title: Effect of opioid active therapeutics on the ascending reflex pathway in the rat ileum.
abstract: For a long time therapeutic agents that interact with opioid receptors have been used in antidiarrheal therapy. The action of the opioid active substances on motility and transit have already been characterized; however, their effects on myenteric reflexes and their possible luminal action have not yet been investigated. Loperamide, fedotozine and beta-casomorphin-4, as well as the casomorphin-analogue beta-CM-4027, are, or have been, suggested as therapeutic agents and were studied in the isolated rat ileum for their effect on the ascending reflex pathway. beta-CM-4027 > fedotozine > loperamide > beta-casomorphin-4 caused a concentration-dependent inhibition of the ascending contractile reflex response with an IC(50)of 1.4x10(-7)M, 1.5x10(-6)M, 4.1x10(-6)M and 4.5x10(-6)M respectively. At the same time as the oral contractile reflex response was inhibited, all four opioid agonists (CM-4027 > beta-casomorphin-4 > fedotozine > loperamide) increased the latency of the reflex response. Both effects were blocked by naloxone, indicating the involvement of opioid receptors. These results demonstrate that opioid-active drugs and substances modify the peristaltic reflex by reducing the efficacy of the reflex response and modulating the timing of the reflex pathway. In a second series of experiments, luminal application of opioid-active drugs was compared with serosal application. beta-casomorphine-4 caused a concentration-dependent inhibition of the oral reflex response with an IC(50)of 3x10(-3)M which was 750 times higher than after serosal application. In contrast, a stable and highly selective kappa opioid agonist (U-50,488), which caused potent inhibition upon serosal application (IC(50): 2.3x10(-7)M), showed no inhibitory effect after luminal application up to a concentration of 10(-2)M. Thus casomorphins could have a local effect on the gut wall with no need for systemic absorption. This might be used for a possible therapeutic application.
authors.affiliation: Department of Internal Medicine II, Technical University of Munich, Ismaningerstr. 22, 81675 Munich, Germany. hans.allescher@lrz.tu-muenchen.de
authors.forename: H D
authors.initials: HD
authors.lastname: Allescher
authors.forename: M
authors.initials: M
authors.lastname: Storr
authors.forename: C
authors.initials: C
authors.lastname: Piller
authors.forename: V
authors.initials: V
authors.lastname: Brantl
authors.forename: V
authors.initials: V
authors.lastname: Schusdziarra
mesh_terms: D000818:Animals; D000930:Antidiarrheals / Q000494:pharmacology*; D001593:Benzyl Compounds / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004723:Endorphins / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D008139:Loperamide / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012018:Reflex / Q000187:drug effects
chemical_list: D000930:Antidiarrheals; D001593:Benzyl Compounds; D004723:Endorphins; D010446:Peptide Fragments; D011437:Propylamines; D008139:Loperamide; C043158:beta-casomorphin 4; C047075:beta casomorphin 4027; C067749:fedotozine