Mu and kappa opioid receptor modulation of 5-HT3 and NK-3 receptor-evoked release of acetylcholine from the guinea-pig ileum myenteric plexus

Abstract

The effects of three different opioid agonists on contractions and [3H]-acetylcholine (ACh) release evoked by 5-hydroxytryptamine3 (5-HT3) and neurokinin-3 (NK-3) receptor activation were examined in the guinea-pig ileum longitudinal muscle-myenteric plexus strip (LMMP) preparation. The selective mu (mu)-opioid receptor agonist (D-Ala2,NMe-Phe4,Gly-ol]-enkephalin (DAMGO; 1 nM-100 nM) and the selective kappa (kappa)-opioid receptor agonist U50488 (10 nM-1 microM) inhibited contractile responses to 5-HT and to the selective NK-3 receptor agonist senktide, producing a concentration-related progressive flattening of their concentration-response curves. IC50 estimates for DAMGO and U50488 were somewhat higher for inhibition of 5-HT-evoked as compared to senktide-evoked contractions, and overall lay in the range 6 nM-51 nM. The selective delta (delta)-opioid receptor agonist [D-Pen2,5]-enkephalin (DPDPE) inhibited contractile responses only at the highest concentration used (1 microM). 3H-overflow from LMMP preparations preincubated with [3H]-choline was measured as an indicator of [3H]-ACh release. DAMGO (1 nM-100 nM) and U50488 (10 nM-1 microM) inhibited the increases in release of [3H]-ACh evoked by 5-HT (10 microM) and by senktide (10 nM) in a concentration-dependent manner. IC50 estimates for DAMGO and U50488 were not significantly different for inhibition of 5-HT as compared to senktide-evoked increases in [3H]-ACh release and lay in the range 6 nM-23 nM. DPDPE again only inhibited these responses at the maximum concentration used (1 microM).(ABSTRACT TRUNCATED AT 250 WORDS)