Involvement of bradykinin and bradykinin B1 receptor in patients with endometriosis

Abstract

Endometriosis (EM), a benign aseptic inflammatory disease, is associated with the presence of endometrial foci. Pain, one of its typical symptoms, has been reported as a constant stressor, but the etiology and pathogenesis of EM-associated pain are unclear. In the present study, eutopic and ectopic endometrium samples from women with EM (n=50) and normal endometrium samples from control subjects (n=20) were collected. Serum levels of prostaglandin E 2 (PGE 2 ), prostaglandin F2α (PGF2α) and bradykinin (BK) were measured using commercial ELISA kits. The expression of the BKB1 receptor (BKB1R) protein was evaluated by immunohistochemical staining and western blot assay. The mRNA expression of BKB1R was measured by reverse transcription-quantitative PCR. The results revealed that there was a substantial increase in the protein and mRNA expression of BKB1R, as well as the release of PGE 2 , PGF2α and BK in the blood, in the EM group compared with that in the control group. Moreover, PGE 2 , PGF2α and BK levels were significantly correlated with each other, as well as with the pain intensity of EM. The increased expression levels of BKB1R protein and mRNA were positively correlated with the pain degree of EM. Thus, these data indicated that BK and BKB1R were involved in the pathological onset of EM-associated pain and that they may play an important role in EM-related pain by inducing PGE 2 and PGF2α. The data indicate a potential new therapeutic target for EM-related pain.

Bradykinin receptor expression and bradykinin-mediated sensitization of human sensory neurons

“…Icatibant (HOE-140) is a B2 receptor antagonist that has been FDA-approved for the treatment of hereditary angioedema (HAE), a rare and painful inflammatory disorder. Although BK signaling has been implicated in multiple other painful disorders (notably, arthritis) in human studies, 7,23,42 the progress towards repurposing this orphan drug for other inflammatory or generalized pain conditions has been slow. For example, according to the NIH's database on clinicaltrials.gov, only one clinical study has been conducted since 2000 to study icatibant's efficacy against pain in non-HAE patients.…”

“…Persistent upregulation in BK levels has been implicated in painful inflammatory disorders in humans, such as arthritis 7,23,46 and endometriosis. 42 Therefore, we examined how prolonged (18-24 hours) exposure to BK modulates the intrinsic excitability of hDRG neurons. Overnight treatment with BK did not significantly change the proportions of intrinsic firing phenotypes (single vs repetitive) of neurons recorded (Fig.…”

“…11,18,20,43,45,65 In addition, patients with painful disorders such as arthritis, endometriosis, and myalgia exhibit elevated levels of BK in damaged tissue or plasma compared with healthy controls, with the level of kinin correlating with pain degree or disease progression. 5,7,19,23,33,42,46…”

“…11,18,20,43,45,65 In addition, patients with painful disorders such as arthritis, endometriosis, and myalgia exhibit elevated levels of BK in damaged tissue or plasma compared with healthy controls, with the level of kinin correlating with pain degree or disease progression. 5,7,19,23,33,42,46 Bradykinin-mediated hyperalgesia is believed to occur, in part, through the activation of G q -coupled B1 and B2 receptors expressed on sensory neurons. In rodent dorsal root ganglion (DRG) neurons in vitro, acute application of BK can induce inward current, action potential firing, hyperexcitability, and TRPV1 sensitization.…”