Activation and circuitry of uterine‐cervix‐related neurons in the lumbosacral dorsal root ganglia and spinal cord at parturition

Abstract

Stimulation of the uterine cervix at parturition activates neural circuits involving primary sensory nerves and supraspinally projecting neurons of the lumbosacral spinal cord, resulting in output of hypothalamic neurohormones. Dorsal root ganglia (DRG) and spinal neurons of these circuits are not well-characterized. The objectives of this study were to detail the activation of DRG and spinal neurons of the L6/S1 levels that are stimulated at late pregnancy, verify hypothalamic projections of activated spinal neurons, and determine whether activated neurons express estrogen receptor-alpha (ERalpha). Expression of phosphorylated cyclic-AMP response element-binding protein (PCREB) and Fos immunohistochemistry were used to "mark" activated DRG and spinal neurons, respectively. Retrograde tracing identified uterine-cervix-related and spinohypothalamic neurons. Baseline PCREB expression in the DRG increased during pregnancy and peaked during the last trimester. Some PCREB-expressing neurons contained retrograde tracer identifying them as cervix-related neurons. Fos-expressing neurons were few in spinal cords of nonpregnant and day 22 pregnant rats but were numerous in parturient animals. Some Fos-expressing neurons located in the dorsal half of the spinal cord contained retrograde tracer identifying them as spinohypothalamic neurons. Some DRG neurons expressing PCREB also expressed ERalpha, and some spinal neurons activated at parturition projected axons to the hypothalamus and expressed ERalpha. These results indicate that DRG and spinal cord neurons are activated at parturition; that those in the spinal cord are present in areas involved in autonomic and sensory processing; that some spinal neurons project axons to the hypothalamus, ostensibly part of a neuroendocrine reflex; and that sensory and spinal neurons can respond to estrogens. Moreover, some activated sensory neurons may be involved in the animal's perception of labor pain.

Transection of the Pelvic or Vagus Nerve Forestalls Ripening of the Cervix and Delays Birth in Rats1

“…After pelvic nerve transections, there is a loss of afferent connections to local interneurons in the thoracolumbar spinal cord [14], as well as to ascending sensory pathways in the dorsal columns and autonomic intermediolateral columns of the spinal cord that project to brainstem regions, i.e., solitary nucleus and dorsal motor nucleus. These regions receive input from the vagus nerve [17,[51][52][53]. Integration of signals in the brainstem could then influence the ovaries through either a descending spinal cord projection or more directly through an extraspinal vagal pathway [54,55].…”

Glutamate and metabotropic glutamate receptors associated with innervation of the uterine cervix during pregnancy: Receptor antagonism inhibits c‐fos expression in rat lumbosacral spinal cord at parturition

“…The spinal cords were frozen and cut transversely into 40 μm‐thick sections (producing 75–100 sections) using a cryostat (Leica CM 1800) and stored free‐floating at −20°C in vials of cryoprotectant solution (Watson et al, 1986) until tissue from all animals had been collected and sectioned. Sections were then processed for immunohistochemical staining of mGluR5, Fos‐positive neurons, mGluR5 + Fos‐positive neurons, VGluT1, or mGluR5 + VGluT1 (Tables I,II) according to standard methods used in our laboratory routinely (Papka et al, 2001; Papka and Storey‐Workley, 2002; Puder and Papka, 2005).…”

“…In regard to the female reproductive system, recent studies on sensory innervation of the uterine cervix at parturition focused on neuropeptide‐containing sensory nerves (Collins et al, 2002; Papka et al, 2002, 2005, 2006; Papka and Storey‐Workley, 2002; Pokabla et al, 2002; Mowa et al, 2003a, b; Papka and Mowa, 2003; Tong et al, 2003; Mowa et al, 2004; Puder and Papka, 2005). Nonpeptide transmitter systems, e.g., glutamate, of DRG neurons (Broman et al, 1993; Schaffar et al, 1997; Stoyanova et al, 1998; Keast and Stephensen, 2000; Wu et al, 2005), have received little attention relative to female animals or innervation of pelvic organs except for the urinary organs (Keast and Stephensen, 2000; de Groat and Yoshimura, 2006), as well as cutaneous areas (Carlton and Coggeshall, 1999; Walker et al, 2001b).…”

“…Expression of c‐fos immediate early gene, visualized immunohistochemically as nuclear Fos protein, is a marker of activated neurons (Hunt et al, 1987). Inflammation of genitourinary organs increases numbers of Fos‐positive neurons in the lumbosacral cord (Birder et al, 1999; Vizzard, 2000; Tong et al, 2003; Puder and Papka, 2005) whereas, noxious‐stimulated (inflammation) increases in Fos‐positive neurons in the cord are reduced by MPEP (Tao et al, 1997; Bhave et al, 2001; Karim et al, 2001; Bianchi et al, 2003). To test whether glutamate is involved in transmission of sensory information from the cervix (Fig.…”

Spinal neurons activated in response to pudendal or pelvic nerve stimulation in female rats

“…The superficial dorsal horn contains neurons which modulate afferent information through projections to local spinal laminae, other spinal segments and the brain [20,54,62]. The laminae I and II fos-I neurons labeled in the present study could be involved in nociception or regulation of muscle sensitivity and non noxious inputs [37].…”