EVIDENCE FOR A ROLE OF TACHYKININS AS SENSORY TRANSMITTERS IN THE ACTIVATION OF MICTURITION REFLEX

The possible involvement of tachykinin neurokinin-1 and neurokinin-2 r eceptors 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 a lso investigated for comparison. The effect of antagonists was investi gated on: (i) the chemonociceptive vesicovesical reflex activated by t opical application of capsaicin onto the urinary bladder; (ii) the dis tension-induced micturition reflex produced by transvesical filling wi th saline; (iii) distension-induced rhythmic bladder contractions in i sovolumetric conditions (urethra-ligated rats); and (iv) the somatoves ical excitatory reflex caused by noxious perineal pinching. The neurok inin-2 receptor selective antagonists MEN 10,376 and SR 48,968 were in effective in the three models in all doses tested. Selective neurokini n-1 receptor antagonists blocked the chemonociceptive reflex produced by topical application of capsaicin with the rank order of potency (lo west effective dose in brackets): GR 82,334 (1 nmol/rat) > R.P 67,580 (10 nmol/rat) > (+/-)CP 96,345 (100 nmol/rat). Unlike GR 82,3 34, RP 6 7,590 (10 nmol/rat) and (+/-)CP 96,345 (100 nmol/rat) were also effect ive on the distension-induced micturition reflex elicited by transvesi cal 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 e nantiomer of RP 67,580 devoid of neurokinin-1 receptor blocking activi ty, was inactive in both models. 2-Amino-5-phosphonovateric acid (250 nmol/rat) blocked the three types of vesicoexcitatory reflexes. Intrav enous administration of (+/-)CP 96,345, RP 67,580 or 2-amino-5-phospho novateric acid at the same doses proven effective after the intratheca l 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 tachyk inins released from capsaicin-sensitive primary afferent neurons, the effect of RP 67,580 was investigated on the distension-evoked micturit ion 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 contra st, 2-amino-5-phosphonovateric acid produced a further increase in bla dder capacity in capsaicin-pretreated rats. We conclude that tachykini n neurokinin-1 but not neurokinin-2 receptors are involved in the acti vation of vesicoexcitatory micturition-related reflexes in the rat spi nal cord. The ineffectiveness of RP 67,580 following capsaicin-pretrea tment indicates that the role of neurokinin-I receptors is restricted to capsaicin-sensitive afferents. By contrast, the role of N-methyl-D- aspartate receptors in spinal regulation of micturition-related reflex es is not restricted to modulation of afferent input from capsaicin-se nsitive sensory neurons.