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 IC50 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 IC50 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 (IC50: 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. (C) 2000 Harcourt Publishers Ltd.
