Potent NK1 antagonism by SR-140333 reduces rat colonic secretory response to immunocyte activation

The potent neurokinin receptor 1 (NK1) antagonist SR-140333 has previously been shown to reduce castor oil-induced secretion in animal models. The imp ortance of tachykinins in neuroimmune control of secretion and the effect o f SR-140333 on key points in this pathway were elucidated in the present st udy to determine the type of intestinal dysfunction best targeted by this a ntagonist. Rat colonic secretion and substance P (SP) release were determin ed in vitro with the use of Ussing chamber and enzyme immunoassay technique s. NK1 receptors played a secretory role as receptor agonists stimulated se cretion and SR-140333 antagonized the response to SP response (pK(b) = 9.2) . Sensory fiber stimulation released SP and evoked a large secretion that w as reduced by 69% in the presence of SR-140333 (10 nM). Likewise, mastocyte s also released SP. The subsequent secretory response was reduced by 43% in the presence of SR-140333 (50 nM). SP was also released from granulocytes; however, this did not cause secretion. Functional NK3 receptors were prese nt in the colon as senktide stimulated secretion, an effect that was increa sed during stress. We conclude that NK3 receptors may play a role in stress -related disorders, whereas NK1 receptors are more important in mast cell/a fferent-mediated secretion.