Calcitonin gene-related peptide innervation of the rat hepatobiliary system

The digestive system is densely innervated by calcitonin gene-related peptide (CGRP)-immunoreactive neurons. The present study investigated a) the distribution and origin of CGRP-immunoreactive fibers in the rat hepatobiliary tract, and b) their relation with substance P/tachykinin (SP/TK) immunoreactivity using immunohistochemical and radioimmunoassay techniques. CGRP-containing fibers form dense networks in the fibromuscular layer of the biliary tree and surrounding the portal vein. Thin, varicose fibers are present at the base of the mucosa of the ducts. In the liver, labeled fibers are restricted to the portal areas and the stromal compartment. Neonatal treatment with capsaicin, a neurotoxin for primary afferent neurons, or celiac/superior mesenteric ganglionectomy depletes CGRP-containing fibers in the biliary tract, and reduces those associated with the portal vein. In contrast, subdiaphragmatic vagotomy does not appreciably modify the density of these fibers. Radioimmunoassay studies show a reduction of CGRP-immunoreactive contents in the biliary tract and portal vein by 84% and 65%, respectively, following capsaicin treatment, and by 80% and 66%, respectively, following ganglionectomy. By contrast, CGRP concentrations in vagotomized animals are comparable to those of controls. Most CGRP-positive fibers appear to contain SP/TK immunoreactivity, as indicated by double-label studies. These results demonstrate that the rat hepatobiliary tract is prominently innervated by CGRP- and CGRP/SP/TK-immunoreactive fibers, which are likely to originate from spinal afferent neurons. The abundance of these fibers and their association with a variety of targets are in line with the involvement of these peptidergic visceral afferents in regulating hepatobiliary activities, including hemodynamic functions of the hepatic vasculature.