Changes in human uterine innervation in term pregnancy and labor occurence and roles of neurotrophins and TRPV1

Abstract: Objective: Cervical ripening, is a prerequisite for successful labor, which is often very painful and involves an inflammatory reaction. However, little is presently known con-cerning nerve-related changes in the human uterus during labor and the fundamental hy-pothesis tested here was that labor pain emanates primarily from the cervix uteri. To this end, the general innervation of the corpus and cervix uteri, as well as the possible pres-ence of neurotrophins and TPRV1 (major factors involved in nociception) and of sensory corpuscles in these same two tissues were examined in term pregnancy prior to and after the onset of labor and compared to the non-pregnant state. Methods: Biopsies were collected from the corpus and cervix uteri of non-pregnant wom-en after hysterectomy and women who, following term pregnancy, either had a caesarean section prior to onset of labor or an emergency caesarean section during established labor. Serial sections prepared from the frozen biopsies were analyzed immunohistochemically employing antibodies directed specifically against PGP 9.5, S-100, NGF, BDNF, NGFR p75, Trk B, NFILS and TRPV1. Moreover, the levels of the mRNA species encoding NGFbeta, NGFR p75, TrkA and TrkB in these same tissue samples were determined by Real-Time PCR. Results: The innervation of the corpus in term pregnancy, both prior to and after the onset of labor, differed profoundly from that of the cervix under the same conditions, as well as from that of the corresponding non-pregnant tissues. Thus, in term pregnancy, most nerve fibers staining positively for PGP 9.5, NGFR p75, NFILS and TRPV1-IR had virtually disappeared from the corpus, but remained in the cervix. At the same time, the numbers of nerve fibers expressing BDNF-IR, as well as of NGF-positive cells increased in both the corpus and cervix during labor. Corpus levels of NGFbeta, NGFR p75 and TrkB mRNA were lower in term pregnancy with and without labor than in the non-pregnant control tissue, whereas the level of TrkA mRNA in the corpus was elevated. In the case of the cer-vix, expression of both NGFbeta and TrkA mRNA was up-regulated during labor. Moreover, sensory corpuscles were detected in both the non-pregnant corpus and cervix and also in the term pregnant cervix but only prior to the onset of labor. Conclusion: The observations documented here indicate unambiguously that during la-bor, the numbers of nerve fibers and levels of neurotrophins and TRPV1 in the human cervix are considerably higher than in the corpus. These findings lend support to our hypothesis that the cervix uteri is the major site from which labor pain emanates. Further-more, the sensory corpuscles identified in the non-distended corpus and cervix probably convey mechanosensitive (proprioceptive) impulses.