra-ligated rats); and (iv) the somatovesical excitatory reflex caused by noxious perineal pinching. The neurokinin-2 receptor selective antagonists MEN 10,376 and SR 48,968 were ineffective in the three models in all doses tested. Selective neurokinin-1 receptor antagonists blocked the chemonociceptive reflex produced by topical application of capsaicin with the rank order of potency (lowest effective dose in brackets): GR 82,334 (1 nmol/rat) > RP 67,580 (10 nmol/rat) > (+/-)CP 96,345 (100 nmol/rat). Unlike GR 82,334, RP 67,580 (10 nmol/rat) and (+/-)CP 96,345 (100 nmol/rat) were also effective on the distension-induced micturition reflex elicited by transvesical filling. Similarly, distension-induced rhythmic contractions were inhibited by RP 67,580 (10 nmol/rat) and (+/-)CP 96,345 (100 nmol/rat) whereas the effect of GR 82,334 was not significant. RP 68,651, the enantiomer of RP 67,580 devoid of neurokinin-1 receptor blocking activity, was inactive in both models. 2-Amino-5-phosphonovateric acid (250 nmol/rat) blocked the three types of vesicoexcitatory reflexes. Intravenous administration of (+/-)CP 96,345, RP 67,580 or 2-amino-5-phosphonovateric acid at the same doses proven effective after the intrathecal route, had no effect on distension-induced rhythmic contractions. To ascertain whether the effect of neurokinin-1 receptor antagonists or 2-amino-5-phosphonovaleric acid may be related to a blockade of tachykinins released from capsaicin-sensitive primary afferent neurons, the effect of RP 67,580 was investigated on the distension-evoked micturition reflex in capsaicin-pretreated rats. Capsaicin pretreatment (50 mg/kg, subcutaneously, four days before) increased bladder capacity. RP 67,580 was no longer effective in capsaicin-pretreated rats. In contrast, 2-amino-5-phosphonovateric acid produced a further increase in bladder capacity in capsaicin-pretreated rats. We conclude that tachykinin neurokinin-1 but not neurokinin-2 receptors are involved in the activation of vesicoexcitatory micturition-related reflexes in the rat spinal cord.(ABSTRACT TRUNCATED AT 400 WORDS)
通过在氨基甲酸乙酯麻醉的大鼠腰骶脊髓水平鞘内注射选择性神经激肽-1或神经激肽-2受体拮抗剂，评估速激肽神经激肽-1和神经激肽-2受体在各种排尿相关反射激活中的可能作用。还研究了谷氨酸N-甲基-D-天冬氨酸受体拮抗剂2-氨基-5-磷酸戊酸的作用以作比较。研究了拮抗剂对以下方面的作用：（i）通过将辣椒素局部应用于膀胱激活的化学伤害性膀胱-膀胱反射；（ii）经膀胱注入生理盐水产生的扩张诱导排尿反射；（iii）等容条件下（尿道结扎大鼠）扩张诱导的节律性膀胱收缩；（iv）有害会阴挤压引起的躯体-膀胱兴奋性反射。神经激肽-2受体选择性拮抗剂MEN 10,376和SR 48,968在所有测试剂量下对这三种模型均无效。选择性神经激肽-1受体拮抗剂以效力顺序（括号内为最低有效剂量）阻断局部应用辣椒素产生的化学伤害性反射：GR 82,334（1 nmol/大鼠）> RP 67,580（10 nmol/大鼠）>（±）CP 96,345（100 nmol/大鼠）。与GR 8,334不同，RP 67,580（10 nmol/大鼠）和（±）CP 96,345（100 nmol/大鼠）对经膀胱灌注引起的扩张诱导排尿反射也有效。同样，RP 67,580（10 nmol/大鼠）和（±）CP 96,345（100 nmol/大鼠）抑制了扩张诱导的节律性收缩，而GR 82,334的作用不显著。RP 68,651是RP 67,580的对映体，无神经激肽-1受体阻断活性，在两种模型中均无活性。2-氨基-5-磷酸戊酸（250 nmol/大鼠）阻断了三种类型的膀胱兴奋性反射。静脉注射（±）CP 96,345、RP 67,580或2-氨基-5-磷酸戊酸，剂量与鞘内注射后证明有效的剂量相同，对扩张诱导的节律性收缩无影响。为确定神经激肽-1受体拮抗剂或氨基-5-磷酸戊酸的作用是否可能与阻断辣椒素敏感的初级传入神经元释放的速激肽有关，研究了RP 67,580对辣椒素预处理大鼠扩张诱发排尿反射的作用。辣椒素预处理（50 mg/kg，皮下注射，四天前）增加了膀胱容量。RP 67,580在辣椒素预处理的大鼠中不再有效。相反，2-氨基-5-磷酸戊酸使辣椒素预处理大鼠的膀胱容量进一步增加。我们得出结论，速激肽神经激肽-1而非神经激肽-2受体参与大鼠脊髓中膀胱兴奋性排尿相关反射的激活。（摘要截短至400字）
