Mechanism of tachykinin NK3 receptor-mediated colonic ion transport in the guinea pig.

The guinea pig colon was used to elucidate the mechanism of tachykinin-induced secretion. Increased short-circuit current was observed in response to natural and synthetic tachykinins with rank orders of potency of substance P > neurokinin A = neuropeptide K>> neuropeptide gamma; and senktide (tachykinin NK3 receptor agonist)> Sar-substance P (tachykinin NK1 receptor agonist)> betaAlaneurokinin A (tachykinin NK2 receptor agonist)). A functional role of tachykinin NK1 receptors was confirmed as substance P and neurokinin A responsiveness was blocked by the tachykinin NK1 receptor antagonist GR82334. The tachykinin NK3 receptor antagonist SB222200 had no effect, leaving in doubt the identity of the natural tachykinin NK3 receptor ligand in the colon. The response to tachykinin NK3 receptor activation was abolished by tetrodotoxin and predominantly due to atropine sensitive cholinergic activation. The non-cholinergic component resulted from stimulation of tachykinin NK 1 and 5-HT receptors as the response to senktide was blocked by GR82334 and tropisetron. In conclusion, tachykinin NK3 receptor activation stimulates cholinergic and non-cholinergic (tachykinin NK1-receptor and serotonin-mediated) secretory pathways.