Evidence for the involvement of ATP, but not of VIP/PACAP or nitric oxide,in the excitatory effect of capsaicin in the small intestine

The contractile effect of capsaicin in the guinea-pig small intestine invol ves an activation of enteric cholinergic neurons. Our present data show tha t the P-2 purinoceptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-dis ulphonic acid (PPADS, 30 mu M) significantly reduces the contractile respon se to capsaicin (2 mu M) in the presence, but not in the absence, of the ta chykinin receptor antagonists [O-Pro(9), (Spiro-gamma-lactam)Leu(10), Trp(1 1)]physalaemin (1-11) (GR 82334; 3 mu M) and (S)-(N)-(1-(3-(1-benzoyl-3-(3, 4-dichloro- phenyl)piperidin-3-yl)propyl)-4-phenylpiperidine-4-yl)-N-methyl acetamide (SR 142801; 100 nM) (for blocking tachykinin NK1 and NK3 receptor s, respectively). PPADS (30 mu M) fails to influence submaximal cholinergic contractions evoked by cholecystokinin octapeptide (CCK-g; 2-3 nM) or senk tide (1 nM), or the direct smooth muscle-contracting effect of histamine (1 00-200 nM). A higher concentration (300 mu M) of PPADS is also without effe ct against the stimulatory action of cholecystokinin octapeptide. This mean s that PPADS can probably be safely used as a purinoceptor antagonist in in testinal preparations. The putative pituitary adenylate cyclase activating peptide (PACAP) receptor antagonist PACAP-(6-38) (3 mu M) significantly red uces the contractile effect of PACAP-(1-38) (10 nM) and abolishes that of v asoactive intestinal polypeptide (VIP; 10 nM). PACAP-(6-38) (3 mu M) fails to influence the effect of capsaicin (2 mu M) both in the absence and in th e presence of tachykinin receptor antagonists. The nitric oxide (NO) syntha se inhibitor N-G-nitro-L-arginine (L-NOARG; 100 mu M) also fails to inhibit the capsaicin-induced motor response. We conclude that an endogenous ligan d of PPADS-sensitive P-2 purinoceptors (possibly ATP), but not a VIP/PACAP- like peptide or NO, is involved in the nontachykininergic activation of cho linergic neurons in the course of the capsaicin-induced contraction. (C) 20 00 Elsevier Science B.V. All rights reserved.