IDENTIFICATION OF MECHANISMS AND SITES OF ACTIONS OF MU-OPIOID AND DELTA-OPIOID RECEPTOR ACTIVATION IN THE CANINE INTESTINE

Perfusion with ([N-Me-Phe(3),D-Pro(4)]morphiceptin (PL017)), [D-Pen(2, 5)]enkephalin (DPDPE) and Met(5) and Leu(5) enkephalin induced circula r muscle contractions and decreased immunoreactive vasoactive intestin al polypeptide (VIP) venous output in canine ileal segments. Motility and VIP responses to PL017 were abolished by the mu antagonist CTAP (D -Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2) and unchanged by the delta ant agonist ICI 174,864 ([N,N-dially-Tyr(1),Aib(2,3)]Leu-enkephalin) which abolished DPDPE motility and VIP responses. The VIP response to DPDPE was unchanged by CTAP, which reduced motility responses, suggesting a DPDPE interaction with endogenous mu opioids, at a mu/delta(complexed ) receptor. ICI 174,864 abolished Met(5) and Leu(5) enkephalin motilit y responses and Leu(5) enkephalin VIP responses while CTAP was ineffec tive on Leu(5) enkephalin motility responses or on both enkephalin VIP responses. CTAP increased Met(5) enkephalin motility responses sugges ting mu actions to inhibit excitatory nerves. ICI 174,864 reduced Met( 5) enkephalin VIP output decrements requiring CTAP addition for abolit ion, suggesting actions at mu/delta(complexed) receptors. Inhibition o f nitric oxide synthase with N-omega-L-arginine methyl ester (L-NAME) abolished delta opioid and reduced by 30% mu opioid motility responses , leaving the VIP response intact. Hexamethonium and atropine abolishe d tonic VIP output, leaving intact motility responses to PL017 and DPD PE. Subsequently L-NAME eliminated delta opioid and reduced by 1/3 mu opioid motility responses. All opioids reduced the NO-mediated IJPs in myenteric plexus-free ileal circular muscle. Thus mu or delta opioids inhibit both NO and VIP release but removal of NO, not VIP, disinhibi ts circular muscle motility.