ELSEVIER Neuroscience Letters 198 (1995) 103-106 NEUROSClEHC[ LETTERS RP67580, a neurokinin 1 receptor antagonist, decreased restraint stress-induced defecation in rat Ken Ikeda*, Keiji Miyata, Akiko Orita, Hirokazu Kubota, Toshimitsu Yamada, Kenichi Tomioka Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., 21 Miyukigaoka, Tsukuba City, Ibaraki 305, Japan Received 20 July 1995 ; revised version received 22 August 1995; accepted 22 August 1995 Abstract We investigated the possibility that substance P would mediate defecation in rats subjected to restraint-stress. The increases in fecal pellet output caused by restraint-stress were inhibited by a neurokinin (NK)I receptor antagonist, RP67580 with an EDs0 (95% confi- dence limits) value of 0.59 (0.54--0.65) mg/kg i.p. RP68651, the enantiomer of RP67580 devoid of affinity for NK 1 receptors, had little effect on it. In contrast, (±)SR48968, an NK2 receptor antagonist, was with~aut effect. Furthermore, capsaicin treatment (125 mg/kg i.p.) was inactive in this model. These results suggest that the activation of NK 1 receptors and substance P released from intrinsic neurons of the colon would be involved in stress-induced defecation in rats. Keywords: Tachykinins; Substance P; Neurokininfi Irritable bowel syndrome; RP67580; SR48968 Tachykinins are present not only in the capsaicin- sensitive neurons but also in capsaicin-resistant enteric neurons and activate neurokinin (NK)I, NK2 and NK 3 receptors. The proposed endogenous ligands for these receptors are substance P, neurokinin A and neurokinin B, respectively. A spasmogenic action of tachykinins throughout the gastrointestinal tract has been well estab- lished in vitro, including human intestine [10,14]. The involvement of tachykinins in the control of intestinal motility has been also demonstrated by the inhibition of small intestinal transit with a substance P receptor an- tagonist in rats [ 12], and of atropine-resistant motility in guinea-pig colon with NK 1 and NK 2 receptor antagonists [11]. These studies suggest that tachykinins are candi- dates as non-cholinergic excitatory transmitters participat- ing in the regulation of intestinal motility. Several studies have revealed a similarity between the bowel dysfunction shown by rats under stressful condi- tions and the symptoms in humans suffering from gastro- intestinal disorders like irritable bowel syndrome [1,17, 20]. However, the role of tachykinins in the bowel dys- function caused by stress has not been fully documented in rats. The introduction of selective non-peptide antago- * Corresponding author. Tel: +81 298 525111; fax: +81 298 522965. nists for NK1 and NK2 receptors has enabled investigation of the role of endogenous tachykinins under this patho- logical state. In this study, therefore, we examined the efficacy of a selective NKl receptor antagonist RP67580 [7], a selective NK 2 receptor antagonist (+_)SR48968 [4] and the treatment with capsaicin in defecation in rats subjected to restraint-stress. Male Wistar rats weighing 150-300 g (SLC, Shizuoka, Japan) were used, and all experiments were carried out between 1000 h and 1300 h. Food and water were pro- vided ad libitum before the experiments. Experimental protocol was approved by the local committee of animal use and care. (_+)SR48968 ((+)-N-methyl-N[4-(acetylamino-4-phen- ylpiperidino)-2-(3,4-dichlorphenyl)butyl]benzamide) was synthesized in our laboratory. RP67580 ((3aR,7aR)-7,7- diphenyl-2- [ 1-imino-2(2-methoxyphenyl)ethyl] perhydro- isoindol-4-one)) and RP68651 ((3aS,7aS)-7,7-diphenyl-2- [ 1-imino-2(2-methoxyphenyl)ethyl] perhydroisoindol-4- one)) were kindly donated by Dr. Garret, Rhone-Poulenc Rorer (Vitry, France). Capsaicin (Wako Pure Chemical Industries, Osaka, Japan) was dissolved in 10% ethanol and 10% Tween 80 in physiological saline and each por- tion was administered to rats at a volume of 2 ml/kg. All other drugs were prepared by dissolution in diluted HCI and physiological saline at volumes of 4 or 5 ml/kg. In 0304-3940/95/$09.50 © 1995 Elsevier Science Ireland Ltd. All fights reserved SSDI 0304-3940(95)11972-V