Nonsurgical mouse model of endometriosis-associated pain that responds to clinically active drugs

Abstract

Endometriosis is an estrogen-dependent inflammatory disease that affects approximately 10% of women. Debilitating pelvic or abdominal pain is one of its major clinical features. Current animal models of endometriosis-associated pain require surgery either to implant tissue or to remove the ovaries. Moreover, existing models do not induce spontaneous pain, which is the primary symptom of patients with chronic pain, including endometriosis. A lack of models that accurately recapitulate the disease phenotype must contribute to the high failure rate of clinical trials for analgesic drugs directed at chronic pain, including those for endometriosis. We set out to establish a murine model of endometriosis-associated pain. Endometriosis was induced nonsurgically by injecting a dissociated uterine horn into a recipient mouse. The induced lesions exhibited histological features that resemble human lesions along with an increase in proinflammatory cytokines and recruitment of immune cells. We also observed the presence of calcitonin gene–related peptide–, TRPA1-, and TRPV1-expressing nerve fibers in the lesions. This model induced mechanical allodynia, spontaneous abdominal pain, and changes in thermal selection behavior that indicate discomfort. These behavioral changes were reduced by drugs used clinically for endometriosis, specifically letrozole (aromatase inhibitor) and danazol (androgen). Endometriosis also induced neuronal changes as evidenced by activation of the NF-κB signaling pathway in TRPA1- and TRPV1-expressing dorsal root ganglion neurons. In conclusion, we have established a model of endometriosis-associated pain that responds to clinically active drugs and can, therefore, be used to identify novel therapies.

Nociceptive TRP Channels and Sex Steroids

“…The upregulation of these nociceptive channels could be directly associated with spontaneous abdominal pain observed in mice with endometriosis. Interestingly, the treatment of these mice with a synthetic androgen (danazol) or an aromatase inhibitor (letrozole), which are estrogen reducing agents, substantially relieved the spontaneously induced endometriosis pain [106]. These data reinforce the crucial role of estrogens in the development of endometriosis and highlight the importance of the TRPA1 and TRPV1 channels as molecular pain mediators in this debilitating form of abdominal pain.…”

“…Remarkably, theses nerve fibers showed expression of TRPA1 and TRPV1 channels [106]. Furthermore, DRG neurons isolated from mice with induced endometriosis exhibited higher Ca 2+ influx levels than neurons from sham animals, and this effect was through the activation of TRPA1 or TRPV1 channels [106]. The upregulation of these nociceptive channels could be directly associated with spontaneous abdominal pain observed in mice with endometriosis.…”

“…In addition to the above described evidence, the roles of TRPA1 and TRPV1 in endometriosis have been recently strengthened through the establishment of a mouse endometriosis model [106]. The endometriosis-like lesions induced in these animals displayed the presence of nerve fibers and inflammatory cells around the lesions.…”

“…The endometriosis-like lesions induced in these animals displayed the presence of nerve fibers and inflammatory cells around the lesions. Remarkably, theses nerve fibers showed expression of TRPA1 and TRPV1 channels [106]. Furthermore, DRG neurons isolated from mice with induced endometriosis exhibited higher Ca 2+ influx levels than neurons from sham animals, and this effect was through the activation of TRPA1 or TRPV1 channels [106].…”

Pain in Endometriosis

“…The precise mechanisms responsible for cross-organ sensitization are unclear, however, overlap of peripheral afferent pathways within the DRG and spinal cord are crucial ( Aredo et al, 2017 ; Grundy and Brierley, 2018 ; Grundy et al, 2019 ). Following neuroangiogenesis, which includes the presence of CGRP, TRPV1, and TRPA1 expressing nerve fibers ( Fattori et al, 2020 ), the sensory nerves innervating endometriotic lesions may converge into the same spinal pathways from the afferents they originally sprouted from in the periphery. As such, they will share the same cell bodies in the DRG and the same central terminals within the spinal cord ( Costa et al, 2004 ).…”