Adaptive Plasticity of Vaginal Innervation in Term Pregnant Rats

Abstract

Changes in reproductive status place varied functional demands on the vagina. These include receptivity to male intromission and sperm transport in estrus, barrier functions during early pregnancy, and providing a conduit for fetal passage at parturition. Peripheral innervation regulates vaginal function, which in turn may be influenced by circulating reproductive hormones. We assessed vaginal innervation in diestrus and estrus (before and after the estrous cycle surge in estrogen), and in the early (low estrogen) and late (high estrogen) stages in pregnancy. In vaginal sections from cycling rats, axons immunoreactive for the pan-neuronal marker protein gene product 9.5 (PGP 9.5) showed a small reduction at estrus relative to diestrus, but this difference did not persist after correcting for changes in target size. No changes were detected in axons immunoreactive for tyrosine hydroxylase (sympathetic), vesicular acetylcholine transporter (parasympathetic), or calcitonin gene-related peptide and transient receptor potential vanilloid type 1 (TRPV-1; sensory nociceptors). In rats at 10 days of pregnancy, innervation was similar to that observed in cycling rats. However, at 21 days of pregnancy, axons immunoreactive for PGP 9.5 and each of the subpopulation-selective markers were significantly reduced both when expressed as percentage of sectional area or after correcting for changes in target size. Because peripheral nerves regulate vaginal smooth muscle tone, blood flow, and pain sensitivity, reductions in innervation may represent important adaptive mechanisms facilitating parturition.

Estrogen and female reproductive tract innervation: Cellular and molecular mechanisms of autonomic neuroplasticity

“…However, unlike the uterus, chronic exposure to estrogen is also accompanied by depletion of vaginal VAChT-ir cholinergic axons and CGRP-ir nociceptive afferents (Ting et al, 2004). A similar depletion was observed in vaginal innervation of rats at term pregnancy (d21) where serum estrogen has been elevated for several days when compared to pregnant rats at 10 d post-coitus when estrogen levels are low (Liao et al, 2011). Accordingly, it appears that vaginal innervation shows distinct differences from uterine innervation in its time course to respond to estrogen, and in the selectivity of the axonal populations affected.…”

“…Hence, cyclical variations in serum estrogen do not result in detectable changes in any population of vaginal axons in the adult nulliparous rat (Liao et al, 2011), and a single acute injection of 17β-estradiol sufficient to deplete uterine innervation does not alter vaginal innervation in adult OVX rats (unpublished). Accordingly, relative to the uterus, vaginal innervation is apparently more resistant to short-term effects of elevated estrogen.…”

Systemic and topical hormone therapies reduce vaginal innervation density in postmenopausal women

“…We have shown recently that vaginal innervation in rats is also responsive to endogenous and exogenous E 2 resulting in reductions in sympathetic and parasympathetic axons and in peptidergic sensory fibers 20 . Because rising E 2 levels at term pregnancy promote this denervation, we've proposed that these hormonal changes may underlie an important form of physiologically adaptive plasticity that may reduce pain sensitivity and facilitate delivery at parturition 37 .…”

Prostaglandin levels, vaginal innervation, and cyst innervation as peripheral contributors to endometriosis-associated vaginal hyperalgesia in rodents

“…In naïve normal cycling rats and pre-menopausal women, the number and density of sensory and sympathetic fibers within the vagina are similar and estrous-stage dependent fluctuations in nerve fiber density do not occur, nor do changes in vaginal sensitivity (Liao and Smith, 2011; Ting et al, 2004). In rats with a sham-endometriosis (fat surrounding uterus auto-transplanted instead of the uterus) surgery, no changes in vaginal sensitivity occur either.…”