Identification of mechanisms and sites of actions of mu and delta opioid receptor activation in the canine intestine
Fox-Threlkeld, J.E.; Daniel, E.E.; Christinck, F.; Hruby, V.J.; Cipris, S.; Woskowska, Z.
Journal of Pharmacology and Experimental Therapeutics 268(2): 689-700
1994
ISSN/ISBN: 0022-3565 PMID: 8113980 Document Number: 425981
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 circular muscle contractions and decreased immunoreactive vasoactive intestinal 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-NH-2) and unchanged by the delta antagonist 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 motility responses and Leu-5 enkephalin VIP responses while CTAP was ineffective on Leu-5 enkephalin motility responses or on both enkephalin VIP responses. CTAP increased Met-5 enkephalin motility responses suggesting mu actions to inhibit excitatory nerves. ICI 174,864 reduced Met-5 enkephalin VIP output decrements requiring CTAP addition for abolition, suggesting actions at mu/delta-complexed receptors. Inhibition of 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 abolished tonic VIP output, leaving intact motility responses to PL017 and DPDPE. 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, disinhibits circular muscle motility.