Pre- and Post-Synaptic Effects of Spiradoline and U-50488H, Selective Kappa Opioid Receptor Agonists, in Isolated Ileum

Abstract

In guinea pig ileum, spiradoline (2 × 10⁻⁶M or greater) and U-50488H (3 × 10⁻⁶M or greater) suppressed contractile responses to acetylcholine (ACh), histamine, and BaCl₂. Inhibition by spiradoline (2 × 10⁻⁵ M) of ACh-induced contractions was not antagonized by pretreatment with naloxone (3 × 10⁻⁴ M). Spiradoline (2 × 10⁻⁸ M or greater) and U-50488H (3 × 10⁻⁸ M or greater) caused dose-dependent inhibition of the contractile response of guinea pig ileum to transmural electric stimulation. The inhibitory effect of spiradoline or of U-50488H at low concentrations was reduced by a high concentration of naloxone (3 × 10⁻⁴ M). Spiradoline at low concentrations ranging from 2 × 10⁻⁹ to 2 × 10⁻⁷ M reduced spontaneous contractions in rabbit ileum. Naloxone (3 × 10⁻⁴ g/ml) antagonized the spiradoline-induced inhibition, but marked inhibition by spiradoline at 10⁻⁴ g/ml) was not restored by naloxone. These results suggest that both kappa agonists exert presynaptic inhibitory action on cholinergic nerve endings in the myenteric plexus at a low concentration range of 10⁻⁹ to 10⁻⁷ M and directly inhibit the smooth-muscle motility of the gut at greater concentrations.

Key Words:

• Intestine
• kappa opioid receptor agonist
• myenteric plexus
• pre- and post-synaptic effect
• spiradoline (U-62066E)
• U-50488H