Elevated expression of transient receptor potential vanilloid type 1 in dorsal root ganglia of rats with endometriosis

Abstract

Abstract. Pain is the most pronounced complaint of women with endometriosis, however the underlying mechanism is still poorly understood. In the present study, the authors evaluate the effect of transient receptor potential vanilloid type 1 (TRPV1) of dorsal root ganglia (DRG) on endometriosis-associated pain. A total of 36 SD rats were randomly divided into a sham group (n=9) and a Model group (n=27), accepted auto-transplanted pieces of fat or uterus to the pelvic cavity. At 4 weeks, the Model group was randomly subdivided into the following groups: ENDO group (no treatment, n=9), BCTC group (Model + BCTC, an antagonist of TRPV1, n=9), Vehicle group (Model + cyclodextrin, the vehicle of BCTC, n=9). Tail-flick test was performed prior to surgery, 1 h prior to and following treatment of BCTC or cyclodextrin. The expression of TRPV1, substance P (SP), calcitonin gene-related peptide (CGRP) in L1-L6 DRG was measured via immunohistochemistry, western blotting and RT-qPCR. The results indicated that the Model group exhibited a significant decrease in tail flick latency compared to pre-surgical baseline, and the expression of TRPV1, SP, CGRP protein and mRNA in L1-L6 DRG significantly increased compared to the sham group. BCTC significantly improved tail flick latency, and downregulated the expression of TRPV1, SP and CGRP protein and mRNA levels in L1-L6 DRG compared to ENDO group. However, there were no significant differences of those in Vehicle group compared with the ENDO group. Taken together, the current study provides evidence that TRPV1 expressed in DRG may serve an important role in endometriosis-associated pain. IntroductionEndometriosis, a disease in which endometrium-like tissue grows outside of the uterine cavity, has been estimated to affect 2 to 10% of reproductive-age women (1). The chief complaint of women with endometriosis is pain, which negatively affects quality of life. However, the pathogenesis of endometriosis-related pain, in particularly, chronic pain remains elusive and needs further investigation.It is universally accepted that peritoneal inflammation serves an important role in pain production (2). In previous years, the concept of neuropathic pain has been recognized and given much concern and study (3,4). Numerous studies have indicated the presence of nerve fibers with neurotransmitters immunoreactive cells in ovarian and deep infiltrating endometriosis, such as CGRP and SP (5-7). Therefore, the research is crucially needed to explore how the nerve fibers in endometriosis lesions influence dorsal root neurons and brain to evoke pain. The nociceptive sensors in DRG neurons are the first station in the transmission of pain and are, thereby, a research hotspot for pain study (3,8). An increasing number of studies revealed that transient receptor potential vanilloid type 1 (TRPV1) serves an important role in initiating neurogenic inflammation and pain sensitization (9,10). TRPV1 is a member of non-selective cation channels, which mediates responses to pain-inducing stimuli, such as acid (...

Estrogen is an important mediator of mast cell activation in ovarian endometriomas

“…Nav1.8 contributes the most to sustaining the depolarizing stage of action potentials in nociceptive sensory neurons (Renganathan et al 2001, Blair & Bean 2002, while Trpv1 predominantly transmits heat and pain sensation and plays a role in interactions between the inflammatory environment, pain and hyperalgesia (Koerber et al 2010). The former has been extensively reported to play a role in neuropathic pain (Lai et al 2003), while the latter has been reported to participate in the process of pain in patients with endometriosis (Liu et al 2012) or rat models of endometriosis (Lian et al 2017). The upregulated expression of Nav1.8 and Trpv1 under a co-culture environment of RBL2H3 cells under the stimulation of E2 indicated that E2 can stimulate MC degranulation to participate in the process of pain, which may provide a partial explanation for the fact that local high levels of E2, and the activity of MCs, have a positive correlation with endometriosis-related dysmenorrhea.…”

Pain in Endometriosis

“…The nociceptive ion channel TRPV1 has been implicated in other chronic pain conditions such as rheumatoid arthritis, osteo arthritis and IBS ( Wang, 2008 ; Basbaum et al, 2009 ; Sadeghi et al, 2018 ), acting as a molecular sensor to potentiate and integrate responses to pain inducing stimuli, such as acidosis, oxidative stress or inflammatory mediators ( Tominaga and Julius, 2000 ; Wang, 2008 ). Supporting an involvement of TRPV1 in endometriosis associated pain, elevated expression of TRPV1 has been found in dorsal root ganglion (DRG) of rats with endometriosis ( Lian et al, 2017 ) as well as locally on infiltrating adhesions in endometriosis patients, the increase correlating with pain intensity ( Rocha et al, 2011 ; Bohonyi et al, 2017 ). This is not surprising, as a number of the processes responsible for TRPV1 upregulation and sensitization are found in endometriosis patients, including enhanced ROS concentrations and increased levels of neurotrophins such as NGF.…”

Villainous role of estrogen in macrophage-nerve interaction in endometriosis

“…Sustained peripheral sensitization by the inflammatory mediators from macrophages elicits the release of neuropeptides with inflammatory and nociceptive function, which induces a vicious circle to deteriorate the progression of endometriosis-associated pain. TRPV1-positive nerves can induce a neurogenic inflammation through the release of substance P (SP) and calcitonin gene-related peptide (CGRP) [ 88 ]. Further research demonstrates that estrogen can modulate corneal sensitivity by up-regulation of SP [ 89 ].The release of CGRP is also regulated by 17β-estradiol in the visceral pain sensitivity, implicating the role of estrogen in regulating of inflammatory neuropeptides [ 90 ].…”