Extrinsic origin of the capsaicin-sensitive innervation of rat duodenum: possible involvement of calcitonin gene-related peptide (CGRP) in the capsaicin-induced activation of intramural non-adrenergic non-cholinergic neurons

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Abstract
1. Capsaicin produces a concentration-related relaxation of the longitudinal muscle of the rat isolated duodenum in the presence of atropine (3 μM) plus guanethidine (3 μM). This effect of capsaicin is partly (about 40%) antagonized by tetrodotoxin (1.0 μM) suggesting the involvement of intramural non-adrenergic non-cholinergic (NANC) neurons. 2. The capsaicin-induced relaxations are unaffected by previous bilateral vagotomy or removal of the inferior mesenteric ganglion but are completely prevented by removal of the coeliac ganglia plus the superior mesenteric ganglion (72 h before). Acute duodenal denervation did not modify the response to capsaicin. 3. Unlike various neuropeptides (substance P, kassinin, neurokinin A, cholecystokinin octapeptide, somatostatin, vasoactive intestinal polypeptide) only the calcitonin gene-related peptide (CGRP) closely mimicked, both qualitatively and quantitatively, the capsaicin-induced relaxations. The CGRP-induced relaxations were unaffected by hexamethonium and partly reduced (about 40%) by tetrodotoxin. 4. In preparations desensitized to adenosine-triphosphate (ATP) a putative NANC inhibitory neurotransmitter of the rat duodenum, the effects of CGRP were reduced (about 30%) as compared to controls. After ATP-desensitization tetrodotoxin did not produce any further reduction of the CGRP-induced relaxations suggesting the involvement of endogenous ATP in the neuronal (tetrodotoxin-sensitive) component of the CGRP-induced relaxations. 5. Either ATP-or CGRP-desensitization reduced (about 50 and 65% respectively) the amplitude of the capsaicin-induced relaxations. In the presence of both ATP and CGRP capsaicin did not affect motor activity of the rat isolated duodenum indicating a complete desensitization of the effect of endogenously released substance(s). 6. These findings indicate that the capsaicin-induced relaxations of the rat isolated duodenum are due to activation of a neural mechanism of extrinsic origin, presumably primary afferent fibers. CGRP is a likely candidate for the role of neuropeptide released by capsaicin in this preparation. Endogenous CGRP may produce NANC relaxation both directly and by releasing the endogenous NANC neurotransmitter(s).

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