Nociceptin/orphanin FQ opioid peptide receptor-related ligands as potential analgesics in the endometriosis-associated pain

Background: Endometriosis (EM) is a chronic inflammatory disease that mainly affects women of childbearing age. It occurs when endometrial tissue grows outside the uterine cavity. Pain is one of the most common symptoms of EM, however, there are currently no specific and ideal analgesic options available for EM-associated pain therapy. In this context, we aim to provide new insights and prospected analgesic options by summarizing the pathogenesis of EM-associated pain and discussing the expression of the nociception/ orphanin FQ peptide (NOP) receptor in EM-associated nerve fibres (NFs). Methods: This prospective study spanned from May 2012 to May 2019 and included 94 female participants. Peritoneal samples were extracted via laparoscopy from 94 symptomatic women (73 EM and 21 non-EM patients). These samples underwent immunohistochemical staining for NOP, protein gene product 9.5 (PGP9.5), substance P (SP), calcitonin gene-related peptide (CGRP), tyrosine hydroxylase (TH), and vasoactive intestinal peptide (VIP). Furthermore, clear peritoneal fluids were collected during laparoscopy from patients with peritoneal EM (n = 17) and controls (n = 17). Enzyme-Linked Immunosorbent Assay was performed to compare the NOP concentration between EM and control group. Results: Our results show that NFs density was significantly increased in the group of patients with EM compared to the control group. However, the EM group that received hormonal treatment had decreased innervation compared to the EM group without hormonal therapy. Additionally, more NOP-positive NFs and blood vessels were observed in the EM group than in the control group. The EM patients with hormonal treatment did not show any differences in NOP receptor compared to those without hormonal intake. Furthermore, we observed that NOP receptors co-localize with sympathetic, parasympathetic, and sensory fibres in the EM group. No changes in the NOP concentration in the peritoneal fluid of EM patients compared to healthy women could be found. Conclusion: EM-associated pain have a significant impact on a patient's quality of life. Unfortunately, the current treatment strategies for this condition are not entirely satisfactory. Therefore, there is an urgent need for novel treatments that are more effective and tolerable. Our study has shown a connection between the expression of NOP receptors, rASRM, and pain in patients with EM. This suggests that the NOP receptor and N/OFQ, as the endogenous ligand, may play a part in EM-associated pain. Further research is necessary to clarify these connections and determine whether the NOP receptor could be a target model for new therapeutic interventions.