Pharmacological actions of AH-9700 on micturition reflex in anesthetized rats

Abstract

In radioligand binding assays, AH-9700 (1-[2-(3,4-dihydro-6,7-dimethyl-2-naphthalenyl)ethyl]pyrrolidine fumarate) had high affinity for σ receptors and moderate affinity for muscarinic receptors. The affinity of AH-9700 for σ 1 receptors was significantly reduced in the presence of 5′-guanylyl-imidodiphosphate (GppNHp). In isolated bladder strips of rats, AH-9700 inhibited carbachol-induced contractions. In anesthetized rats, i.v. administration of AH-9700 and typical σ receptor ligands, (+)-pentazocine and 1,3-di- o-tolylguanidine (DTG), but not oxybutynin, dose-dependently inhibited rhythmic isovolumetric reflex bladder contractions. AH-9700 and oxybutynin suppressed the amplitude of rhythmic bladder contractions. On the other hand, at doses lower than used i.v., the i.c.v. administration of AH-9700 or the σ receptor ligands inhibited rhythmic bladder contractions without suppressing the amplitude. This inhibitory effect of AH-9700 was markedly reduced by pretreatment with i.c.v. pertussis toxin. These results suggest that AH-9700 exerts a marked anti-micturition reflex effect through central σ receptors possibly related to pertussis toxin-sensitive Gi/o-proteins and a moderate spasmolytic effect based on its peripheral anti-muscarinic activity.