Influence of pregnancy and labor on the occurrence of nerve fibers expressing the capsaicin receptor TRPV1 in human corpus and cervix uteri

Abstract

Background: Cervical ripening is a prerequisite for a normal obstetrical outcome. This process, including labor, is a painful event that shares features with inflammatory reactions where peripheral nociceptive pathways are involved. The capsaicin and heat receptor TRPV1 is a key molecule in sensory nerves involved in peripheral nociception, but little is known regarding its role in the pregnant uterus. Therefore, the aim of this study was to investigate human corpus and cervix uteri during pregnancy and labor and non-pregnant controls for the presence of TRPV1.

Methods: We have investigated human uterine corpus and cervix biopsies at term pregnancy and parturition. Biopsies were taken from the upper edge of the hysterotomy during caesarean section at term (n = 8), in labor (n = 8) and from the corresponding area in the non-pregnant uterus after hysterectomy (n = 8). Cervical biopsies were obtained transvaginally from the anterior cervical lip. Serial frozen sections were examined immunohistochemically using specific antibodies to TRPV1 and nerve markers (neurofilaments/peripherin).

Results: In cervix uteri, TRPV1-immunoreactive fibers were scattered throughout the stroma and around blood vessels, and appeared more frequent in the sub-epithelium. Counts of TRPV1-immunoreactive nerve fibers were not significantly different between the three groups. In contrast, few TRPV1-immunoreactive fibers were found in nerve fascicles in the non-pregnant corpus, and none in the pregnant corpus.

Conclusion: In this study, TRPV1 innervation in human uterus during pregnancy and labor is shown for the first time. During pregnancy and labor there was an almost complete disappearance of TRPV1 positive nerve fibers in the corpus. However, cervical innervation remained throughout pregnancy and labor. The difference in TRPV1 innervation between the corpus and the cervix is thus very marked. Our data suggest that TRPV1 may be involved in pain mechanisms associated with cervical ripening and labor. Furthermore, these data support the concept that cervix uteri may be the major site from which labor pain emanates. Our findings also support the possibility of developing alternative approaches to treat labor pain.

Figure 1

Photomicrographs showing TRPV1-IR nerve fibers in TP cervix (a-c) and a TRPV1-IR nerve fascicle in NP corpus (d). Box plots show the distribution of cervical TRPV1-IR nerve fibers. TRPV1-IR nerve fibers were observed subepithelially (a, arrows) and in the stroma (b, arrow) as well as around blood vessels (c, arrows). Scale bars = 50 μm. TRPV1-IR nerve fibers did not differ significantly between the groups either when presented as total count of positive nerve fibers (e) or as TRPV1 positive nerve fibers/mm² (f)

Figure 2

Photomicrographs showing NFILS-IR nerve fibers in TPL cervix (a) and a NFILS-IR nerve fascicle in NP corpus (b). Box plots show the distribution of NFILS-IR nerve fibers in corpus and cervix uteri. NFILS positive fibers were seen in the stroma and in the subepithelial region (a, short arrows). Nerve fibers penetrating the basal epithelium were observed, but only rarely (a, long arrow). A NFILS-IR nerve fascicle is seen in control, non-pregnant corpus (b). Scale bars = 50 μm. The box plot in (c) shows the distribution of NFILS-IR nerve fibers in the three groups of the corpus counted as nerve fibers/mm². There is a significant decrease of IR-nerve fibres/mm² in the term pregnant group compared to non-pregnant controls, p < 0.0001. A statistically significant decrease of IR-nerve fibers/mm² is also observed in labor compared to the non-pregnant group, p < 0.01. There is no significant difference between TP and TPL. Comparison of NFILS-IR nerve fibers between the "corpus groups" presented as total count of positive nerves also shows significantly different values (d). There is a statistically significant decrease in the occurrence of IR nerve fibers in the term pregnant compared to the non-pregnant corpus, p < 0.001, and between the non-pregnant group compared to the term pregnant in labor, p < 0.05. However, there is no significant difference between the two pregnant groups. The box plot in (e) shows and compares the distribution of NFILS-IR nerve fibers in the cervical groups. Values did not reach statistical significance.