THE INHIBITORY MODULATION OF GUINEAPIG INTESTINAL PERISTALSIS CAUSED BY CAPSAICIN INVOLVES CALCITONIN-GENE-RELATED PEPTIDE AND NITRIC-OXIDE

The effect of capsaicin-induced stimulation of afferent neurons on per istalsis and the possible neural mediators involved in this action wer e examined in the guinea-pig isolated ileum, The intraluminal pressure threshold for eliciting peristaltic waves was used to quantify facili tation (decrease in threshold) or inhibition (increase in threshold) o f peristalsis, Capsaicin (0.1-1 mu M) caused an initial short-lasting stimulation of peristalsis followed by a prolonged inhibition of peris taltic activity. Capsaicin (1 mu M) was ineffective when the gut segme nts had been pretreated with 3.3 mu M capsaicin, which is indicative o f an afferent neuron-dependent action of the drug. In contrast, the ab olition of peristalsis caused by a high concentration of capsaicin (33 mu M) was fully reversible on removal and reproducible on readministr ation of capsaicin, a feature characteristic of a nonspecific depressi on of smooth muscle excitability. Baseline peristalsis and the excitat ory/inhibitory effect of capsaicin (1 mu M) on peristalsis remained un altered by a combination of the tachykinin NK1 receptor antagonist (+) -(2S, 3S)-3-(2-methoxybenzylamino)-2-phenyl piperidine (CP-99,994; 0.3 mu M) and the tachykinin NK2 receptor antagonist -piperidino-2-(3,4-d ichlorophenyl)butyl]-benzamide (SR-48,968; 0.1 mu M). Further experime nts, performed in the presence of a low concentration of atropine (10 nM) showed that the calcitonin gene-related peptide (CGRP) antagonist human alpha-calcitonin gene-related peptide (8-37) [hCGRP (8-37); 10 m u M] attenuated the delayed inhibitory effect of capsaicin on peristal sis, but did not influence baseline peristaltic activity and the capsa icin-induced facilitation of peristalsis. Blockade of nitric oxide (NO ) synthesis by N-G-nitro-L-arginine methylester (L-NAME, 300 mu M) fac ilitated baseline peristaltic activity and reduced the delayed inhibit ion of peristalsis caused by capsaicin (1 mu M) without affecting the initial peristalsis-stimulating action of capsaicin. The effects of L- NAME were prevented by L-arginine (1 mM), The data of the current stud y indicate that capsaicin-sensitive afferent neurons do not participat e in the neural pathways subserving peristalsis in the guinea-pig smal l intestine, but modulate peristaltic activity upon stimulation with c apsaicin. The initial stimulant action of capsaicin on peristalsis is independent of tachykinins acting via NK1 or NK2 receptors, while the delayed capsaicin-induced depression of peristalsis involves CGRP and NO.