MEN 11,420, a peptide tachykinin NK2 receptor antagonist, reduces motor responses induced by the intravesical administration of capsaicin in vivo

This study investigates the role of tachykinin NK1 and NK2 receptors in motor responses induced by the intravesical instillation of capsaicin in urethane-anaesthetized rats. SR 140,333 (1 mu mol/kg, i.v.), a non- peptide NK, receptor antagonist, abolished urinary bladder contractions induced by the selective NK1 receptor agonist [Sar(9)]SP-sulfone (0.1-100 nmol/kg, i.v.) without affecting those induced bq the NK2 receptor agonist [beta Ala(8)]NKA(4-10). MEN 11,420 (100 nmol/kg, i.v.), a cyclic peptide NK2 receptor antagonist, abolished blad- der contractions induced by [beta Ala(8)]NKA(4-10) (0.3- 300 nmol/kg, i.v.) without modifying those induced by [Sar(9)]SP-sulfone. Intravesical instillation of capsaicin (6 nmol/0.6 ml/rat) produced a motor response consisting in a primary contraction followed by a series of high amplitude phasic contractions. The intravesical instillation of saline (0.6 ml/rat) produced a primary contraction of lower amplitude with respect to that induced by capsaicin and the total area under the curve was also lower in saline-instilled rats, however the number and the amplitude of phasic contractions was similar to that induced by capsaicin. MEN 11,420 (100 nmol/kg, i.v.) did not modify motor responses induced by the intravesical administration of saline. In contrast, in capsaicin-instilled rats, MEN 11,420 (100 nmol/kg. i.v.) reduced the primary contraction, the area under the curve and also the number of phasic contractions. SR 140,333 (1 mu mol/kg, i.v.) reduced the primary contraction but not other parameters. The combination of SR 140,333 (1 mu mol/kg, i.v.) and MEN 11,420 (100 nmol/kg, i.v.) produced an additive inhibitory effect on the primary contraction but not a further inhibition on other parameters with respect to that observed with MEN 11,420 alone. In hexamethonium (110 mu mol/kg, i.v.)-pretreated animals the intravesical instillation of capsaicin produced a tonic contraction having greater amplitude and area than that induced by saline, MEN 11,420 but not SR 140,333, significantly reduced the bladder response to capsaicin in hexamethonium-pretreated rats. Again, the combined administration of MEN 11,420 and SR 140,333 did not produce further inhibitory effect in comparison to MEN 11,420 alone. It is concluded that the motor responses induced by the intravesical instillation of capsaicin are mediated by the activation of peripheral tachykinin NK2 receptors.