Wood creosote prevents CRF-induced motility via 5-HT3 receptors in proximal and 5-HT4 receptors in distal colon in rats
Introduction
Corticotropin-releasing factor (CRF) is a 41-amino acid hypothalamic peptide and a major regulator of the hypothalamic–pituitary–adrenal (HPA) axis contributing to endocrine, autonomic, immunologic, and behavioral responses to stress (Chrousos, 1995, Vale et al., 1981). Two types of receptors, CRF receptor type 1 and type 2 have been identified and their actions have been widely investigated (Bampton et al., 2001, Liaw et al., 1996, Lovenberg et al., 1995). The intracerebroventricular (i.c.v.) injection of CRF in rats has been reported to suppress gastric emptying of solid nutrient meal via CRF type 2 receptors (Martínez et al., 1998) and stimulate defecation via CRF type 1 receptors (Martínez and Taché, 2001). On the other hand, it has been shown that stress-induced alterations of the GI motility, such as decreased gastric emptying and increased colonic motility are blocked by CRF type 2 receptor antagonists and CRF type 1 receptor antagonists, respectively (Martínez and Taché, 2001, Taché et al., 2001).
Wood creosote is a major component of Seirogan™ that has been used as a remedy for acute diarrhea caused by food poisoning for more than one hundred years in Japan. Wood creosote (CAS no. 8021-39-4) is an herbal medication obtained from fractional distillation of wood tar produced by fume of beech wood. Wood creosote does not cause any serious adverse events in healthy subjects according to the regulation of FDA and has no carcinogenicity in an animal study (Kuge et al., 2001, Kuge et al., 2003). In animal experiments, wood creosote reversed the altered ion-secretion in the intestinal mucosa induced by heat-labile or heat-stable Escherichia coli enterotoxin and also reversed the altered intestinal motility by electrical stimulation, mechanical stimulation with the insertion of glass beads into the distal colon, or acetylcholine administration (Ogata et al., 1993, Ogata et al., 1999, Ataka et al., 1996). Recently, it has been shown that wood creosote normalizes the altered ion secretion induced by restraint stress in rats (Ataka et al., 2003). However no previous studies have examined the effects of wood creosote on stress-related alterations of colonic motility.
In the present study we aimed to examine the effects of intravenous wood creosote on CRF-induced alterations of colonic motility. We used manometric measurements for the pressure waves in the colon of freely moving conscious rats (Ferre and Ruckebusch, 1985, Fujimiya et al., 2000), because this method seems to be appropriate to examine the effects of i.c.v. injected CRF on the physiological state of colonic motility. Involvement of 5-HT receptors mediating the action of wood creosote to prevent CRF-induced alteration of colonic motility was also examined, because 5-HT3 and 5-HT4 receptors are well known to mediate colonic motor activity.
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Animals
Male Wistar Hannover GALAS rats (Clea Japan, Tokyo, Japan), weighing 200–250 g were housed at two per cage under conditions of controlled illumination (12:12-h light–dark cycle; lights on 8:00 AM and off at 8:00 PM), humidity (44–46%), and temperature (22–24 °C), with free access to a standard rat diet (CE-2; Clea Japan) and water. All protocols were approved by Shiga University of Medical Science's Animal Welfare Committee.
Preparation of drugs
Wood creosote (TA-03) supplied by Taiko Pharmaceutical Co., Ltd.
Recordings of basal pressure waves in the proximal and distal colon
Cyclic changes of pressure waves were detected in both proximal and distal colon (Fig. 1). The pressure waves consist of the quiescence period during which relatively low amplitude contractions occur, followed by a grouping of strong contractions (phase III-like contractions, shown as arrowheads). Phase III-like contractions were defined as clusters of strong contractions with an amplitude of more than 10 cm H2O accompanied with an elevation of baseline lasting at least 3 min in the proximal
Discussion
To evaluate the colonic motor activity in vivo, manometric measurements for the pressure waves have been preferentially used in human study (Bampton et al., 2001, Rao et al., 2001, Scott, 2003). In animal experiments, on the other hands, most of the previous studies have used the strain gauge transducer to measure the myoelectrical activity in the colon of dogs (Sarna, 1986, Sarna et al., 1984) or rats (Ferre and Ruckebusch, 1985, Li et al., 2002), however a few study has applied the manometric
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