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The liver is innervated by both the sympathetic and the parasympathetic nerve systems. These nerves are derived from the splanchnic and vagal nerves that surround the portal vein, hepatic artery, and bile duct. The afferent fiber delivers information regarding osmolality, glucose level, and lipid level in the portal vein to the central nervous system (CNS). In contrast, the efferent fiber is crucial in the regulation of metabolism, blood flow, and bile secretion. Furthermore, liver innervation has been associated with hepatic fibrosis, regeneration, and circadian rhythm. Knowledge of these mechanisms can be applied for potential liver disease treatment. [ABSTRACT FROM AUTHOR]

The liver is innervated by sympathetic efferent, spinal afferent, vagal afferent and probably also vagal efferent fibres. To assess potential functional roles of the various neuronal subsets, data on transmitter systems are of crucial importance. This study was aimed at elucidating a possible opioidergic system in the mouse and rat liver. In particular relationships of opioidergic neurons to immune cells were emphasised. Material from perfusion-fixed mice (n=29) of different strains (BALB/c, NMRI, C57Bl6, SV 129 inbred) and Wistar rats (n=7) was cryosectioned at 12–14 μm and incubated for single or double immunofluorescence. Antibodies directed against dynorphin A, met-enkephalin, endomorphin 1 and 2, μ-, κ- and δ-opioid receptors (MOR, KOR, DOR), tyrosine hydroxylase (TH), dopamine β-hydroxylase (DBH), CD4, CD8 and macrophages were used. Binding sites were detected using Cy3-, FITC-, DTAF-, Cy2-, Alexa 555- and Texas red-tagged secondary antibodies. Specimens were analysed using confocal laser scanning microscopy (CLSM). Numerous nerve fibres staining for dynorphin were found in periportal areas of both mouse and rat livers. Neither met-enkephalin nor endomorphin could be detected in axons. No immunopositive neuronal cell bodies or other cellular elements were seen. All dynorphin positive fibres costained for TH while not every TH-positive fibre costained for dynorphin. Thus, most if not all dynorphin-positive nerve fibres may be of sympathetic origin. KOR immunostaining could be localised to round mononuclear cells which often costained for CD4, less frequently for CD8 and rarely for the pan-macrophage marker BM8. Altogether, about 45% of KOR-positive cells were identified as T-lymphocytes. In some instances, close appositions of dynorphin-positive axons to KOR-positive cells were revealed by CLSM. No KOR immunoreactivity was detected in nerve fibres. Hence, sympathetic neurons innervating the liver may interfere with inflammatory processes, in addition to their well-established β2-adrenergic effect, via an opioidergic action on immune cells. [ABSTRACT FROM AUTHOR]

The rat's vagal hepatic branch and associated tissues were studied using light and electron microscopy. Whole mounts, serial sections, and vascular endocasts were used to characterize the tissue from the anterior vagal trunk to the porta hepatis. Fiber number and caliber as well as intraneural organization were analyzed from complete cross-sectional electron micrographic montages of the hepatic branch sampled at its point of separation from the anterior vagal trunk. The hepatic branch ramified from the anterior vagus in one (in 47% of the specimens), two (in 37%) or three (in 16%) bundles. The single bundled hepatic branch contained 2887±287 unmyelinated fibers, and their size distribution, with a mean diameter of 0.66±0.02 μm, was Gaussian. Myelinated fibers numbered only 21±4 per branch and had a complex size distribution ranging from 0.5 to 1.8 μm with a mean of 1.2±0.03 μm. Forty four ±6% of the myelinated fibers were found in a single 'subfascicle' in the dorso-medial pole of the nerve. Whole mounts at this level revealed that a distinct bundle, here designated an extrinsic 'hepato-gastric bundle', occurred within the hepatic branch and linked the omental hepatic branch and the distal anterior gastric branch, apparently without central vagal connections. In the lesser omentum, between the esophagus and the hepatic artery proper, the hepatic branch formed a plexus which was characterized by numerous nerve divisions, anastomoses and large paraganglia (196-463 glomus cells per paraganglion). This plexiform segment ended with the recombining of the hepatic branch into 5-7 bundles which variously ascended in the porta, descended on the hepatic artery proper, or traversed the portal vein. Through its omental course, the hepatic branch traveled in close apposition to the hepato-esophageal artery and the corresponding vein as well as a prominent lymphatic vessel with associated hemolymph nodes. [ABSTRACT FROM AUTHOR]

Hepatic arterial infusion (HAI) chemotherapy as treatment for human colorectal liver metastases is promising, but not entirely satisfactory. Improved drug delivery during HAI may be achieved by manipulating the different control mechanisms of normal versus tumour blood vessels. The peptidergic/aminergic innervation of vessels in normal liver and in two animal models of liver metastasis (Lister Hooded rat with syngeneic MC28 sarcoma; athymic (nude) rat with human HT29 carcinoma) was investigated to assess the suitability of these models for future pharmacological studies. Normal liver and metastases were studied immunohistochemically for the presence of protein gene product 9.5 (PGP), neuropeptide Y (NPY), tyrosine hydroxylase (TH), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP) and substance P (SP). Perivascular innervation was also examined by transmission electron microscopy. In Lister rat normal livers, perivascular immunoreactive nerve fibres containing PGP, NPY, TH, CGRP and SP were observed around the interlobular blood vessels near the hilum and in the portal tracts. The highest density was seen for PGP, followed in decreasing order, by NPY, TH, CGRP and SP. VIP-immunoreactive nerves were absent. No immunoreactive nerves were observed in the hepatic lobule. In athymic rat livers, the pattern of innervation was similar, except that SP immunoreactivity was more sparse. No perivascular immunoreactive nerves were observed in either MC28 or HT29 tumours. Electron microscopy confirmed the absence of perivascular nerves. Smooth muscle cells were not observed in tumour blood vessel walls. These results are comparable with previous observations on human liver metastases and suggest that the animal models may be suitable for pharmacological studies on vascular manipulation of HAI chemotherapy. [ABSTRACT FROM AUTHOR]