Abstract
The primary afferent innervation of the uterus is incompletely understood. The aim of this study was to identify the location and characteristics of primary afferent neurons that innervate the uterine horn of mice and correlate the different morphological types of putative primary afferent nerve endings, immunoreactive to the sensory marker, calcitonin gene related peptide (CGRP). Using retrograde tracing, injection of 5–10 μL of 1,1′-didodecyl-3,3,3,3′-tetramethylindocarbocyanine perchlorate (DiI) into discrete single sites in each uterine horn revealed a biomodal distribution of sensory neurons in dorsal root ganglia (DRG) with peak labeling occurring between T13-L3 and a second smaller peak between L6-S1. The mean cross sectional area of labeled cells was 463 μm2 ± s.e.m. A significantly greater proportion of labeled neurons consisted of small cell bodies (<300 μm2) in the sacral spinal cord (S2) compared with peak labeling at the lumbar (L2) region. In both sections and whole mount preparations, immunohistochemical staining for CGRP revealed substantial innervation of the uterus by CGRP-positive nerve fibers located primarily at the border between the circular and longitudinal muscle layers (N = 4). The nerve endings were classified into three distinct types: “single,” “branching,” or “complex,” that often aligned preferentially in either the circular or longitudinal axis of the smooth muscles. Complex endings were often associated with mesenteric vessels. We have identified that the cell bodies of primary afferent neurons innervating the mouse uterus lie primarily in DRG at L2 and S1 spinal levels. Also, the greatest density of CGRP immunoreactivity lies within the myometrium, with at least three different morphological types of nerve endings identified. These findings will facilitate further investigations into the mechanisms underlying sensory transduction in mouse uterus.
Highlights
The perception of pain from internal organs is a fundamental physiological phenomenon, with pain from the viscera one of most common symptoms in a variety of disease states (Ness and Gebhart, 1990; Robinson et al, 2004)
Injection of 5–10 μL of 1,1 -didodecyl-3,3,3,3 -tetramethylindocarbocyanine perchlorate (DiI) into discrete single sites in each uterine horn revealed a biomodal distribution of sensory neurons in dorsal root ganglia (DRG) with peak labeling occurring between T13-L3 and a second smaller peak between L6-S1
The distinct pattern of labeling at specific DRG spinal segments was consistent between animals, indicating that retrograde labeling was specific from the injection sites in each uterine horn
Summary
The perception of pain from internal organs is a fundamental physiological phenomenon, with pain from the viscera one of most common symptoms in a variety of disease states (Ness and Gebhart, 1990; Robinson et al, 2004). Additional inputs from the hypogastric and vagal nerves transmit sensation centrally, arising rostrally via the T13-L4 region and directly from the brainstem via the nodose ganglia respectively (Inyama et al, 1986; Berkley et al, 1988; Collins et al, 1999). These relay sensory signals such as the degree of distension, nociception, and vascular state of the uterus and reproductive tract (Chaban, 2012). While the autonomic innervation and endocrine control of the uterus has been reasonably well characterized, in both health and disease states (Ness and Gebhart, 1990; Gnanamanickan and Llewellyn-Smith, 2011) few studies exist in mice; and no studies have characterized the primary afferent innervation in mouse uterus
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