Morphological and neurochemical differences in peptidergic nerve fibers of the mouse vagina

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The vagina contains nerves which respond to mechanical and chemical stimuli (Berkley, 2005; Berkley, Robbins, & Sato, 1993), regulate vaginal blood flow and lubrication (Ottesen et al., 1987), help maintain tissue integrity (Hu, Wang, Cheng, Zhou, & Li, 2012), and provide reflexes critical in parturition (Cueva‐Rolon, Gomez, Komisaruk, & Munoz‐Martinez, 1995). Dysfunction of these nerves is implicated in disabling disorders such as vulvodynia and vestibulodynia (Bohm‐Starke, Falconer, Rylander, & Hilliges, 2001; Nunns, 2000; Tympanidis et al., 2004), pelvic organ prolapse (Hu et al., 2012), and stillbirth (Cueva‐Rolon et al., 1995). The ontology of the mouse urogenital tract was only recently comprehensively analyzed (Georgas et al., 2015) and to date, only one animal model has been developed to investigate sensory changes associated with vestibular infection (Farmer et al., 2011). Comprehensive descriptions of vaginal innervation, fundamental to the understanding of functional changes that occur in important and prevalent clinical conditions, are still absent in the literature.
Vaginal innervation includes sympathetic, parasympathetic, and sensory fibers. Regarding the latter, the entire length of the vagina contains sensory endings of pelvic nerve fibers, associated with low lumbar and upper sacral dorsal root ganglia (DRG). In addition, the cervical region of the vagina contains fibers of the hypogastric nerve, mainly associated with low thoracic and upper lumbar DRG (Berkley et al., 1993). Regional differences in vaginal innervation may reflect distinct embryological origins. The proximal (cervical) third of the vagina develops from the urogenital sinus in humans and mice and the distal, vulvar segment originates from the clitoral urethra (Georgas et al., 2015). Interestingly, these regions demonstrate different functional responses to sensory stimulation. In the rat vagina, pelvic nerve fibers exhibit greater sensitivity to mechanical and chemical stimuli than hypogastric nerve fibers (Berkley et al., 1993).
In human and mouse vagina, nerve fibers containing peptides such as vasoactive intestinal polypeptide (VIP), calcitonin gene‐related peptide (CGRP), substance P (SP), and neuropeptide tyrosine (NPY) have been identified (Berkley, 2005; Blank et al., 1986; Hoyle, Stones, Robson, Whitley, & Burnstock, 1996; Huang et al., 1984; Polak & Bloom, 1984), as has the enzyme nitric oxide synthase (nNOS) (Hoyle et al., 1996; Uckert et al., 2005). It is known that these neurochemical compounds can act peripherally and centrally to impact on vascular function and nociceptive signaling (Taylor et al., 2014), but it is not known if they coexist in subpopulations of nerve fibers, or if neurochemically distinct subpopulations of fibers in different regions of the vagina contribute to observed differences in function. We have demonstrated a unique innervation pattern of the external genitalia of female guinea‐pigs and mice by sensory fibers when compared with surrounding perineal tissues (Vilimas, Yuan, Haberberger, & Gibbins, 2011), and here extend these studies to the mouse vagina.
This study investigated vaginal innervation in C57BL/6 mice with a focus on fibers containing VIP, CGRP, SP, NPY, and nNOS. We compared innervation in cervical and vulvar segments of the vagina due to their different embryological origins and functional characteristics. Further, to investigate naturally occurring changes within mouse reproductive life, we compared vaginal innervation in 6‐ to 8‐week‐old nulliparous (NP) to that in nine to 12‐month‐old multiparous (MP) mice.
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