Neuropeptide Y-induced contraction is mediated by neuropeptide Y Y2 and Y4 receptors in the rat colon

Abstract Ascending and descending segments of the rat colon were studied to analyze their contractile responses to neuropeptide Y and related peptides. These responses are (a) completely eliminated by tetrodotoxin (1 μM), (b) reduced to a variable extent (20 to 60%) by atropine (1 μM) and (c) not modified by indomethacin, diphenhydramine or methysergide. The order of potency of agonists for peptides related to neuropeptide Y was as follows: human pancreatic polypeptide=rat pancreatic polypeptide>peptide YY=peptide YY-(3–36)=[Leu 31 ,Pro 34 ]neuropeptide Y>neuropeptide Y-(2–36)>C2-neuropeptide Y=neuropeptide Y>neuropeptide Y-(13–36), with minor differences observed between the two parts of the colon. This selectivity pattern does not correspond to the profile of any known cloned neuropeptide Y receptors. BIBP3226, a selective antagonist for the neuropeptide Y Y 1 receptor sub-type, was found to be inactive, while a neuropeptide Y Y 2 receptor antagonist, T 4 -[NPY-(33–36)] 4 , reduced the effects of neuropeptide Y, peptide YY, peptide YY-(3–36) and C2-neuropeptide Y without affecting those of human pancreatic polypeptide, rat pancreatic polypeptide and [Leu 31 ,Pro 34 ]neuropeptide Y. JCF 104 (compound 28), a putative neuropeptide Y Y 5 receptor antagonist, showed no effect or a weak inhibition of human pancreatic polypeptide or [Leu 31 ,Pro 34 ]neuropeptide Y-induced contraction. Taken together, these data suggest that: (1) at least two neuropeptide Y receptor types are present in the rat colon autonomic nerve terminals and modulate the release of acetylcholine and possibly other transmitters; (2) a proportion of the receptors mediating the contractile response of the rat colon (especially descending part) to neuropeptide Y and related peptides appears to be of the Y 2 type and (3) the significant portion of the response is mediated by a receptor which is insensitive to neuropeptide Y Y 1 , Y 2 and to neuropeptide Y Y 5 receptor antagonists. This receptor behaves as a neuropeptide Y Y 4 receptor sub-type and appears to be located on enteric nerves.