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Nociceptive afferent axons innervate the stomach and send signals to the brain and spinal cord. Peripheral nociceptive afferents can be detected with a variety of markers (e.g., substance P [SP] and calcitonin gene‐related peptide [CGRP]). We recently examined the topographical organization and morphology of SP‐immunoreactive (SP‐IR) axons in the whole mouse stomach muscular layer. However, the distribution and morphological structure of CGRP‐IR axons remain unclear. We used immunohistochemistry labeling and applied a combination of imaging techniques, including confocal and Zeiss Imager M2 microscopy, Neurolucida 360 tracing, and integration of axon tracing data into a 3D stomach scaffold to characterize CGRP‐IR axons and terminals in the whole mouse stomach muscular layers. We found that: (1) CGRP‐IR axons formed extensive terminal networks in both ventral and dorsal stomachs. (2) CGRP‐IR axons densely innervated the blood vessels. (3) CGRP‐IR axons ran in parallel with the longitudinal and circular muscles. Some axons ran at angles through the muscular layers. (4) They also formed varicose terminal contacts with individual myenteric ganglion neurons. (5) CGRP‐IR occurred in DiI‐labeled gastric‐projecting neurons in the dorsal root and vagal nodose ganglia, indicating CGRP‐IR axons were visceral afferent axons. (6) CGRP‐IR axons did not colocalize with tyrosine hydroxylase or vesicular acetylcholine transporter axons in the stomach, indicating CGRP‐IR axons were not visceral efferent axons. (7) CGRP‐IR axons were traced and integrated into a 3D stomach scaffold. For the first time, we provided a topographical distribution map of CGRP‐IR axon innervation of the whole stomach muscular layers at the cellular/axonal/varicosity scale. [ABSTRACT FROM AUTHOR]

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Nociceptive afferents innervate the stomach and send signals centrally to the brain and locally to stomach tissues. Nociceptive afferents can be detected with a variety of different markers. In particular, substance P (SP) is a neuropeptide and is one of the most commonly used markers for nociceptive nerves in the somatic and visceral organs. However, the topographical distribution and morphological structure of SP‐immunoreactive (SP‐IR) axons and terminals in the whole stomach have not yet been fully determined. In this study, we labeled SP‐IR axons and terminals in flat mounts of the ventral and dorsal halves of the stomach of mice. Flat‐mount stomachs, including the longitudinal and circular muscular layers and the myenteric ganglionic plexus, were processed with SP primary antibody followed by fluorescent secondary antibody and then scanned using confocal microscopy. We found that (1) SP‐IR axons and terminals formed an extensive network of fibers in the muscular layers and within the ganglia of the myenteric plexus of the whole stomach. (2) Many axons that ran in parallel with the long axes of the longitudinal and circular muscles were also immunoreactive for the vesicular acetylcholine transporter (VAChT). (3) SP‐IR axons formed very dense terminal varicosities encircling individual neurons in the myenteric plexus; many of these were VAChT immunoreactive. (4) The regional density of SP‐IR axons and terminals in the muscle and myenteric plexus varied in the following order from high to low: antrum‐pylorus, corpus, fundus, and cardia. (5) In only the longitudinal and circular muscles, the regional density of SP‐IR axon innervation from high to low were: antrum‐pylorus, corpus, cardia, and fundus. (6) The innervation patterns of SP‐IR axons and terminals in the ventral and dorsal stomach were comparable. Collectively, our data provide for the first time a map of the distribution and morphology of SP‐IR axons and terminals in the whole stomach with single‐cell/axon/synapse resolution. This work will establish an anatomical foundation for functional mapping of the SP‐IR axon innervation of the stomach and its pathological remodeling in gastrointestinal diseases. [ABSTRACT FROM AUTHOR]

Since mice with a deletion of the neurotrophin-4 (NT-4) gene exhibit a loss of both nodose ganglion neurons and vagal afferent terminals in the small intestines, we hypothesized that the reduced intestinal innervation of the NT-4 knockout (NT-4KO) mouse would lead to a corresponding reduction in the preabsorptive feedback from macronutrients. To explore this prediction, we measured meal patterns in NT-4KOs and controls, while, on different days, intragastric infusions of either lipids (Intralipid; 10%, 20%) or glucose (12.5%, 25%) were yoked to each animal's spontaneous feeding of a pelleted diet (~1 kcal infused/1 kcal ingested). NT-4KO mice were relatively, though not completely, insensitive to the lipid infusions, whereas they were as sensitive as controls to glucose infusions. More specifically, the regulatory deficits of NT-4KOs included 1) attenuated satiation from the lipid infusions, as measured by smaller intrameal reductions of both meal size and meal duration, 2) defects in satiety associated with the fat infusions, as measured by smaller intermeal increases of both satiety ratio and intermeal interval, and (3) losses in daily compensatory responses for lipid calories. These results support the hypothesis that NT-4KO mice have deficits in macronutrient feedback from the gastrointestinal tract, indicate that the defects are specific insofar as they do not include impairments in the feedback of glucose infusions on feeding, and suggest that early feedback about dietary lipids is important in the regulation of satiation, satiety, and longer-term compensation of daily caloric intake. satiation; meal analysis; vagus nerve; Intralipid; glucose doi:10.1152/ajpregu.00825.2006