Mashiningan Improves Opioid-Induced Constipation in Rats by Activating Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel

Abstract

Opioid receptor stimulants are analgesics used in patients with and without cancer; however, they often cause constipation, resulting in poor adherence and deterioration of the quality of life. Hence, suitable treatments for constipation are required. In this study, we investigated the pharmacological mechanisms of action of mashiningan (MNG), a Kampo medicine used to treat constipation, and evaluated the effect of MNG on opioid-induced constipation in rats. MNG (100 or 300 mg/kg) was orally administered to normal or codeine phosphate (CPH)-induced constipation in rats, and its effect was evaluated on the basis of fecal counts, characteristics, and weight. Small intestinal fluid secretion was measured after treatment with MNG alone or coadministration with a cystic fibrosis transmembrane conductance regulator (CFTR)-specific inhibitor (CFTRinh-172). The effects of MNG on the CFTR and type-2 chloride channel were determined using patch-clamp or short-circuit current experiments, respectively. MNG increased the fecal weight and proportion of soft feces in normal rats. CPH-induced constipation in rats decreased fecal counts and weight, whereas MNG prevented these effects and increased the proportion of soft feces. MNG increased the electronic chloride current, and this effect was inhibited by the CFTRinh-172 in the CFTR assay. Furthermore, MNG increased small intestinal fluid secretion, and this effect was abolished by coadministration with the CFTRinh-172. MNG improved opioid-induced constipation in rats, and this improvement may have been mediated by increasing intestinal fluid secretion via CFTR chloride channel activation. Therefore, MNG is expected as a medicine of the treatment of constipation in patients taking opioids.

The combination of Cassia obtusifolia L. and Foeniculum vulgare M. exhibits a laxative effect on loperamide-induced constipation of rats

“…These alterations of fecal properties have been used as indicators of constipation symptoms and as indices of therapeutic effects against constipation [ 40 ]. Therefore, improvements of discharged fecal parameters, including increases of stool numbers and soften stools, and intestinal transit time, is one of the important strategy for the constipation treatment [ 41 , 42 ]. Previous studies showed dramatically decreased the stool-related parameters, including stool numbers, weights and water contents in lop-treated rats [ 12 , 43 ].…”

Cell Volume-Activated and Volume-Correlated Anion Channels in Mammalian Cells: Their Biophysical, Molecular, and Pharmacological Properties

“…A flavonoid, genistein, which is a known potent PTK inhibitor, can PTK-independently activate CFTR from the extracellular (not intracellular) side (French et al, 1997;Wang et al, 1998;Zhou et al, 1998;Niisato et al, 1999). CFTR was also activated by some herbs such as menthol (Morise et al, 2010), which is a cyclic terpene alcohol produced by the peppermint herb; mashiningan (Harada et al, 2017), which is a Japanese herbal (Kampo) medicine used to treat constipation; as well as Junchoto, another Kampo medicine empirically prescribed for chronic constipation (Numata et al, 2018).…”

Cellular mechanism for herbal medicine Junchoto to facilitate intestinal Cl−/water secretion that involves cAMP-dependent activation of CFTR

“…Indeed, the evidence supportive of these observations has been briefly described: oral administration of JCT (300 or 1000 mg/kg) greatly improves opioid-induced severe constipation in a rat model with increased fecal count and dried fecal weight [ 9 ]. A similar CFTR-targeted improvement of constipation has been investigated in detail in a rat model treated with another Kampo medicine, Mashiningan, although in this case stimulation of cGMP-mediated signaling was presumed to be responsible for CFTR activation [ 10 ]. However, again, whether CFTR is involved here was not unequivocally proved because of the considerably higher concentration of the drug used to selectively inhibit CFTR (CFTR-inhbitor-172, 20 μM).…”

“…JCT and MNG are prescribed exclusively for elderly patients suffering from spastic constipation, which results mostly in softened stool. Recently, it was suggested that such laxative actions of JCT and MNG may involve CFTR activation [ 9 , 10 ]. However, this speculation relies entirely on the presumptive specificity of an organic CFTR inhibitor used (CFTRinh-172) which also inhibits other types of Cl − channels including volume-sensitive anion channels [ 11 ] and ClC-2 [ 12 ] at micromolar concentrations, thus lacking rigorous proof at the molecular level.…”