5-HT4 receptor agonists and delta-opioid receptor antagonists act synergistically to stimulate colonic propulsion.
Opioid neurons exert a tonic restraint on inhibitory VIP/PACAP/NOS motoneurons of the enteric nervous system. A decrease in opioid peptide release during the descending phase of the peristaltic reflex, which underlies propulsive activity, leads to an increase in vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), and nitric oxide (NO) release and circular muscle relaxation. These effects are accentuated by opioid receptor antagonists. Endogenous opioid peptides and selective opioid delta-, kappa- and mu-receptor agonists decreased the velocity of pellet propulsion in isolated segments of guinea pig colon, whereas selective antagonists increased velocity in a concentration-dependent fashion with an order of potency indicating preferential involvement of delta-receptors. 5-HT4 agonists (HTF-919 and R-093877), which also increase the velocity of propulsion, acted synergistically with the delta-receptor antagonist naltrindole; a threshold concentration of naltrindole (10 nM) shifted the concentration-response curve to HTF-919 to the left by 70-fold. A combination of 10 nM naltrindole with threshold concentrations of the 5-HT4 agonists caused significant increases in the velocity of propulsion (50 +/- 7 to 77 +/- 8%). We conclude that 5-HT4 agonists and opioid delta-receptor antagonists act synergistically to facilitate propulsive activity in isolated colonic segments.
Foxx-Orenstein
A E
AE
Departments of Medicine and Physiology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298-0551, USA.
Jin
J G
JG
Grider
J R
JR
D000818:Animals; D044482:Benzeneacetamides; D003106:Colon / Q000187:drug effects / Q000502:physiology*; D004399:Dynorphins / Q000494:pharmacology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004743:Enkephalin, Leucine / Q000494:pharmacology; D004744:Enkephalin, Methionine / Q000494:pharmacology; D004745:Enkephalins / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D010528:Peristalsis / Q000187:drug effects / Q000502:physiology*; D011759:Pyrrolidines / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000502:physiology*; D011985:Receptors, Serotonin / Q000502:physiology*; D044422:Receptors, Serotonin, 5-HT4; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology
D044482:Benzeneacetamides; D004745:Enkephalins; D009292:Narcotic Antagonists; D010446:Peptide Fragments; D011759:Pyrrolidines; D017465:Receptors, Opioid, delta; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; D044422:Receptors, Serotonin, 5-HT4; C051844:norbinaltorphimine; D013004:Somatostatin; D004744:Enkephalin, Methionine; D004743:Enkephalin, Leucine; D009271:Naltrexone; C026843:dynorphin (1-13); D004399:Dynorphins; C055382:naltrindole; C045444:U 69593