Lack of beneficial effect of a tachykinin receptor antagonist in experimental colitis.
Nerves within the wall of the intestine may contribute to inflammatory responses, such as those occurring in inflammatory bowel disease. Studies in an experimental model of colitis have demonstrated that neuromodulation, through chemical sympathectomy or administration of lidocaine, can markedly attenuate granulocyte infiltration and tissue injury. Given the many pro-inflammatory effects of substance P, we have evaluated the effects of a tachykinin receptor (NK-1) antagonist, RP 67580, in models of acute colitis in the rat and guinea pig. While administration of RP 67580 and a second NK-1 antagonist (CP-96,345-1) significantly reduced the infiltration of granulocytes into colonic tissue during the first 12 h after induction of colitis in the rat, repeated administration of RP 67580 over a three day period failed to significantly affect granulocyte recruitment or the severity of tissue injury. In contrast, lidocaine enemas were effective in reducing both indices of inflammation/injury. In the guinea pig, similar observations were made. These observations demonstrate that blockade of NK-1 receptors over a three day period failed to significantly modify the course of experimental colitis. It remains possible that the beneficial effects of lidocaine may be due, in part, to inhibition of substance P release, and that the contribution of substance P to inflammation in experimental colitis occurs through NK-1 receptor-independent mechanisms.
Wallace
J L
JL
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Calgary, Alberta, Canada. wallacej@acs.ucalgary.ca
McCafferty
D M
DM
Sharkey
K A
KA
D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D003092:Colitis / Q000188:drug therapy* / Q000473:pathology; D006098:Granulocytes; D006168:Guinea Pigs; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D054833:Isoindoles; D008012:Lidocaine / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors*
D000700:Analgesics; D001713:Biphenyl Compounds; D007211:Indoles; D054833:Isoindoles; D018039:Receptors, Tachykinin; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; D008012:Lidocaine; C066892:CP 96345