Chronic Estrogen Sensitizes a Subset of Mechanosensitive Afferents Innervating the Uterine Cervix

Abstract

Liu, Baogang, James C. Eisenach, and Chuanyao Tong. Chronic estrogen sensitizes a subset of mechanosensitive afferents innervating the uterine cervix. J Neurophysiol 93: 2167-2173, 2005; doi:10.1152/ jn.01012.2004. Estrogen increases reflex nocifensive responses to distension of the uterus and the urinary bladder, but estrogen's effects on afferent response to distension of the uterine cervix, the site of obstetric and some gynecologic pain, has not been studied. Here, single fiber recording of hypogastric nerve responses to uterine cervical distension were obtained from ovariectomized (OVX) rats and OVX rats treated with estrogen (ES). Spontaneous activity was greater in the ES group (13 of 24 units; 54%) than in the OVX group (6 of 27 units; 22%). ES differentially altered the response of low-and high-threshold units to distension. For high-threshold units, firing frequency was increased two-to fourfold with 60 -100 gm distension in ES compared with OVX groups (P Ͻ 0.05). In contrast, the response of low-threshold units to distension was not altered by ES. About one-half of units tested in each group responded to a temperature increase from 35 to 49°C. A greater proportion of thermosensitive units were also mechanosensitive in the ES group (7 of 8 afferents, 88%) than in the OVX group (5 of 11 afferents, 45%). Acute application of ES in OVX rats failed to evoke or increase distensioninduced responses. These data show the polymodal nature of afferent fibers innervating the uterine cervix. Increased spontaneous activity with ES may play a part in remodeling of the cervical tissue, whereas selective sensitization of high-threshold units by ES might underlie increased pain responses to cervical distension. Failure of acute ES treatment to mimic this suggests a genomic effect.

Estrogen alters spinal NMDA receptor activity via a PKA signaling pathway in a visceral pain model in the rat

“…Estrogen receptors are expressed in primary afferent neurons (Papka et al 1997;Taleghany et al 1999) as are NMDA receptors (Liu et al 1994;Carlton et al 1998;McRoberts et al, 2001;Chaban et al 2004) and estradiol modulates primary afferent excitability (Robbins et al 1992;Chaban et al 2003;Liu et al 2005;Hucho et al 2006;McRoberts et al 2007). Colonic inflammation increases NMDA receptor activity in colonic afferents (Li et al 2006), but it is unknown if estradiol mediates this increase in primary afferent NMDA receptor activity.…”

Pregnancy Increases Excitability of Mechanosensitive Afferents Innervating the Uterine Cervix

“…23 Lumbosacral afferent neurons which innervate the uterus express estrogen receptors, 24 and estrogen increases their synthesis of substance P. 25 We previously showed that tonic estrogen exposure increases excitability of hypogastric afferents and their response to uterine cervical distension in nonpregnant female rats. 7 Curiously in that study estrogen selectively increased excitability of high, but not low threshold afferents, whereas pregnancy in the current study increased excitability primarily of low threshold afferents. Whether this indicates that estrogen signaling in afferent neurons is not responsible for the change in excitability during late pregnancy or that there is a difference between tonic or phasic stimulation of estrogen or the interaction between estrogen and progesterone is unclear.…”

“…6,7 In brief, on the day of experiment, the rat was anesthetized with inhalation of halothane (2% in oxygen) and the right jugular vein and carotid artery were catheterized for fluid administration and continuous monitoring of arterial blood pressure and heart rate. A tracheotomy was performed for mechanical ventilation at 60 breaths/min.…”

“…5 These data suggest that the study of hypogastric afferents in the rat could improve our understanding of the neurophysiology of labor pain. Over the past a few years, we have demonstrated that afferents in the rat hypogastric nerve which innervate the lower uterine segment and endocervix are primarily or exclusively C fibers, 6 respond in a polymodal fashion to mechanical distension, noxious heat and to chemical stimuli such as bradykinin, 7 and become more excitable in the presence of tonic estrogen. 7 The effects of pregnancy on properties of nerves innervating the uterus and cervix are unknown, yet several observations suggest changes may occur during pregnancy.…”

“…Over the past a few years, we have demonstrated that afferents in the rat hypogastric nerve which innervate the lower uterine segment and endocervix are primarily or exclusively C fibers, 6 respond in a polymodal fashion to mechanical distension, noxious heat and to chemical stimuli such as bradykinin, 7 and become more excitable in the presence of tonic estrogen. 7 The effects of pregnancy on properties of nerves innervating the uterus and cervix are unknown, yet several observations suggest changes may occur during pregnancy. The cervical ripening process which immediately precedes labor involves release of proinflammatory substances, including prostaglandins, cytokines, and nitric oxide, into the cervical tissue, 8 and these inflammatory substances are known to sensitize nociceptors.…”